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I risultati dello Screening Neonatale StepOne® possono essere utilizzati da medici qualificati per la diagnosi e la cura tempestiva di numerose malattie ereditarie. I segnali di queste condizioni patologiche sono rilevati nella grande maggioranza delle persone affette, tuttavia, a causa della variabilità genetica, dello stato di salute e dell'età al momento della raccolta del campione, possono verificarsi falsi negativi. Questa probabilità scende fino quasi allo zero nel caso in cui il prelievo sia effettuato immediatamente dopo la nascita.

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Malattie rilevate mediante spettrometria di massa Tandem

Profilo dell’Acilcarnitina

Malattie legate al metabolismo degli acidi grassi
  • Deficit da Carnitina-Acilcarnitina Translocasi
    • Carnitine/Acylcarnitine Translocase Deficiency

      Background
      Carnitine/Acylcarnitine Translocase (CACT) Deficiency is a disorder of fatty acid oxidation. Fatty acid oxidation generates ATP in the mitochondria and provides acetyl-CoA for gluconeogenesis. CACT normally acts to transport long-chain acyl- carnitine across the inner mitochondrial membrane into the mitochondrial matrix where ß-oxidation occurs. CACT also facilitates the export of free carnitine out of the mitochondria where it can be utilized for formation of acylcarnitines. Deficiency of this transport protein results in impaired long-chain fatty acid oxidation and causes the accumulation of long-chain acylcarnitines outside the mitochondria and in plasma. Short- and medium-chain (C8 and less) fatty acids do not require CACT for entry into the mitochondria and are therefore available for energy metabolism.

      Clinical
      There are two clinical presentations of CACT Deficiency. The severe form has neonatal onset of acute cardiorespiratory symptoms in the first days of life. If the patients survive the initial illness, they suffer from chronic muscle weakness, cardiac hypertrophy, hypo- glycemia and hyperammonemia. Plasma carnitine is low. Death may occur due to cardio- myopathy complications. These patients have no measurable CACT activity.
      A second phenotype may have milder symptoms because they possess some residual CACT activity. These patients exhibit hypoglycemia, which may result in early death, but lack cardiac symptoms. Severe steatosis has been reported in liver, heart and kidneys at autopsy.

      Testing
      Newborn screening of a dried blood spot using tandem mass spectrometry reveals elevations of several long-chain acylcarnitines (i.e. C16, C18, C18:1 and C18:2). These findings are characteristic but not definitive of CACT Deficiency, because Carnitine Palmitoyl Transferase II Deficiency has similar results. Quantitative urine organic acid determination is usually not helpful, as elevations of long chain fatty acids, including dicarboxylic and 3-hydroxy-dicarboxylic acids are inconsistently present. Plasma acyl- carnitine profile testing can confirm elevations of the above acylcarnitines. Definitive diagnosis of CACT Deficiency requires testing cultured fibroblasts or performing DNA mutation analysis of the gene. Prenatal diagnosis can be accomplished using DNA analysis if mutations are identified in the parents.

      Treatment
      This rare disorder is treated by preventing hypoglycemia and suppressing the need for long-chain fatty acid oxidation. Dietary medium-chain triglyceride oil bypasses the CACT step in fatty acid oxidation and provides safe calories. Aggressive supportive treatment in the newborn period and during intercurrent illnesses is important, since any infection is potentially life threatening.
      Because the diagnosis and therapy of CACT Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Chalmers, R.A., Stanley, C.A., English, N. and Wigglesworth, J.S. Mitochondrial carnitine-acylcarnitine translocase deficiency presenting as sudden neonatal death. J Pediatrics 131:220, 1997.
      • Morris, A.A.M., Olpin, S.E., Brivet, M., et al. A patient with carnitine-acylcarnitine translocase deficiency with a mild phenotype. J Pediatrics 132:514, 1998.
      • Ogier de Baulney, H., Slama, A., Touati, G., et al. Neonatal hyperammonemia caused by a defect of carnitine-acylcarnitine translocase. J Pediatrics 127:723, 1995
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297-2326.

  • Deficit da Carnitina Palmitoil Transferasi Tipo I (CTP-I)
    • Carnitine Palmitoyl Transferase Deficiency Type I

      Background


      Mitochondrial ß-oxidation plays a major role in energy production and glucose homeo- stasis, especially during periods of fasting. Fatty acids are mobilized from adipose stores and released into the circulation to be taken up by the cell and quickly activated to their acyl-CoA esters. To be subsequently oxidized in mitochondria, the fatty acyl-CoAs must be converted to acyl-carnitine esters, a reaction that is catalyzed by Carnitine Palmitoyl Transferase I (CPT I), which is bound to the outer mitochondrial membrane. The acyl- carnitines are then transported across the inner mitochondrial membrane for subsequent fatty acid ß-oxidation. In liver, CPT I is inhibited by malonyl-CoA, which provides a mechanism for regulation of fatty acid oxidation. Deficiency of CPT I prevents fatty acids from being transported into mitochondria and disrupts the normal regulation of fatty acid oxidation. There are three isoforms of CPT I and each tends to be more specific for the liver (CPT IA), muscle (CPT IB) or brain (CPT IC), but only the hepatic CPT I has been found to be deficient in patients identified so far. Hepatic CPT I deficiency has been described in patients with a wide range of ethnic origins.

      Clinical
      Patients with hepatic CPT I deficiency usually present after the newborn period with episodic, life-threatening symptoms associated with a viral illness and prolonged fasting. Among the signs most commonly observed in patients are lethargy, hepatomegaly, and seizures progressing to coma. Laboratory tests reveal hypoketotic hypoglycemia, mild metabolic acidosis with or without lactic acidemia, elevated transaminases, and hyper- ammonemia. Urinary ketones are conspicuously absent. Chronic muscle weakness and cardiomyopathy are not typical of this disease. Unlike many other defects in fatty acid oxidation, plasma carnitine levels are normal or elevated, and urinary dicarboxylic acids are absent. Testing Newborn screening of the heel stick dried blood spot using tandem mass spectrometry finds elevation of free carnitine and reduction of long-chain acylcarnitines (i.e. C16:0 and C18:0), resulting in an increased ratio of free carnitine to C16:0 and C18:0 acyl- carnitines. The definitive diagnosis of CPT I deficiency is made by measuring enzyme activity in fibroblasts, leukocytes, or liver. A variety of mutations have been detected in the gene for hepatic CPT I, but no common mutations have been found to allow easy DNA diagnosis.

      Treatment
      Any intercurrent infection or illness is potentially life threatening to affected patients. CPT I deficiency is treated by preventing prolonged fasting and administering IV glucose during acute episodes to prevent hypoglycemia and suppress release of fatty acids from adipose stores. Medium-chain fatty acids bypass the metabolic block, because they do not require conversion to acylcarnitine esters in order to enter the mitochondria. Medium- chain triglyceride oil may therefore be beneficial to patients. Because the diagnosis and therapy of CPT I deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Bonnefont JP, Djouadi F, Prip-Buus C, et al. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 25:495, 2004.
      • Brown NF, Mullur RS, Subramanian I, et al. Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme. J Lipid Res 42:1134, 2001.
      • Fingerhut R, Roschinger W, Muntau AC, et al. Hepatic carnitine palmitoyltransferase I deficiency: acylcarnitine profiles in blood spots are highly specific. Clin Chem 47:1763, 2001.
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, Scriver, Beaudet, et al. McGraw-Hill. Chap 101, pg. 2297-2326, 2001.

  • Deficit da 3-Idrossi Acil-CoA Deidrogenasi a catena lunga
    • 3-Hydroxy Long Chain Acyl-CoA Dehydrogenase Deficiency (LCHAD)

      Background

      Long-chain-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a disorder of mitochondrial fatty acid ß-oxidation. LCHAD is one of two enzymes that carry out the third step (of 4) in the ß-oxidation of fatty acids – the other enzyme being short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), which acts on shorter-chain substrates. LCHAD activity resides on the Mitochondrial Trifunctional Protein, which acts to catalyze 3 sequential steps in ß-oxidation. LCHAD deficiency occurs as an isolated defect (described here) or together with deficiency of the other 2 enzymes in Mitochondrial Trifunctional Protein deficiency. LCHAD deficiency impairs oxidation of dietary and endogenous fatty acids of long-chain length (16 carbons and longer).

      Clinical
      LCHAD deficiency can present clinically from day one to 3 years of age. Two clinical scenarios have been described. One group of LCHAD deficiency patients presents with symptoms of cardiomyopathy, which may lead to death. Several cardiac problems have been described, including cardiomegaly, left ventricular hypertrophy, and poor contractility. Onset may be acute or chronic. A second group of patients presents, usually following fasting, with non-ketotic hypoglycemia, vomiting, hypotonia, and hepatomegaly. Rhabdomyolysis may occur. Both presentations are highly variable and may have overlapping features. Symptoms may be initiated by a seemingly innocuous illness (a cold or otitis media), leading to prolonged fasting. Symptoms often precede onset of hypoglycemia. Hypoglycemia occurs from an inability to meet gluconeogenic requirements during fasting despite activation of an alternate pathway of substrate production – proteolysis. Physical examination of the acutely ill child may find mild to moderate hepatomegaly and muscle weakness. Laboratory examination of blood may reveal hypoglycemia, elevated CK and abnormal transaminases. Unique among the fatty acid oxidation disorders, LCHAD patients may develop a sensorimotor peripheral neuropathy and pigmentary retinopathy over time. Fatty liver is noted at autopsy, often leading to a misdiagnosis of Reye’s syndrome or Sudden Infant Death Syndrome (SIDS) in an infant.
      A complication of pregnancy, HELLP Syndrome (hemolysis, elevated liver enzymes, and low platelets), has been described in women carrying a fetus affected with LCHAD deficiency.

      Testing
      Newborn screening using tandem mass spectrometry of a dried blood spot identifies elevated levels of several long chain hydroxyacylcarnitines (C16-OH, C16:1-OH, C18-OH, C18:1-OH, C18:2-OH, and generalized C12 through C14 species). Biochemical testing of blood and urine for carnitine, acylcarnitines, acylglycines, and organic acids is diag- nostic for this disorder. Dicarboxylic and hydroxydicarboxylic acids are usually found with urine organic acid analysis, but may be “normal” when the patient is not acutely ill. Analysis of LCHAD activity in fibroblasts can reveal affected individuals compared to heterozygous carrier and normal fibroblast lines. LCHAD activity should be assayed after antibody precipitation of SCHAD activity, due to the overlap in substrate recognition.
      LCHAD patients have a common mutation (1528G>C) in the -subunit of mitochondrial trifunctional protein. Detection of mutations in the DNA of affected individuals allows for confirmation of biochemical test results and accurate detection of asymptomatic carriers among other family members. Prenatal diagnosis is possible by enzyme assay of cultured amniocytes or by in vitro probe of the ß-oxidation pathway. DNA analysis can also be used for prenatal diagnosis of affected fetuses in at-risk pregnancies when both parents carry a known mutation.

      Treatment

      Fundamental to the medical management of LCHAD is the avoidance of fasting, particularly during periods of high metabolic stress, such as illness. Overnight fasts should last no longer that twelve hours and infants should receive late evening feedings to reduce this period. The addition of food-grade uncooked cornstarch mixed in liquid at bedtime has helped some infants decrease the frequency of morning hypoglycemia. A diet high in natural fat should be avoided. Medium-chain triglyceride supplementa- tion bypasses the metabolic block and provides safe calories. Supplementation with oral L-Carnitine has not been shown to be beneficial in avoiding or ameliorating clinical symptoms.
      High carbohydrate intake should be encouraged during illness, with initiation of intra- venous glucose supplementation if the child is unsuccessful in keeping down fluids, or unable to take adequate oral feedings. For individuals with LCHAD deficiency, it is imperative that the lethargic patient receive parenteral dextrose to avoid hypoglycemia during evaluation.
      Because the diagnosis and therapy of LCHAD deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297-2326.
      • Tyni, T., Palotie, A., Viinikka, L., et al. Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: Clinical presentation of thirteen patients. J Pediatrics 130:67, 1997.

  • Deficit da 2,4-Dienoil-CoA Reduttasi
    • 2,4-Dienoyl-CoA Reductase Deficiency

      Background

      One patient has been reported with 2,4-Dienoyl-CoA Reductase Deficiency. This enzyme is necessary for the degradation of unsaturated fatty acids having even numbered double bonds.

      Clinical
      The patient was born with a small body habitus, a short trunk, arms and fingers, and microcephaly. She was readmitted to the hospital on day 2 of life with symptoms of sepsis, hypotonia, decreased feeding and intermittent vomiting. A low carnitine level was found in her plasma. She responded poorly to treatment in the hospital, and later developed respiratory acidosis and died at 4 months of age.

      Testing
      Newborn screening using tandem mass spectrometry may reveal C10:2 acylcarnitine as a pathognomonic finding. Urine organic acid analysis was normal in the one patient and plasma amino acids showed elevated lysine. The enzyme deficiency can be demon- strated in liver and muscle tissue.

      Treatment
      Suggested treatment for 2,4-Dienoyl-CoA Reductase Deficiency involves feeding the patient a formula containing fat derived from medium-chain triglycerides (MCT), administering pharmacologic doses of carnitine, and avoiding fasting.
      Because the diagnosis and therapy of metabolic disorders like this is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders, affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Roe, C.R., Millington, D.S., Norwood, D.L., et al. 2,4-Dienoyl-CoA Reductase Deficiency: A possible new disorder of fatty acid oxidation. J Clinical Investigation 85:1703, 1990.
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297 - 2326.

  • Deficit da Acil-CoA Deidrogenasi a catena media
    • Medium Chain Acyl-CoA Dehydrogenase Deficiency

      Background

      Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency is a disorder of fatty acid ß-oxidation, occurring in at least 1 in 20,000 live births. The enzyme deficiency is medium-chain acyl-CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydro- genases that carry out the initial dehydrogenation step in the ß-oxidation of fatty acids. MCAD deficiency results in an impaired ability to oxidize dietary and endogenous fatty acids of medium-chain length (6-12 carbons).

      Clinical
      MCAD deficiency generally presents between the second month and the second year of life, although onset as early as two days and as late as adulthood has been reported. Clinical presentation is often triggered by a seemingly innocuous illness like otitis media or a viral syndrome. The initiating event is probably prolonged fasting, which increases lipolysis and the need for fatty acid oxidation. Symptoms include vomiting, lethargy, apnea, coma, cardiopulmonary arrest, or sudden unexplained death. Initial symptoms often precede the onset of profound hypoglycemia, and are probably related to high free fatty acid levels. Hypoglycemia occurs from an inability to meet gluconeogenic require- ments during fasting despite activation of an alternate pathway of substrate production (protein catabolism). Physical examination of the acutely ill child is remarkable for mild to moderate hepatomegaly, and some patients may also have demonstrable muscle weak- ness. Without prior indication of metabolic disease, 20–25 percent of patients with this disease will die with their first episode of illness. Cerebral edema, and fatty liver, heart, and kidneys are noted at autopsy, often leading to a misdiagnosis of Reye’s syndrome or Sudden Infant Death Syndrome (SIDS). This disorder accounts for about one percent of SIDS deaths.

      Testing
      Newborn Screening by tandem mass spectrometry of the heel stick dried blood spot identifies elevated levels of octanoylcarnitine (C8 acylcarnitine), usually accompanied by decanoyl (C10), hexanoyl (C6) and decenoyl (C10:1) carnitine esters. When symptomatic, laboratory examination of blood may reveal hypoglycemia, metabolic acidosis, mild lactic acidosis, hyperammonemia, elevated BUN, and high uric acid levels. Serum transaminases are usually elevated. The urine often shows inappropriately low or absent ketones due to impaired fatty acid oxidation. Low serum and urine carnitines are typically found in the untreated patient. Biochemical testing of blood and urine for carnitine, acylcarnitines, acylglycines, and organic acids is diagnostic for this disorder. A general- ized dicarboxylic aciduria is noted, characterized by elevations of suberylglycine and hexanoylglycine. In fibroblasts, the activity of medium chain acyl-CoA dehydrogenase
      is severely deficient in affected individuals, while heterozygous carriers for the disease usually have intermediate levels of activity, but are otherwise clinically and metabol- ically unaffected.
      Detection of mutations in the MCAD gene on chromosome 1 in affected individuals confirms the biochemical results and accurately detects asymptomatic carriers among other family members. A common 985A>G mutation is responsible for up to 85% of cases. DNA analysis of postmortem tissue is possible when plasma and urine samples are not available. Prenatal diagnosis is possible by enzyme assay of amniocyte cultures. DNA analysis in amniocytes or chorionic villi can also be helpful in the diagnosis of an affected fetus in at-risk pregnancies.

      Treatment
      Fundamental to the medical management of MCAD is the need to avoid fasting, particularly during periods of high metabolic stress, such as illness. Overnight fasts should be managed with nighttime or late evening feedings where appropriate. The addition of food-grade cornstarch mixed in liquid at bedtime has also helped to decrease the frequency of morning hypoglycemia in some patients. High carbohydrate intake should be encouraged during illnesses, with initiation of intravenous glucose supplementation if the child is unsuccessful in keeping down fluids or unable to take adequate oral feedings.
      The preventive efficacy of a low fat diet versus a normal fat diet is unclear, but high intake of long and medium-chain fatty acids should be avoided. Supplementation with oral L-Carnitine has been associated with a reduction in the frequency and severity of episodes. The continued need for carnitine supplementation post-puberty is uncertain, and has not been adequately studied.
      Because the diagnosis and therapy of MCAD deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Coates, P.M., Hale, D.E., Stanley, C.A., et al. Genetic deficiency of medium chain Acyl-CoA dehydrogenase. Studies in cultured skin fibroblasts and peripheral mononuclear leukocytes. Pediatric Research 19:672, 1985.
      • Roe, C.R., Millington, D.S., Maltby, D.A., et al. Recognition of Medium Chain Acyl- CoA Dehydrogenase Deficiency in asymptomatic siblings of children dying of Sudden Infant Death or Reye like syndromes. J Pediatrics 108:13, 1986.
      • Ding, J-H, Roe, C.R., Iafolla, A.K., et al. Diagnosis of Medium Chain Acyl-CoA Dehy- drogenase Deficiency in children dying suddenly without explanation by mutation analysis in post-mortem fixed tissue. New England J of Medicine 325:61, 1991.
      • Roe, C.R. and Ding, J-H. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg.2297-2326.
      • Nada, M.A., Chace, D.H., Spracher, H., et al. Investigation of beta oxidation intermediates in normal and MCAD-deficient fibroblasts using tandem mass spectrometry. Biochem Molec Med 54:59, 1995.
      • Nada, M.A., Vianey-Saban, C., Roe, C.R., et al. Prenatal diagnosis of mitochondrial fatty acid oxidation defects. Prenatal Diag 16:117, 1996.

  • Deficit multiplo da Acil-CoA Deidrogenasi
    • Multiple Acyl-CoA Dehydrogenase Deficiency

      Background

      Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is also known as Glutaric Acidemia Type II (GA-II). It is associated with deficiency of several mitochondrial dehydrogenase enzymes that utilize Flavin Adenine Dinucleotide (FAD) as cofactor, at least 9 of which are known. These include the acyl-CoA dehydrogenases of fatty acid ß-oxidation, and enzymes that degrade glutaric acid, isovaleric acid, and sarcosine
      (a precursor to glycine). During these dehydrogenation reactions, reduced FAD contri- butes its electrons to the oxidized form of Electron Transfer Flavoprotein (ETF) and subsequently to the respiratory chain to produce ATP. The reduced form of ETF is recycled to oxidized ETF by action of ETF- ubiquinone oxidoreductase (ETF-QO, also known as ETF dehydrogenase). Deficiency of ETF or ETF-QO therefore results in decreased activity of many FAD-dependent dehydrogenases and the combined metabolic derangements seen in MADD. Some MADD patients have had normal ETF and ETF-QO, suggesting the existence of genetic defects in other unidentified proteins.

      Clinical
      Three clinical presentations are reported for MADD. Two newborn presentations are seen – one with congenital anomalies, and one without. Those with congenital anomalies are often premature, and develop symptoms in the first 24-48 hours consisting of hypotonia, hepatomegaly, severe nonketotic hypoglycemia, metabolic acidosis and variable body odor of sweaty feet. Dysmorphic facial features and dysplastic, cystic kidneys are present. Plasma carnitine levels are low. Those patients with no congenital anomalies have similar symptoms and metabolic abnormalities. With both neonatal presentations, most patients do not live past a few weeks, though some older survivors succumb at a few months of age from hypertrophic cardiomyopathy. Heart, liver and kidneys are infiltrated with fat. The third cohort of patients has a mild and/or later onset with variable symptoms including lipid storage myopathy.

      Testing
      Newborn screening using a dried blood spot has identified MADD patients by detecting elevated acylcarnitine (C4, C5, C8, C10, and C16). Severe hypoglycemia without ketosis is a cardinal finding. Analysis of the urine for abnormal organic acids in a suspected patient usually reveals elevated glutaric acid, and always shows elevated 2-hydroxy- glutaric acid which is pathognomonic. Plasma and urine sarcosine levels are elevated in the milder patients, but not in the severe neonatal cases. Cultured fibroblasts and amniocytes have been used to measure dehydrogenase substrate oxidation. Mutations have been identified in the genes for ETF and ETF-QO. Prenatal diagnosis has been performed by finding elevated glutaric acid and elevated acylcarnitines in amniotic fluid. Prenatal diagnosis by DNA analysis is restricted to those families in which the mutation(s) is known.

      Treatment
      There is no effective treatment for the severe forms of MADD that present in the neonatal period. Patients with later onset less severe symptoms may respond to riboflavin (a precursor to FAD) and L-carnitine supplementation. Dietary restriction of fats and protein has had variable results.
      Because the diagnosis and therapy of MADD is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Frerman, F.E. and Goodman, S.I. Defects of Electron Transfer Flavoprotein and Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 103, pg. 2357-2365.
      • Goodman, S.I., Reale, M. and Berlow, S. Glutaric acidemia type II: A form with deleterious intrauterine effects. J Pediatrics 102:411, 1983.
      • Goodman, S.I., Stene, D.O., McCabe, E.R.B, et al. Glutaric aciduria type II: Clinical, biochemical and morphologic considerations. J Pediatrics 100:946, 1982.
      • Harpey, J.P., Charpentier, C., Goodman, S.I., et al. Multiple acyl-CoA dehydrogenase deficiency occurring in pregnancy and caused by a defect in riboflavin metabolism in the mother. J Pediatrics 103:394, 1983.
      • Mitchell, G., Saudubray, J.M., Gubler, M.C., et al. Congenital anomalies in Glutaric aciduria type 2. J Pediatrics 104:961, 1984.
      • Stockler, S., Radner, H., Felizitas, K., et al. Symmetric hypoplasia of the temporal cerebral lobes in an infant with Glutaric aciduria type II (multiple acyl-CoA dehydrogenase deficiency). J Pediatrics 124:601, 1994.
      • Sweetman, L., Nyhan, W.L., Trauner, D.A., et al. Glutaric aciduria type II. J Pediatrics 96:1020, 1980.

  • Deficit neonatale da Carnitina Palmitoil Transferasi Tipo II
    • Neonatal Carnitine Palmitoyl Transferase Deficiency- Type II (CPT-II)

      Background

      Carnitine Palmitoyl Transferase II (CPT II) Deficiency is a disorder of mitochondrial fatty acid oxidation. Fatty acid oxidation normally generates ATP inside the mitochondria and provides acetyl-CoA for gluconeogenesis. Long-chain fatty acids require carnitine for transport into the mitochondria as long-chain acyl-carnitine esters (i.e. carnitine esterified to a fatty acid). CPT II is located on the inner mitochondrial membrane and acts to convert long-chain acyl-carnitine substrates that are transported across the outer mitochondrial membrane to acyl-CoAs for subsequent ß-oxidation. Deficiency of CPT II results in the accumulation of long-chain acylcarnitines inside the mitochondria and in the plasma. Medium- and short-chain (C8 and shorter) fatty acids do not require CPT II and are metabolized normally. Muscle is particularly dependent on fatty acid oxidation for energy production.

      Clinical
      There are three clinical presentations of CPT II Deficiency. The classic form has adult onset of exercise-induced muscle weakness, often with rhabdomyolysis and myoglo- binuria that can be associated with acute renal failure. CK levels are found to be elevated only during a symptomatic period. Carnitine levels are normal.
      A second phenotype is often fatal in the period from 3 to 18 months of age. Presentation can be onset of seizures with hepatomegaly, non-ketotic hypoglycemia, cardiomyopathy, hypotonia, and muscle weakness. Plasma free carnitine levels are low and acyl-carnitine high.
      A severe form presents in the newborn period with non-ketotic hypoglycemia, cardiomyopathy, muscle weakness, and renal dysgenesis in some patients. All of these patients have expired within days of birth.
      These different clinical presentations appear to be correlated with residual CPT II enzyme activity. Adult onset patients are found to have approximately 25% of normal activity while the other clinical groups have less than 15%.

      Testing
      Newborn screening of a dried blood spot using tandem mass spectrometry detects elevations of several long-chain acylcarnitines (i.e. C16, C18, C18:1 and C18:2). These findings are characteristic but not definitive of CPT II Deficiency, because Carnitine/ Acylcarnitine Translocase Deficiency has similar findings. Quantitative urine organic acid determination is usually not helpful, as elevations of long chain fatty acids, including dicarboxylic and 3-hydroxy-dicarboxylic acids, are not always present. Plasma acylcarnitine profile results confirm the findings on a dried blood spot. Definitive testing is performed by direct enzyme testing in fibroblasts, leukocytes, liver, or muscle biopsy.

      Treatment
      CPT II deficiency varies with the clinical type. Patients with adult-onset muscle form of the disease must alter their lifestyle and refrain from rigorous exercise. It is probably prudent to avoid prolonged fasting. Medium-chain triglyceride oil may be beneficial for all patients, because it bypasses the need for CPT II activity. Aggressive treatment of acutely ill infants with IV glucose and cardiac support is critical. L-Carnitine supple- mentation should be instituted. Any intercurrent infection or illness will be life threat- ening to patients affected with the childhood form.
      Because the diagnosis and therapy of CPT II Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Demaugre, F., Bonnefont, J-P., Colonna, M., et al. Infantile form of Carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death. Physiopathological approach to Carnitine palmitoyltransferase II deficiency. J Clin Invest 87:859, 1991.
      • Hug, G., Bove, K.E. and Soukup, S. Lethal neonatal multiorgan deficiency of Carnitine palmitoyltransferase II. N Engl J Med 325:1862, 1991.
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297-2326.
      • Zinn, A.B., Zurcher, V.L., Kraus, F., et al. Carnitine palmitoyltransferase B (CPT B) deficiency: a heritable cause of neonatal cardiomyopathy and dysgenesis of the kidney. Pediatr Res 29:73A, 1991.

  • Deficit da Acil-CoA Deidrogenasi a catena corta
    • Short Chain Acyl-CoA Dehydrogenase Deficiency (SCAD)

      Background

      Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency is a disorder of fatty acid ß- oxidation. The defect involves short-chain (butyryl) acyl-CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydrogenases that carry out the initial dehydrogenation step in the ß-oxidation cycle. SCAD deficiency impairs oxidation of fatty acids of short-chain length (4 carbons).

      Clinical
      SCAD deficiency usually has clinical onset between the second month and second year of life, although presentations as early as two days and as late as adulthood have been reported. Clinical presentation is highly variable with patients having constant symptoms marked by episodic deterioration. Patients have hypotonia, progressive muscle weakness, developmental delay and, possibly seizures. Failure to thrive, vomiting, and hypoglycemia may be seen. Symptoms may be worsened by a seemingly innocuous illness (a cold or otitis media) that is associated with prolonged fasting, which may lead to lethargy, coma, apnea, cardiopulmonary arrest, or sudden unexplained death. Physical examination of the acutely ill child may reveal mild to moderate hepatomegaly. Symptoms often precede the onset of hypoglycemia, which occurs from an inability to meet gluconeogenic requirements during fasting despite activation of an alternate pathway of substrate production – proteolysis. Cerebral edema and fatty liver and muscle are noted at autopsy, often leading to a misdiagnosis of Reye’s Syndrome or Sudden Infant Death Syndrome (SIDS). SCAD deficiency accounts for about one of every 100 SIDS deaths. Older patients who present chiefly with progressive muscle involve- ment may respond to riboflavin (Vitamin B2) supplementation and have a generalized multiple acyl-CoA dehydrogenase deficiency. SCAD enzyme is the most vulnerable dehydrogenase to low riboflavin levels.

      Testing
      Newborn screening by tandem mass spectrometry of a dried blood spot identifies elevated levels of butyrylcarnitine (C4 acylcarnitine), usually with an elevated C4/C2 ratio. These results can be seen with another metabolic genetic defect (Isobutyryl-CoA Dehydrogenase Deficiency – IBDH) and therefore require further testing. Laboratory examination of blood may reveal hypoglycemia, mild metabolic acidosis, mild lactic acidosis, hyperammonemia, elevated BUN, and high uric acid levels. Liver function tests are often abnormal. Examination of the urine may show ketones, and urine organic acids often have elevated ethylmalonic acid. Plasma carnitine may be normal or low. Analysis of fibroblasts for the activity of SCAD identifies affected individuals, while heterozygous carriers for the defect usually have intermediate levels of activity, but are otherwise clinically and biochemically unaffected. SCAD activity should be assayed after antibody precipitation of MCAD activity, due to the overlap of substrate recognition.
      Detection of mutations in the SCAD gene on chromosome 12 in affected individuals allows for confirmation of biochemical testing and detection of asymptomatic carriers in other family members. In addition to disease-causing mutations, the gene has two common polymorphisms, which may interact to cause reductions in SCAD activity and complicate the genetic analysis. DNA analysis of postmortem tissue is possible when plasma and urine samples are not available. Prenatal diagnosis is possible from cultured amniocytes using direct enzyme assay. DNA analysis in amniocytes or chorionic villi can also be helpful in the diagnosis of affected fetuses in pregnancies at risk where
      both parents carry a known mutation.

      Treatment
      Fundamental to the medical management of SCAD deficiency is to avoid fasting, particularly during periods of high metabolic stress, such as illness. Overnight fasts should be managed with nighttime or late evening feedings where appropriate. The addition of food-grade uncooked cornstarch mixed in liquid for a bedtime feeding has helped to decrease the frequency of morning hypoglycemic episodes in several patients. High carbohydrate intake should be encouraged during illness, with initiation of intravenous glucose supplementation if the child is unsuccessful in keeping down fluids, or unable to take adequate oral feedings. The preventive efficacy of a low fat diet versus a normal fat diet is unclear, but high intake of long and medium chain fatty acids should be avoided. Supplementation with oral L-Carnitine may be indicated during acute illness. For individuals with SCAD deficiency, it is imperative that the lethargic patient receives parenteral dextrose to avoid hypoglycemia during evaluation.
      Because the diagnosis and therapy of SCAD deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:

      • Amendt, B.A., Greene, C., Sweetman, L., et al. Short-chain acyl-coenzyme A dehydrogenase deficiency: Clinical and biochemical studies in two patients. J Clinical Investigation 79:1303, 1987.
      • Coates, P.M., Hale, D.E., Finocchiaro, G., et al. Genetic deficiency of short-chain acyl-coenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness. J Clinical Investigation 81:171, 1988.
      • Corydon, M.J., Vockley, J., Rinaldo, P., et al. Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 49:18, 2001.
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297-2326.

  • Deficit da Idrossi Acil-CoA Deidrogenasi a catena corta
    • Short Chain Hydroxy Acyl-CoA Dehydrogenase Deficiency (SCHAD)

      Background

      Short-chain-3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency is a disorder of mitochondrial fatty acid ß-oxidation. SCHAD is one of two enzymes that carry out the third step (of 4) in the ß-oxidation of fatty acids – the other enzyme being long-chain hydroxyacyl-CoA dehydrogenase (LCHAD), which acts on longer-chain substrates. SCHAD deficiency impairs oxidation of fatty acids of short-chain length (4 carbons and shorter). The gene for SCHAD has been cloned and mutations identified in several patients.

      Clinical
      SCHAD deficiency has been reported in only a few patients and the true spectrum of the disease remains to be defined. Most patients have hypoglycemia as the major symptom with seizures, neurologic sequela or even death as the outcome. Several patients have presented in the first days or months of life with hypoglycemic seizures secondary to hyperinsulinism. Other patients have presented after one year of age with acute onset of vomiting, lethargy and hyponatremic seizures. One patient has presented at 16 years of age with recurrent episodes of hypoketotic hypoglycemia, myoglobinuria, encepha- lopathy and cardiomyopathy.

      Testing
      Newborn screening for SCHAD deficiency using tandem mass spectrometry of a dried blood spot identifies elevated levels of hydroxybutyryl-carnitine (C4-OH). Urine organic acid analysis may reveal the presence of 3-hydroxyglutaric acid in some patients. Plasma insulin measurement should be obtained at the time a child presents with hypoglycemia to rule out hyperinsulinism. Measurement of SCHAD activity in fibroblasts allows the diagnosis of affected individuals. Identification of mutations in the SCHAD gene raises the possibility of prenatal diagnosis.

      Treatment
      Although the most effective therapy for SCHAD deficiency is not established, prevention of hypoglycemia with frequent feedings seems appropriate. Fasting should be avoided, particularly during times of illness. Dietary supplementation with uncooked food-grade cornstarch after the first year or two of life should be considered, because it may permit longer periods of normoglycemia. Those patients with documented hyperinsulinism have responded to treatment with diazoxide. High carbohydrate intake should be encouraged during illness, with initiation of intravenous glucose supplementation if the child is unsuccessful in keeping down fluids, or unable to take adequate oral feedings. It is recommended that parents have written instructions in their possession at all times to present to emergency personnel should the child become symptomatic.
      Because the diagnosis and therapy of SCHAD deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Clayton, P.T., Eaton, S., Aynsley-Green, A., et al. Hyperinsulinism in short- chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of ß-oxidation in insulin secretion. J Clin Invest 108:457, 2001.
      • Molven, A., Matre, G.E., Duran, M., et al. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 53:221, 2004.
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297-2326.

  • Deficit da Proteina Trifunzionale
    • Trifunctional Protein Deficiency

      Background

      Mitochondrial Trifunctional Protein (TFP) Deficiency is a defect in mitochondrial fatty acid ß-oxidation. Three enzyme activities that act sequentially in the oxidation of fatty acids reside together on the TFP enzyme complex located on the inner mitochondrial membrane. The enzymes are Long-Chain-2-Enoyl-CoA Hydratase, Long-Chain Hydroxy- Acyl-CoA Dehydrogenase (LCHAD), and ß-KetoAcyl-CoA Thiolase. The TFP complex consists of two different protein subunits (· and ß) coded for by two nuclear genes. The TFP complex has specificity toward fatty acids of ten carbons (C10) or longer.

      Clinical
      Diverse clinical presentations have been reported in patients having TFP Deficiency. The usual presentation is in infancy and follows a period of fasting associated with a minor illness. Patients develop non-ketotic hypoglycemia, hypotonia, and lactic acidemia. Areflexia and cardiomyopathy is often found on physical exam, and sudden death can occur. Patients may have elevated CK levels and even rhabdomyolysis, and a few have had hyperammonemia. Low carnitine levels have been measured in serum and muscle. Hepatic steatosis is found at biopsy. Many of these patients succumb to severe muscular hypotonia with respiratory distress.

      Testing
      Newborn screening of a dried blood spot using tandem mass spectrometry detects elevations of several long-chain and hydroxy acylcarnitines (i.e. C16-OH, C16:1-OH, C16, C18-OH, C18:1-OH, and C18). These findings are characteristic but not definitive of TFP Deficiency, because isolated LCHAD deficiency shows similar findings. Quantitative urine organic acid determination is usually not helpful, as elevation of C6 to C14 dicarboxylic and 3-hydroxy-dicarboxylic acids may or may not be present. Plasma acylcarnitine profile can demonstrate elevations of the above acylcarnitines noted in a dried blood spot. Definitive testing is performed by direct enzyme testing using leukocytes or fibroblasts or by probing cultured fibroblasts for the TFP activities using labeled fatty acid substrate.
      TFP deficiency can be caused by mutations in either the -subunit or ß-subunit genes for TFP. No common mutation in TFP deficiency has been reported, but prenatal diagnosis is theoretically possible if both mutations are known.

      Treatment
      Supportive care for the acutely ill child involves treating hypoglycemia, lactic acidosis, and hyperammonemia with IV fluids containing glucose and bicarbonate. Administration of L-Carnitine should be considered. Avoidance of fasting is important to prevent symp- tomatic episodes.
      Because the diagnosis and therapy of TFP Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Dionisi-Vici, C., Garavaglia, B., Burlina, A.B., et al. Hypoparathyroidism in mitochondrial Trifunctional protein deficiency. J Pediatrics 129:159-162, 1996.
      • Ibdah, J.A., Tein, I., Dionisi-Vici, C., et al. Mild Trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation. J Clinical Investigation 102:1193, 1998.
      • Jackson, S., Singh Kler, R., Bartlett, K., et al. Combined enzyme defect of mitochondrial fatty acid oxidation. J Clinical Investigation 90:1219, 1992.
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Oxidation Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297-2326.
      • Ushikubo, S., Aoyama, T., Kamijo, T., et al. Molecular characterization of mitochondrial Trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits. Amer J Human Genetics 58:979-988, 1996.
      • Wanders, R.J.A., Ijlst, L., Poggi, F., et al. Human Trifunctional protein deficiency: A new disorder of mitochondrial fatty acid ß-oxidation. Biochem Biophys Res Communications 188:1139, 1992.

  • Deficit da Acyl-CoA Deidrogenasi a catena molto lunga
    • Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)

      Background

      Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) is a disorder of ß- oxidation of fatty acids. The enzymatic deficiency is one of four mitochondrial acyl-CoA dehydrogenases that carries out the initial dehydrogenation step in the ß-oxidation of fatty acids. VLCAD deficiency impairs oxidation of dietary and endogenous fatty acids of long chain length (16 carbons and longer). The buildup of the long chain fatty acid acyl- CoA intermediates results in toxic effects to normal metabolism. The gene is on chromo- some 17 and encodes a protein that functions on the inner mitochondrial membrane.

      Clinical
      Two general presentations have been reported with VLCAD deficiency, although both can vary considerably. Infants can present with severe, sepsis-like symptoms resembling a Reye-like syndrome, which is often lethal. The patient may be hypoglycemic with fasting and have metabolic acidosis, elevated liver enzymes with hepatomegaly (due to steatosis), cholestasis, hypertrophic cardiomyopathy, proteinuria, and hematuria. A second presentation has later onset and exhibits lethargy and coma with fasting. These patients have hypoketotic hypoglycemia, hepatomegaly, recurrent “infections”, and easy fatigue resulting in recurrent sore muscles. Some present with exercise-induced rhabdomyolysis.

      Testing
      Newborn screening using tandem mass spectrometry detects increased levels of C14:1, C16, and C12 acylcarnitines indicating a probable case of VLCAD deficiency. Clinical testing may reveal hypoglycemia with elevations of lactate, pyruvate, ammonia, and CK. Elevated dicarboxylic acids, both saturated and unsaturated, are often seen on urine organic acid analysis when the patient is ill. Enzyme studies performed on cultured fibroblasts can also be used to indirectly detect VLCAD activity using a labeled probe for ß-oxidation.

      Treatment
      VLCAD deficiency patients are treated with carnitine supplementation and strict avoidance of fasting. Maintaining glucose homeostasis is accomplished with frequent feedings, restricting dietary fat and increasing carbohydrates, using medium-chain triglycerides (MCT) oil supplementation and possibly cornstarch if necessary to prevent hypoglycemia. Workup of a suspected VLCAD deficient patient should rule out Medium Chain Acyl-CoA Dehydrogenase deficiency (MCAD) or Glutaric Aciduria Type II (GA-II), because MCT oil supplementation is contra-indicated for these disorders. For indivi- duals with VLCAD, it is imperative that the lethargic patient receives parenteral glucose to avoid hypoglycemia.
      Because the diagnosis and therapy of VLCAD Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition, but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Cox, G.F., Souri, M., Aoyama, T., et al. Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in a very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatrics 133:247, 1998.
      • Roe, C.R. and Ding, J. Mitochondrial Fatty Acid Disorders. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 101, pg. 2297 - 2326.
      • 68
      • Yamaguchi, S., Indo, Y., Coates, P.M., et al. Identification of very-long-chain acyl- coenzyme A dehydrogenase deficiency in three patients previously diagnosed with long-chain acyl-CoA dehydrogenase deficiency. Pediatric Research 34:111-113, 1993.
 
Malattie legate al metabolismo degli acidi organici
  • Deficit da 3-Idrossi-3-Metilglutaril-CoA Liasi
    • 3-Hydroxy-3-Methylglutaryl-CoA (HMG) Lyase Deficiency

      Background

      3-Hydroxy-3-MethylGlutaryl-CoA (HMG-CoA) Lyase has a dual function in the breakdown of Leucine and in regulating production of ketone bodies. It is located predominantly in mitochondria, but is also found in peroxisomes. In the last step in Leucine metabolism, it cleaves 3-hydroxy-3-methylglutaryl-CoA, producing acetyl-CoA and acetoacetate, one of the ketone bodies. HMG-CoA Lyase Deficiency was first described in 1971 and more than 60 patients have subsequently been diagnosed.

      Clinical
      HMG-CoA Lyase Deficiency typically presents within the first week of life, though some patients have onset later in the first year. The onset of symptoms is initiated by fasting, infection, dietary protein load, or simply the stress of birth. Symptoms progress from vomiting, lethargy, trachypnea and dehydration to coma and possibly death. Hepatomegaly and neurologic abnormalities are seen on physical exam. Laboratory studies reveal non-ketotic hypoglycemia, metabolic acidosis, hyperammonemia and elevated liver transaminases. Abnormal urine organic acids are present as well as the distinctive elevated plasma acylcarnitine species.

      Testing
      Newborns can be screened for HMG-CoA Lyase Deficiency using tandem mass spectrometry analysis of a dried blood spot. The finding of elevated six-carbon dicarboxylic acylcarnitine (C6-DC) and C5-hydroxy acylcarnitine (C5-OH), suggests the metabolic defect. To make a diagnosis, further testing is required. Urine organic acid analysis of a patient with HMG-CoA Lyase Deficiency will reveal elevation of 3-hydroxy- 3-methylglutaric, 3-methylglutaconic and 3-hydroxyisovaleric acids. A diagnosis should be confirmed by measurement of HMG-CoA Lyase enzyme activity in fibroblasts or leukocytes. Prenatal diagnosis is possible by measuring 3-hydroxy-3-methylglutaric acid in amniotic fluid and by assaying HMG-CoA Lyase enzyme activity in cultured amniocytes and chorionic villi cells. Mutations in the HMG-CoA Lyase gene on chromosome 1 have been identified in a number of patients and prenatal diagnosis can be accomplished using DNA analysis.

      Treatment
      Acute symptoms of HMG-CoA Lyase Deficiency should be treated with IV glucose, bicarbonate for the metabolic acidosis and restriction of protein (Leucine). During an acute episode, patients may require assisted ventilation. For the long-term treatment, affected patients should avoid fasting and restrict protein intake.
      Because the diagnosis and therapy of HMG-CoA Lyase Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Duran, M., Schutgens, R.B.H., Ketel, A., et al. 3-Hydroxy-3-MethylGlutaryl-CoA Lyase deficiency: Postnatal management following prenatal diagnosis by analysis of maternal urine. J Pediatrics 95:1004, 1979.
      • Mitchell, G. and Fukao, T. Inborn Errors of Ketone Body Metabolism. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al., ed., McGraw-Hill. Chapter 102:2327-2356.
      • Schutgens, R.B.H., Heymans, H., Ketel, A., et al. Lethal hypoglycemia in a child with a deficiency of 3-Hydroxy-3-MethylGlutaryl-CoA Lyase. J Pediatrics 94:89, 1979.
      • Sweetman, L. and Williams, J.C. Branched Chain Organic Acidurias. In: The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al., ed., McGraw-Hill. Chapter 93:2125-2163.

  • Acidemia Glutarica Tipo I
    • Glutaric Acidemia-Type I (GA I)

      Background

      Glutaric Acidemia, Type I (GA I), was first described in 1975. The disease is caused by a genetic deficiency of the enzyme, Glutaryl-CoA Dehydrogenase (GCD), which leads to the buildup of Glutaric acid in the tissues and its excretion in the urine of affected patients. GCD is involved in the catabolism of the amino acids, Lysine, Hydroxylysine, and Tryptophan.
      Over 200 cases of GA I have been reported in the medical literature. GA I is one of the most common organic acidemias and has an estimated incidence of about 1 in 50,000 live births. Because of the initial slow progression of clinical symptoms, GA I is frequently undiagnosed until an acute metabolic crisis occurs.

      Clinical
      Newborns with GA I may appear normal at birth or have macrocephaly. Development is typically normal during the first year of life until the infant experiences an acute encephalopathic crisis brought on by an intercurrent illness. Symptoms are characterized by metabolic acidosis, dystonia, athetosis, and seizures. The patient is often left with permanent dystonia and long-term loss of motor function. Neurologic recovery is rare and incomplete. As an alternate presentation, an affected infant may be delayed in achieving early motor milestones and appear irritable, jittery, hypotonic, and have impaired voluntary movements. This may progress as a gradual neurological disorder with preservation of mental abilities. Both presentations involve destruction of the caudate and putamen resulting in the movement disorder typical of GA I. Affected patients have a very high risk for neurologic problems before age five.

      Testing
      Newborn screening using tandem mass spectrometry of the heel stick dried blood spot identifies patients with GA I by the presence of glutaric acid covalently bound to carnitine (C5-dicarboxylic acylcarnitine, C5-DC). This permits the earliest possible diagnosis and initiation of treatment for presymptomatic patients. In acutely ill patients, large amounts of glutaric acid can be detected in blood and urine by organic acid analysis. Analysis of the urine for abnormal organic acids in a suspected patient may reveal glutaric acid, 3-hydroxyglutaric acid (which is pathognomonic for GA I), and possibly glutaconic acid. These organic acids may be missing, however, in patients who are not acutely ill, in which case acylcarnitine analysis or enzymatic testing is preferred. GCD enzyme activity can be assayed in cultured fibroblasts, cultured amniocytes and chorionic villus (direct or cultured). Prenatal diagnosis has also been accomplished by finding elevated glutaric acid in amniotic fluid. DNA mutation analysis for prenatal diagnosis requires knowing the mutation(s) in the parents prior to testing. Free carnitine levels are often low and acylated carnitine levels are high at diagnosis. Plasma amino acids are usually normal and not helpful in diagnosis.
      Several different gene mutations have been found to cause GA I. There has been no correlation of the DNA mutation with the clinical severity of the disorder for a given patient.

      Treatment
      Early, aggressive treatment prior to onset of clinical symptoms may prevent development of neurological damage. At the onset of any sickness or metabolic decompensation, prompt, vigorous initiation of IV fluids, including glucose and carnitine, with monitored administration of insulin, is recommended. Restriction of protein, i.e. Lysine and Tryptophan restriction, has not produced clear clinical benefits.
      Because the diagnosis and therapy of GA I is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is suggested that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Goodman, S.I. and Frerman, F.E. Organic acidemias due to defects in Lysine oxidation: 2-ketoadipic acidemia and Glutaric Acidemia. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 95, pg. 2195 - 2204.
      • Lipkin, P.H., Roe, C.R., et al. A case of Glutaric acidemia type I: effect of riboflavin and carnitine. J Pediatrics 112:62, 1988.
      • Aamir, N., Eleleg, O.N., et al. Glutaric aciduria type I: Enzymatic and neuroradiologic investigations of two kindreds. J Pediatrics 114:983, 1989.

  • Deficit da Isobutiril-CoA Deidrogenasi
    • Isobutyryl-CoA Dehydrogenase Deficiency

      Background

      Isobutyryl-CoA Dehydrogenase (IBD) is an enzyme involved in the metabolism of Valine, a branched-chain amino acid. Deficiency of IBD was recently described and only a few patients have been identified. The gene for IBD (ACAD8), located on chromosome 9, has been cloned and mutations have been identified in several patients.

      Clinical
      The clinical features of IBD deficiency are poorly defined and may have a highly variable presentation. The first patient described with this disease had failure to thrive and developed dilated cardiomyopathy associated with anemia at 11 months of age. Plasma carnitine levels were profoundly decreased. Several other patients have been identified by newborn screening and appear “asymptomatic”. Long-term clinical follow- up, however, is lacking and the true clinical spectrum of the disease is yet to be determined.

      Testing
      Newborns can be screened for IBD deficiency using tandem mass spectrometry analysis of a dried blood spot. The finding of elevated 4-carbon acylcarnitine (C4) indicates either IBD deficiency or short-chain acyl-CoA dehydrogenase deficiency. C4-acylcarnitine may also be seen in Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), but this is usually accompanied by other acylcarnitine metabolites. To differentiate and make a diagnosis of IBD deficiency, further testing with urine organic acid analysis is required. Urine from a patient suspected of IBD deficiency may reveal an elevation of isobutyryl- glycine or be normal, whereas patients with Short-Chain Acyl-CoA Dehydrogenase deficiency (SCAD) excrete ethylmalonic acid. Plasma free carnitine levels may be low. Identification of mutations in the ACAD8 gene should permit genetic counseling and prenatal diagnosis.

      Treatment
      The proper treatment of IBD deficiency is not yet established, because of the wide variation in clinical phenotype and lack of long-term follow-up. Asymptomatic patients may not require specific treatment, whereas those patients who are symptomatic and have low plasma carnitine may benefit from carnitine supplementation.
      Because the diagnosis of IBD deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Koeberl DD, Young SP, Gregersen NS, et al. Rare disorders of metabolism with elevated butyryl-and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. J Pediatrics Res 54:219-23, 2003.
      • Nguyen TV, Andresen BS, Corydon TJ, et al. Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans. Mol Genet Metab 77:68-79, 2002.
      • Roe CR, Cederbaum SD, Roe DS, et al. Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. Mol Genet Metab 65:264-271, 1998.
      • Sass JO, Sander S, Zschocke J. Isobutyryl-CoA dehydrogenase deficiency: isobutyrylglycinuria and ACAD8 gene mutations in two infants. J Inherit Metab Dis 27:741-745, 2004.

  • Deficit Acidemia Isovalerica
    • Isovaleric Acidemia (IVA)

      Background

      Isovaleric Acidemia results from a defect in the metabolism of the amino acid, Leucine. The first patient with Isovaleric Acidemia was described in 1966 and the deficiency of Isovaleryl-CoA Dehydrogenase activity was found a few years later. Isovaleryl-CoA Dehydrogenase functions in the inner mitochondrial matrix. The gene is located on chromosome 15.

      Clinical
      Isovaleryl-CoA Dehydrogenase deficiency has two general presentations. The first occurs within days or weeks of life as an acute, overwhelming illness with vomiting and ketoacidosis progressing to lethargy, coma and death in greater than 50% of the patients. Other laboratory findings include variable hyperammonemia, hypocalcemia, neutropenia, thrombocytopenia, and pancytopenia. A second cohort has onset later in the first year of life or after. These patients develop chronic, intermittent illnesses brought on by infection or a large protein intake. Laboratory findings will be as noted above, but perhaps not so severe. Both groups are susceptible to infection. The patient commonly has a distinctive odor of “sweaty feet” during an illness because of the volatile isovaleric acid that accumulates.

      Testing
      Newborns can be screened for Isovaleric Acidemia using tandem mass spectrometry analysis of a heel-stick dried blood spot specimen. The finding of elevated five-carbon acylcarnitine (C5) indicates either Isovaleryl-CoA Dehydrogenase deficiency or 2- MethylButyryl-CoA Dehydrogenase deficiency. To differentiate the two diseases, further testing is required. Urine organic acid analysis of a patient with Isovaleric Acidemia will reveal an elevation of isovalerylglycine with lesser elevation of 3-hydroxyisovaleric acid. The odiferous Isovalerate is found in a urine specimen only during acute illness when its levels are significant. Due to its volatility (thus producing the odor), it is lost prior to and during specimen preparation for urine organic acid determination. In contrast, patients with 2-MethylButyryl-CoA Dehydrogenase deficiency have 2-methylbutyrate and 2-methylbutyrylglycine in their urine. Prenatal diagnosis is possible by measuring isovalerylglycine in amniotic fluid and by measuring isovaleryl-CoA dehydrogenase enzyme activity in chorionic villus specimens or cultured amniocytes. The activity can also be measured in fibroblasts and leukocytes.

      Treatment
      Treatment of patients with Isovaleric Acidemia involves reducing protein intake, particularly the branched-chain amino acid Leucine. During an acute episode, aggressive use of glucose and electrolytes is necessary. Glycine supplementation has proven beneficial because this amino acid is conjugated to isovalerate, forming the less harmful isovalerylglycine. Carnitine treatment is similarly effective. Strict dietary control and aggressive treatment have resulted in normal development in some patients. However, many patients with Isovaleric Acidemia show neurologic abnormalities from acute illness.
      Because the diagnosis and therapy of Isovaleric Acidemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist and dietician. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Fries, M.H., Rinaldo, P., Schmidt-Sommerfeld, E., et al. Isovaleric acidemia: Response to a Leucine load after three weeks of supplementation with Glycine, L- carnitine and combined glycine-carnitine therapy. J Pediatrics 129:449, 1998.
      • Millington, D.S., Roe, C.R., Maltby, D.A., et al. Endogenous catabolism is the major source of toxic metabolites in isovaleric acidemia. J Pediatrics 110:56, 1987.
      • Roe, C.R., Millington, D.S., Maltby, D.A., et al. L-Carnitine therapy in isovaleric acidemia. J Clinical Investigation 74:2290, 1984.
      • Sweetman, L. and Williams, J.C. Branched Chain Organic Acidurias. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al., ed., McGraw-Hill. Chapter 93, pgs. 2125-2163.
  • Deficit da 2-Metilbutiril-CoA Deidrogenasi

    • 2-Methylbutyryl-CoA Dehydrogenase Deficiency

      Background

      Deficiency of 2-Methylbutyryl-CoA Dehydrogenase (also called Short/Branched-Chain Acyl-CoA Dehydrogenase or SBCAD) results from a defect in the metabolism of the branched-chain amino acid Isoleucine. The disorder was described in 2000 and only a few patients have been identified. The gene (SBCAD), located on chromosome 10, has been cloned and mutations identified in several patients.

      Clinical
      SBCAD Deficiency can have a highly variable presentation, ranging from poor feeding, lethargy, hypoglycemia, and metabolic acidosis at a few days of age to completely “asymptomatic” individuals. Those patients with symptoms have tended to display developmental delay, seizure disorder, or progressive muscle weakness in infancy and childhood. Long-term clinical follow-up, however, is lacking and the true clinical spectrum of the disease is yet to be determined. It is possible that some patients may have escaped onset of symptoms because they were not subjected to a metabolic stress.

      Testing
      Newborns can be screened for SBCAD Deficiency using tandem mass spectrometry analysis of a dried blood spot. The finding of elevated five-carbon acylcarnitine (C5) indicates either SBCAD Deficiency or Isovaleryl-CoA Dehydrogenase deficiency. To differentiate and make a diagnosis, further testing is required. Urine organic acid analysis from a patient suspected of SBCAD Deficiency will reveal elevation of 2-methylbutyryl- glycine with lesser increases of 2-methylbutyrylcarnitine and 2-methylbutyric acid. Plasma free carnitine levels are low to normal. Identification of mutations in the SBCAD gene may permit prenatal diagnosis.

      Treatment
      Treatment of patients with SBCAD Deficiency involves a low protein diet, particularly reduction of the amino acid Isoleucine, and carnitine supplementation. During an acute episode, aggressive use of glucose and electrolytes will be necessary. Carnitine is indicated during acute episodes, and perhaps chronically in some patients.
      Because the diagnosis and therapy of SBCAD Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Andresen, B.S., Christensen, E., Corydon, T.J., et al. Isolated 2- methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. Am J Hum Genet 67:1095, 2000.
      • Gibson, K.M., Burlingame, T., Hogema, B., et al. 2-MethylButyryl-CoA dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism. Pediatr Res 47:830, 2000.
      • Matern, D., He, M., Berry, S.A., et al. Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in the Hmong population by newborn screening using tandem mass spectrometry. J Pediatrics 112:74, 2003.
  • Deficit da 3-Metilcrotonil-CoA Carbossilasi

    • 3-Methylcrotonyl-CoA Carboxylase Deficiency (3-MCC Deficiency)

      Background

      3-Methylcrotonyl-CoA Carboxylase (3-MCC) Deficiency has been recognized since 1984. It is a defect in the degradation of the amino acid Leucine. As a carboxylase enzyme, 3- MCC requires biotin for activity. There are four carboxylases in man that utilize biotin and each can be deficient singly or together. If biotin metabolism is defective, activities of all four carboxylases will be low, resulting in Multiple Carboxylase Deficiency. Some of the biochemical findings in 3-MCC Deficiency overlap with those seen in Multiple Carboxylase Deficiency, necessitating careful testing to distinguish the two disorders.

      Clinical
      The clinical presentations of 3-MCC deficiency range from severe to benign. The age of onset of symptoms is usually during the first several years of life, but later onsets and even asymptomatic adults have been reported. Symptoms often have onset with an infection, illness, or prolonged fasting. Patients with 3-MCC deficiency can lapse into catabolic stress leading to vomiting, lethargy, apnea, hypotonia, or hyperreflexia and seizures. Patients may have profound hypoglycemia, mild metabolic acidosis, hyperammonemia, elevated liver transaminases, and ketonuria. Plasma free carnitine levels may be very low. Other patients may present with failure to thrive beginning in the neonatal period or developmental delay. Some individuals with 3-MCC deficiency have no apparent symptoms. Asymptomatic women with 3-MCC deficiency may pass along the 3-MCC metabolite transplacentally to their infants, who are then found to have elevated 3-MCC by newborn screening with tandem mass spectrometry, but who themselves do not have the disease.

      Testing
      Newborn Screening using tandem mass spectrometry reveals an elevation of C5-hydroxy acylcarnitine from the dried blood spot of an affected patient. Diagnosis of 3-MCC deficiency then requires further testing. Urine organic acid analysis finds elevation of 3- hydroxyisovaleric acid and usually 3-methylcrotonylglycine. Following carnitine supplementation, 3-hydroxyisovalerylcarnitine is usually elevated in an acylcarnitine profile using tandem mass spectrometry. If C3 acylcarnitine is elevated, the disorder is multiple carboxylase deficiency. To further confirm isolated 3-MCC deficiency, the enzyme activity should be assayed in fibroblasts or leukocytes, along with at least one other carboxylase having normal enzyme activity. 3-MCC activity can also be measured in chorionic villus specimens. Mothers of all infants found to have elevated 3-MCC with newborn screening should be tested with a blood acylcarnitine profile to determine whether they have 3-MCC deficiency rather than their infant. The testing should also extend to other family members.

      Treatment
      Treatment of 3-MCC deficiency involves reducing dietary Leucine intake using a special leucine-depleted formula or instituting a general protein restricted diet. With onset of illness, IV glucose is needed and the acidosis must be corrected. Both carnitine and glycine supplementation have proven beneficial. Patients should undergo an early trial of biotin supplementation on the possibility that the defect is with biotin metabolism rather than isolated 3-MCC; biotin may be discontinued if there is no response.
      Because the diagnosis and therapy of 3-MCC deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Elpeleg, O.N., Havkin, S., Barash, V., et al. Familial hypotonia of childhood caused by isolated 3-MethylCrotonyl-CoA Carboxylase Deficiency. J Pediatrics 121:407, 1992.
      • Gibson, K.M., Bennett, M.J., Naylor, E.W., et al. 3-MethylCrotonyl-CoA Carboxylase Deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children. J Pediatrics 132:519, 1998.
      • Koeberl, D.D., Millington, D.S., Smith, W.E., et al. Evaluation of 3-Methylcrotoonyl- CoA Carboxylase Deficiency Detected by Tandem Mass Spectrometry Newborn Screening. J Inherit Metab Dis 26:25, 2003.
      • Sweetman, L. and Williams, J.C. Branched Chain Organic Acidurias. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 93, pg. 2125 - 2163.
      • Tsai, M.Y., Johnson, D.D., Sweetman, L., et al. Two siblings with biotin-resistant 3- MethylCrotonyl-CoA Carboxylase Deficiency. J Pediatrics 115:110, 1989.
      • Tuchman, M., Berry, S.A., Thuy, L.P., et al. Partial MethylCrotonyl-CoA Carboxylase Deficiency in an infant with failure to thrive, gastrointestinal dysfunction and hypertonia. Pediatrics 91:664, 1993.

  • Deficit da 3-Metilglutaconil-CoA Idratasi
    • 3-Methylglutaconyl-CoA Hydratase Deficiency

      Background

      3-Methyl Glutaconyl-CoA Hydratase is an enzyme involved in the metabolism of the amino acid Leucine. It is located in mitochondria along with other associated enzymes of leucine catabolism. Deficiency of the enzyme leads to impaired leucine breakdown and massive excretion of 3-methylglutaconic acid. The gene has been cloned and some mutations identified in affected patients.

      Clinical
      Few patients have been described with this disorder, but the disease seems to have a wide range of clinical severity. Some patients develop acute life-threatening cardiopulmonary symptoms soon after birth, whereas others have a more chronic picture with psychomotor retardation, hypotonia, failure to thrive, microcephaly, seizures, and spasticity. Some patients have acute episodes of vomiting, metabolic acidosis and lethargy progressing to coma. Carnitine levels are variably low. Recurrent acidosis is occasionally seen with prolonged fasting and/or intercurrent illness. Speech retardation was the isolated neurological manifestation in one family.

      Testing
      Newborn screening for this disorder can be performed on a dried blood spot by tandem mass spectrometry. Infants with this disorder have increased C5-hydroxy acylcarnitine (C5-OH). This finding, however, is not specific to 3-Methyl Glutaconyl-CoA Hydratase Deficiency and the diagnosis requires additional testing. Urinary organic acid analysis reveals elevations of 3-methylglutaconate and 3-hydroxyisovalerate. The diagnosis can be confirmed with measurement of hydratase enzyme activity in lymphocytes or fibroblasts. Measurement of metabolites in amniotic fluid or enzyme assay of amniocytes may be useful for prenatal diagnosis. Knowledge of gene mutations in a family offers the potential for reliable prenatal diagnosis.

      Treatment
      Treatment of 3-Methylglutaconyl-CoA Hydratase Deficiency involves reducing protein intake, particularly the branched-chain amino acid Leucine. Carnitine supplementation may be indicated. Prolonged fasting should be avoided, because it can exacerbate the abnormal biochemical findings.
      Because the diagnosis and therapy of 3-Methylglutaconyl-CoA Hydratase Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • IJlst L, Loupatty FJ, Ruiter JP, et al. 3-Methylglutaconic aciduria type I is caused by mutations in AUH. Am J Hum Genet. 71:1463, 2002.
      • Ly TB, Peters V, Gibson KM, et al. Mutations in the AUH gene cause 3- methylglutaconic aciduria type I. Hum Mutat. 21:401, 2003.
      • Sweetman, L. and Williams, J.C. Branched Chain Organic Acidurias. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al., ed., McGraw-Hill.
  • Acidemie Metilmaloniche
    Deficit da Metilmalonil-CoA Mutasi
    Alcuni difetti di sintesi di Adenosilcobalamina
    Deficit materna di Vitamina B12

    • Methylmalonic Acidemias

      Background

      Methylmalonic Acidemia (MMA) can result from several different genetic disorders, including Methylmalonic-CoA mutase deficiency and defects of enzymes in cobalamin (vitamin B12) metabolism. Methylmalonic acidemia is one of the most studied metabolic defects, having been first reported in 1967. The incidence is at least 1 in 48,000 births, but is probably higher due to lack of recognition and diagnosis. Multiple DNA mutations for MMA have been identified.

      Clinical
      Because of the dependence of Methylmalonyl-CoA Mutase activity upon cobalamin metabolism and function, the different defects producing MMA have a similar clinical presentation. The picture of methymalonic acidemia as recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, and lethargy that can lead to coma and death is often seen in the first week of life. Metabolic acidosis is pronounced. Ketoacidosis, hyperglycinemia, hypoglycemia, and hyperammonemia are often found, along with leukopenia, thrombocytopenia, and anemia. This same scenario can present later in the first month of life, manifesting as failure-to-thrive and mental retardation. All patients are reportedly susceptible to infection. A long-term complication of MMA is renal failure.

      Testing
      Newborns can be screened for MMA using tandem mass spectrometry analysis of a heel- stick dried blood spot specimen. The finding of elevated three-carbon acylcarnitine (C3) indicates a possible metabolic defect, either MMA or Propionic Acidemia. With MMA, C4-dicarboxylic acylcarnitine may be found as well. To make a diagnosis, further testing is required. Urine organic acid analysis of a patient with MMA will reveal massive elevation of Methylmalonic acid, together with precursor metabolites ß-hydroxy- propionate and methylcitrate. These metabolites and others inhibit mitochondrial function. Methylmalonyl-CoA Mutase activity and cobalamin metabolism can be studied in several tissues. A trial of vitamin B12 therapy has diagnostic importance in identifying those patients who have defects in cobalamin metabolism. Prenatal diagnosis is possible by measuring methylmalonic acid in amniotic fluid or maternal urine, and by enzyme activity studies in cultured amniocytes.

      Treatment
      Treatment of patients with MMA involves reducing protein intake, particularly the branched-chain amino acids Valine and Isoleucine, along with Methionine and Threonine. Special formulas are commercially available for this purpose. All patients should be given a trial of cobalamin supplementation to evaluate a response, since the management of B12-responsive patients is considerably easier and the prognosis is better. Carnitine supplementation has proven beneficial. Oral antibiotics help control infections and hypothetically reduce intestinal bacteria, which produce Propionic acid that can be absorbed through the gut and contribute to methylmalonic acid production. Strict control is most crucial throughout childhood. Several older patients with mild metabolic defects are reported to function untreated.
      Because the diagnosis and therapy of MMA is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist and dietician. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Fenton, W.A., Gravel, R.A. and Rosenblatt, D.S. Disorders of Propionate and Methyl- malonate Metabolism. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 94, pg. 2165-2193.
      • Kahler, S.G., Millington, D.S., Cederbaum, S.D., et al. Parenteral nutrition in propionic and methylmalonic acidemia. J Pediatrics 115:235-241, 1989.
      • Koletzko, B., Bachmann, C. and Wendel, U. Antibiotic therapy for improvement of metabolic control in methylmalonic aciduria. J Pediatrics 117:99, 1990.
      • Roe, C.R., Hoppel, C.L., Stacey, T.E., et al. Metabolic response to carnitine in methylmalonic aciduria. Arch Diseases of Childhood 58:916, 1983.
      • Sniderman, L.C., Lambert, M., Giguere, R., et al. Outcome of individuals with low- moderate methylmalonic aciduria detected through a neonatal screening program. J Pediatrics 134:680, 1999.
  • Deficit da Acetoacetil-CoA Tiolasi Mitocondriale
    • Mitochondrial Acetoacetyl-CoA Thiolase Deficiency

      Background

      Mitochondrial Acetoacetyl-CoA Thiolase (commonly called ß-Ketothiolase) is an enzyme with a dual function in metabolism. It acts in the breakdown of acetoacetyl-CoA generated from fatty acid oxidation and regulates production of ketone bodies. It also catalyzes a late step in the breakdown of the amino acid Isoleucine. ß-Ketothiolase Deficiency was first described in 1971 and more than 40 cases have been reported.

      Clinical
      ß-Ketothiolase Deficiency has a variable presentation. Most affected patients present between 5 and 24 months of age with symptoms of severe ketoacidosis. Symptoms can be initiated by a dietary protein load, infection or fever. Symptoms progress from vomiting to dehydration and ketoacidosis. Neutropenia and thrombocytopenia may be present, as can moderate hyperammonemia. Blood glucose is typically normal, but can be low or high in acute episodes. Developmental delay may occur, even before the first acute episode, and bilateral striatal necrosis of the basal ganglia has been seen on brain MRI. Some patients may develop cardiomyopathy. An exaggerated ketogenic response to fasting or illness should raise suspicion of this disease.

      Testing
      Newborns can be screened for ß-Ketothiolase Deficiency using tandem mass spectrometry analysis of a dried blood spot. The finding of elevated five-carbon acylcarnitine (C5) suggests the metabolic defect. To make a diagnosis, further testing is required. Urine organic acid analysis of a patient with ß-Ketothiolase Deficiency will find elevations of 2-methyl-3-hydroxybutyric acid, tiglic acid, and tyglylglycine. A diagnosis should be confirmed by measuring enzyme activity in fibroblasts or leukocytes. Prenatal diagnosis is possible by measuring enzyme activity in cultured amniocytes or chorionic villus cells.
      A variety of mutations have been identified in patients with ß-Ketothiolase Deficiency. There are no common mutations, however, that would permit rapid screening. The potential for prenatal diagnosis exists if the mutations are known in a family.

      Treatment
      The acute acidosis of ß-Ketothiolase Deficiency should be treated aggressively with sodium bicarbonate, keeping in mind the possibility of iatrogenic hypernatremia. Plasma levels of glucose, electrolytes, and ammonia should be normalized. Carnitine supplementation may be helpful.
      For the long-term, affected patients should avoid fasting, eat frequently, and restrict protein intake. Intravenous glucose can be used when the patient is febrile or vomiting. Carnitine supplementation is reasonable. With appropriate monitoring and therapy, there is a good prognosis for normal development.
      Because the diagnosis and therapy of ß-Ketothiolase Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Henry, C.G., Strauss, A.W., Keating, J.P., and Hillman, R.E. Congestive cardio- myopathy associated with beta-ketothiolase deficiency. J Pediatrics 99:754, 1981.
  • Acidemia Propionica
    • Propionic Acidemia (PA)

      Background

      Propionic Acidemia (PA) is characterized by the accumulation of propionic acid due to a deficiency in Propionyl CoA Carboxylase, a biotin dependent enzyme involved in amino acid catabolism. Propionic acid may also accumulate in Multiple Carboxylase deficiency and Methylmalonic Acidemia. Multiple mutations for PA have been identified.

      Clinical
      Patients with PA typically present in the first days of life with dehydration, lethargy, hypotonia, vomiting, ketoacidosis, and hyperammonemia. Seizures, neutropenia, thrombocytopenia, and hepatomegaly may be present. Untreated patients can progress to coma and die. Most patients who survive the neonatal period have episodes of metabolic acidosis precipitated by infection, fasting, or a high protein diet. In some cases, episodic hyperammonemia seems to predominate over the metabolic acidosis. Psychomotor retardation is a life-long complication. Some patients have first presented later in infancy with encephalopathy and associated ketoacidosis, or developmental delay.

      Testing
      Newborns can be screened for PA using tandem mass spectrometry analysis of a heel- stick dried blood spot. The finding of elevated three-carbon acylcarnitine (C3) indicates a possible metabolic defect, either PA, Methylmalonic Acidemia, or less likely a defect in biotin metabolism. With Methylmalonic Acidemia, C4-dicarboxylic acylcarnitine may also be found, helping distinguish this disorder from PA. To make a diagnosis, further testing is required. Urine organic acid analysis of a patient with PA will demonstrate massive elevations of propionic acid and related compounds such as methylcitrate, propionylglycine, ß-hydroxypropionate, and tiglic acid. In PA, carnitine deficiency
      due to increased renal excretion of propionyl carnitine is often seen.

      Treatment
      Treatment of PA involves reducing protein intake, particularly the amino acids Valine, Isoleucine, Methionine, and Threonine that feed into the defective pathway. This requires placing the infant on a special metabolic formula depleted in these amino acids. Until the diagnosis of PA is clearly established, all patients should be given a trial of cobalamin and biotin to evaluate a response. Carnitine supplementation has proven beneficial. Oral antibiotics help control infections and hypothetically reduce intestinal bacteria, which produce propionic acid that can be absorbed through the gut and contribute to metabolic stress. Prevention of constipation is important. Strict control
      is most crucial throughout childhood. Rarely, older patients with mild forms of PA are reported to function untreated.
      Because the diagnosis and therapy of metabolic disorders like PA is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Fenton, W.A., Gravel, R.A. and Rosenblatt, D.S. Disorders of Propionate and Methylmalonate Metabolism. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill.
  • Deficit Multiplo da CoA Carbossilasi
    • Multiple-CoA Carboxylase Deficiency

      Background

      There are four carboxylase enzymes in man that require biotin for activity. These enzymes are propionyl-CoA carboxylase, 3-methylcrotonoyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase. If biotin metabolism is defective, all four carboxylases will be deficient. Biotin is covalently linked to a key lysine residue in each carboxylase by action of holocarboxylase synthetase. When the carboxylase proteins are degraded, biotinoyl-lysine is subsequently cleaved by biotinidase releasing free biotin that can be reutilized. The two defects in biotin metabolism associated with Multiple Carboxylase Deficiency are caused by deficient activity of holocarboxylase synthetase and biotinidase. The disorders tend to present clinically at different ages, with holocarboxylase synthetase deficiency being known as early-onset (neonatal) multiple carboxylase deficiency and biotinidase deficiency referred to as late-onset multiple carboxylase deficiency. Both respond to biotin supplementation.

      Clinical
      Patients affected with deficient holocarboxylase synthetase usually present in the first days or weeks of life with poor feeding, lethargy, hypotonia, and seizures, sometimes progressing to coma. Generalized rash and alopecia may be present. Affected patients exhibit metabolic acidosis and mild to moderate hyperammonemia. In contrast, Biotinidase deficiency, which constitutes the vast majority of patients with Multiple Carboxylase Deficiency, typically presents after several months of life with neurocutaneous symptoms including developmental delay, hypotonia, seizures, ataxia, hearing loss, alopecia, and skin rash. In some patients, the disease can be life-threatening.

      Testing
      Biotinidase deficiency is readily detected by measuring the activity of the enzyme on a heel stick dried blood spot. Newborn screening using tandem mass spectrometry may reveal an elevation of C5-hydroxy acylcarnitine from the dried blood spot of a patient affected with holocarboxylase synthase deficiency. Diagnosis of holocarboxylase synthetase deficiency requires further testing. Urine organic acid analysis reveals elevations of ß-hydroxyisovaleric acid, ß-methylcrotonylglycine, and tyglylglycine. Urine may also contain metabolites seen in Propionyl CoA Carboxylase deficiency
      and ß-Methylcrontonyl CoA Carboxylase deficiency. Discriminating these disorders is important to ensure proper therapy is initiated.

      Treatment
      Treatment of patients with Multiple Carboxylase Deficiency involves administration of high doses of biotin. An excellent and rapid clinical response to biotin is characteristic of both enzyme defects associated with Multiple Carboxylase Deficiency. This highlights the importance of accurate and timely diagnostic evaluation of affected infants.
      Because the diagnosis and therapy of Multiple Carboxylase Deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Sweetman, L. and Williams, J.C. Branched Chain Organic Acidurias. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill.
      • Wolf, B. Disorders of Biotin Metabolism. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill.

  • Aciduria Malonica
    • Malonic Aciduria

      Background

      Malonic Aciduria is a rare disorder caused by deficiency of Malonyl-CoA Decarboxylase (MCD). MCD is an enzyme that catalyzes the degradation of malonyl-CoA. Malonyl-CoA is a substrate for fatty acid synthesis and it also regulates oxidation of fatty acids by controlling their uptake into mitochondria. MCD may therefore regulate fatty acid synthesis and oxidation by affecting intracellular malonyl-CoA levels, but its function is not completely known. The gene for MCD, located on chromosome 16, has been cloned and mutations identified in patients with MCD deficiency.

      Clinical
      The presentation of malonic aciduria due to MCD deficiency is variable, ranging from an acute neonatal onset to later in childhood. Patients have symptoms of developmental delay, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, and ketosis. Hypertrophic cardiomyopathy can be seen.

      Testing
      Newborn screening of a dried blood spot using tandem mass spectrometry reveals elevation of malonyl-carnitine, which is characteristic of the disorder. Confirmatory studies include urine organic acids, which show elevations in malonic acid, methylmalonic acid, and possibly other organic acids. Studies on cultured fibroblasts confirm a decrease in MCD activity. Identification of mutations in the MCD gene may be useful for genetic counseling.

      Treatment
      There is limited experience in managing this rare disorder. Dietary modification to increase the amount of calories from carbohydrate relative to fat has been effective in improving metabolic abnormalities. Extended fasting should be avoided. Carnitine supplementation has been beneficial in some patients.
      Because the diagnosis and therapy of Malonic Aciduria is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • FitzPatrick DR, Hill A, Tolmie JL, et al. The molecular basis of malonyl-CoA decarboxylase deficiency. Am J Hum Genet 65:318-326, 1999.
      • MacPhee, et.al.; Malonyl coenzyme A decarboxylase deviciency. Arch. Dis. Child. 69:433-436, 1993.
      • Santer R, Fingerhut R, Lassker U, et al. Tandem mass spectrometric determination of malonylcarnitine: diagnosis and neonatal screening of malonyl-CoA decarboxylase deficiency. Clin Chem 49:660-662, 2003.
      • Sweetman L, Williams JC. Branched chain organic acidurias. The Metabolic and Molecular Basis of Inherited Disease. 8th Edition. Scriver, Beaudet, et al. McGraw- Hill. pg. 2155-2157, 2001.
 
Profilo Aminoacidico
Malattie legate al metabolismo degli aminoacidi
  • Argininemia
    • Argininemia

      Background

      Argininemia is a rare Urea Cycle defect caused by deficiency of Arginase in liver and erythrocytes. Arginase is the final enzyme in the Urea Cycle that catalyzes the breakdown of arginine to ornithine and urea, which is the major metabolite carrying waste nitrogen destined for urinary excretion. Patients with Arginase deficiency have elevated levels arginine in blood. The deficient Arginase gene is located on chromosome 6.

      Clinical
      Patients with Argininemia may present from two months to four years of age. Symptoms are progressive spastic paraplegia, failure to thrive, delayed milestones, hyperactivity and irritability, with episodic vomiting, hyperammonemia and seizures. Mental retardation is a result of cerebral atrophy which leads to microcephaly. Hepatomegaly may be present.

      Testing
      Argininemia may be detected by newborn screening using tandem mass spectrometry of a dried blood spot. Affected patients have elevations in arginine ranging from 5- to 10- fold, while other amino acids are usually in the normal range. Arginase enzyme activity can also be eluted and measured from the dried blood spot. Hyperammonemia is moderately severe. The patient’s urine contains elevated levels of orotic acid, along with increased levels of the diamino acids: arginine, lysine, cystine and ornithine. The deficient Arginase activity is tissue specific for the liver and erythrocyte. Heterozygous carrier individuals have partially reduced enzyme activity, but are clinically unaffected. Several mutations have been reported in the gene. Identification of the mutations allows prenatal diagnosis and genetic testing for other family members.

      Treatment
      Argininemia is a rare disorder and few patients have been treated from an early age, prior to onset of disabling symptoms. Dietary restriction of protein is the basic treatment, with supporting therapy to prevent and control the hyperammonemia.
      Because the diagnosis and therapy of argininemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Brusilow, S. and Horwich, A. Urea Cycle Enzymes. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 85, pg. 1909-1963.
      • Bernar, J., Hanson, R.A., Kern, R., et al. Arginase deficiency in a 12 year old boy with mild impairment of intellectual function. J Pediatrics 108:432, 1986.
      • Qureshi, I.A., Letarte, J., Ouellet, R., et al. Treatment of hyperargininemia with sodium benzoate and arginine restriction diet. J Pediatrics 104:473, 1984.

  • Aciduria Argininosuccinica/ Citrullinemia
    • Argininosuccinic Aciduria (ASA LYASE)/ Citrullinemia (ASA Synthase)

      Background

      The finding of elevated Citrulline in a newborn screen dried blood spot suggests one of two metabolic defects: Argininosuccinic Acid Synthetase Deficiency or Arginino- succinate Lyase Deficiency. Both are disorders of the Urea Cycle and are associated with severe, episodic hyperammonemia. Argininosuccinic Acid Synthetase Deficiency (commonly called Citrullinemia) occurs in 1:57,000 births and causes a dramatic eleva- tion of plasma Citrulline. Argininosuccinate Lyase Deficiency causes a less dramatic increase of plasma Citrulline, but is no less clinically devastating. It is found in 1:70,000 births.

      Clinical
      Both forms of Citrullinemia have a similar clinical presentation. With an early onset presentation, the newborn appears normal for the first 24 hours. Symptoms develop in association with worsening hyperammonemia. By 72 hours, lethargy, feeding difficulties and vomiting usually appear. The patient develops hypothermia, respiratory alkalosis and often requires ventilation. Seizures progressing to coma and death are typical in untreated patients. Physical examination reveals encephalopathy, which is due to brain edema and swollen astrocytes from glutamine accumulation and the resulting water retention. Patients with Argininosuccinate Lyase Deficiency may exhibit hepatomegaly. These patients are frequently mistaken for a case of sepsis. A key laboratory abnormality suggesting a Urea Cycle defect is low blood urea nitrogen, which should dictate measurement of ammonia. Patients who survive the newborn period may have a neurologic impairment. These neonatal onset patients have recurrent episodes of hyperammonemia associated with viral infections or increased dietary protein intake. Some patients with either disorder have a later onset with a less severe course making diagnosis difficult.

      Testing
      Newborn screening by tandem mass spectrometry using a dried blood spot can detect elevated levels of Citrulline with either disorder. The levels of Citrulline in Arginino- succinic Acid Synthetase Deficiency range up to 100 times the normal limit. Arginino- succinate Lyase Deficiency patients have measurable levels of Argininosuccinic acid in plasma, which is not normally detected. The activity of either enzyme can be measured from a liver biopsy. Both genes have been isolated and mutations identified. DNA studies can be performed for prenatal diagnosis when the mutation is known from both parents. Biochemical studies of cultured amniocytes and chorionic villus tissue are also informative. The presence of Argininosuccinic acid in the amniotic fluid of Arginino- succinate Lyase Deficiency patients has been used for prenatal diagnosis.

      Treatment
      The symptoms of Citrullinemia seem to originate from the hyperammonemia rather than Citrulline accumulation. Acute hyperammonemia may necessitate hemodialysis, which is more effective for lowering ammonia than peritoneal dialysis or arterio- venous hemofiltration. Sodium benzoate is given to conjugate Glycine, a major amino acid that contributes ammonia to the urea cycle, forming hippurate, which is subsequently excreted in the urine. Intravenous Arginine results in ammonia clearance by enhancing formation of Citrulline in Argininosuccinic Acid Synthetase Deficiency or Argininosuccinate in Argininosuccinate Lyase Deficiency. Both of these metabolites are excreted in the urine and draw off excess nitrogen from ammonia. Patients who survive the initial presentation are placed on protein restriction. Patients with either defect having onset in the newborn period face a poor outcome and significant risk of neurological damage or demise.
      Because the diagnosis and therapy of these metabolic disorders is complex, the pediatrician is strongly advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      These disorders most often follow an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Brusilow, S.W. and Horwich, A. Urea Cycle Enzymes. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 85, pg. 1909-1963.
      • Maestri, N.E., Hauser, E.R., Bartholomew, D., et al. Prospective treatment of urea cycle disorders. J Pediatrics 119:923, 1992.
      • Maestri, N.E., Clissold, D.B., Brusilow, S.W. Long-term survival of patients with Argininosuccinate Synthetase deficiency. J Pediatrics 127:929, 1995.
      • Rutledge, S.L., Havens, P.L., Haymond, M.W., et al. Neonatal hemodialysis: Effective therapy for the encephalopathy of inborn errors of metabolism. J Pediatrics 116:125, 1990.

  • 5-Ossoprolinuria
    • 5-Oxoprolinuria (Pyroglutamic Aciduria)
      5-OXOPROLINEMIA – GLUTATHIONE SYNTHETASE DEFICIENCY GLUTAMYLCYSTEINE SYNTHETASE DEFICIENCY 5-OXOPROLINASE DEFICIENCY

      Background

      5-Oxoprolinemia is a rare clinical condition caused by a deficiency of any one of three enzymes in the γ-Glutamyl Cycle. The Cycle provides antioxidant for the body in the form of Glutathione. Three enzymes are involved in the sequential processing of 5- Oxoproline to form glutathione. A deficiency of any one of the enzymes causes 5- Oxoprolinemia, and two of the defects lead to low levels of glutathione. Patients with 5-Oxoprolinemia have been described in several ethnic groups around the world.

      Clinical
      Clinical presentation of these deficiencies is variable, from severe to very mild. Gluta- thione Synthetase Deficiency is the most common defect, reported in over 40 cases worldwide. It usually presents in the newborn period with marked metabolic acidosis, hemolytic anemia, electrolyte imbalance, and jaundice. Patients who survive the initial onset may later have episodes of metabolic decompensation during intercurrent illnesses. They often develop progressive central nervous system symptoms. 5-Oxoproline can reach very high levels during illness.
      Glutamylcysteine Synthetase Deficiency is less severe than Glutathione Synthetase Deficiency, lacking the metabolic acidosis and having lower 5-Oxoproline levels in plasma and urine. Patients have mild compensated hemolytic anemia as the most consistent finding.
      Only a few patients have been reported with 5-Oxoprolinase Deficiency. Their clinical symptoms vary tremendously and may not be due to the metabolic defect. They have normal glutathione levels in erythrocytes and no evidence of hemolytic anemia.

      Testing
      Newborn Screening of dried blood spots using tandem mass spectrometry identifies 5-Oxoproline. Elevated levels should dictate further diagnostic testing. Glutathione Synthetase and Glutamylcysteine Synthetase activity can be measured in erythrocytes, leukocytes, and fibroblasts. 5-Oxoprolinase is not present in erythrocytes, but is present in leukocytes and fibroblasts. Glutathione Synthetase Deficiency has been diagnosed prenatally by enzyme assay of amniocytes or chorionic villi cells, or by finding elevated 5-Oxoproline in amniotic fluid. The gene is on chromosome 20 and mutations have been found in affected patients, raising the possibility for DNA-based prenatal diagnosis. Glutamylcysteine Synthetase is composed of two different proteins and mutations have been found in one of the genes.

      Treatment
      Patients with Glutathione Synthetase Deficiency require intravenous sodium bicarbonate for acute episodes and oral alkali for chronic acidosis. Severe anemia is corrected with blood transfusions. Patients with Glutathione Synthetase or Glutamylcysteine Synthetase Deficiencies may benefit from supplementation with Vitamin E and Vitamin C for their antioxidant effects.
      Because the diagnosis and therapy of 5-Oxoprolinemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Beutler E, Gelbart T, Kondo T, et al. The molecular basis of a case of gamma- glutamylcysteine synthetase deficiency. Blood. 94:2890-4, 1999.
      • Konrad, P.N., Richards II, F., Valentine, W.N., et al. ?-Glutamylcysteine Synthetase deficiency. A cause of hereditary hemolytic anemia. New England J Medicine 286:557, 1972.
      • Larson, A. and Anderson, M.E. Glutathione Synthetase Deficiency and Other disorders of the ?-Glutamyl Cycle. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 96, pg. 2205 - 2216.
      • Mayatepek, E., Hoffman, G.F., Carlsson, B., et al. Impaired synthesis of lipoxygenase products in glutathione synthetase deficiency. Pediatric Research 35:307, 1994.

  • Carenza di Carbamoilfosfato Sintetasi
    • Carbamoylphosphate Synthetase Deficiency

      Background

      Metabolism of amino acids generates ammonia, a highly toxic nitrogen-containing molecule that is eliminated from the body by its incorporation into urea, a non-toxic end product excreted through the kidneys. Carbamyl Phosphate Synthetase (CPS) catalyzes the first step in the detoxification of ammonia through formation of carbamyl phosphate, which enters the urea cycle and ultimately contributes its nitrogen to urea. Deficiency of CPS results in hyperammonemia and life-threatening symptoms. CPS is localized to the mitochondrial matrix and is present in high amount in liver and intestine. The CPS gene has been cloned and mutations identified in patients.

      Clinical
      Newborns with CPS deficiency appear normal for the first 24 hours. By 72 hours, symptoms of lethargy, vomiting, hypothermia, respiratory alkalosis and seizures progressing to coma appear. These patients are frequently thought to have sepsis. However, a key laboratory abnormality suggesting a urea cycle defect is low blood urea nitrogen, which should prompt measurement of ammonia. Patients who survive the newborn period often have recurrent episodes of hyperammonemia associated with viral infections or increased dietary protein intake. A neurologically damaged outcome is characteristic of CPS deficiency. Some patients have a later onset with a less severe course making diagnosis difficult.

      Testing
      Newborn screening by tandem mass spectrometry using a dried blood spot can detect elevated levels of glutamine and glutamate, together with low citrulline, suggesting CPS deficiency. Further testing is critical for the correct diagnosis. Plasma amino acids, urine organic acids and plasma acylcarnitine profiles will help distinguish CPS deficiency from other metabolic disorders exhibiting neonatal hyperammonemia. In contrast to several other urea cycle defects, patients with CPS deficiency do not excrete high levels of orotic acid. The activity of CPS can be measured in a liver biopsy. Mutation analysis of the CPS gene may be useful for prenatal diagnosis in future pregnancies.

      Treatment
      Treatment of acute hyperammonemia caused by CPS deficiency includes hemodialysis, peritoneal dialysis or arteriovenous hemofiltration. Several drugs conjugate major amino acids, forming metabolites that are excreted in the urine, which eliminates a major source of nitrogen from being converted to ammonia. Administration of sodium phenyl- butyrate (or phenylacetate) conjugates glutamine, forming phenylacetylglutamine, which is excreted by the kidneys and removes waste nitrogen. In a similar fashion, citrulline is given to conjugate aspartic acid forming argininosuccinic acid. Administration of sodium benzoate results in conjugation of glycine, which is subsequently excreted in the urine. Patients who survive the initial presentation are placed on chronic treatment with phenylbutyrate, benzoate and supplemental arginine along with dietary protein restriction. Patients having onset in the newborn period face a poor outcome and significant risk of neurological damage or demise.
      Because the diagnosis and therapy of CPS deficiency is complex, the pediatrician is strongly advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Brusilow, S.W. and Horwich, A. Urea Cycle Enzymes. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 85, pg. 1909-1963.
      • Caldovic L, Morizono H, Panglao MG, et al. Null mutations in the N- acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet 112:364-8, 2003.
      • Funghini S, Donati MA, Pasquini E, et al. Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions. Hum Mutat 22:340-341, 2003.
      • 60
      • Maestri, N.E., Hauser, E.R., Bartholomew, D., et al. Prospective treatment of urea cycle disorders. J Pediatrics 119:923, 1992.
      • Rutledge, S.L., Havens, P.L., Haymond, M.W., et al. Neonatal hemodialysis: Effective therapy for the encephalopathy of inborn errors of metabolism. J Pediatrics 116:125, 1990.

  • Omocistinuria - Ipermetioninemia 
    • Homocystinuria (Hypermethioninemia)

      Background

      The finding of elevated Methionine in a dried blood spot upon newborn screening suggests one of two metabolic defects: 1) Homocystinuria due to Cystathionine ß- Synthase (CBS) deficiency or 2) hepatic methionine adenosyltransferase deficiency. The most likely defect is a deficiency of CBS, which causes a connective tissue disease with several manifestations. Many patients with homocystinuria have been described since the deficiency was first reported in 1962. Methionine accumulates at the beginning of a metabolic pathway that sequentially converts this amino acid to Homocysteine, Cysta- thionine and Cysteine. The step in the pathway that converts Homocysteine to Cysta- thionine is catalyzed by CBS. Although it is highly elevated, Homocysteine is not detected with newborn screening because of its reactive nature with many components in blood, including itself with the formation of the dimer Cystine. The elevation of Methionine, therefore, is used to detect this disorder in newborn screening. The incidence of CBS deficiency is about 1 in 60,000, although several investigators believe this disease is more common.

      Clinical
      While the metabolic defect is present at birth, initial symptoms of homocystinuria usually have onset later in infancy and childhood. Developmental delay may be the first sign and is a harbinger of mental retardation, but is not obligate. An early and distinctive finding is dislocation of the lens of the eye (ectopia lentis). Patients are at high risk for developing thromboembolism that may occur at any age. These may lead to stroke, seizures, permanent neurologic sequela and death. Increased clotting ability makes surgery a risk. Osteoporosis is a long-term complication of homocystinuria.

      Testing
      Newborn screening of a dried blood spot using tandem mass spectrometry reveals elevated levels of methionine, which should prompt testing plasma for amino acids, including homocysteine. Elevated methionine and homocysteine in plasma indicate CBS deficiency, while an isolated increase in methionine suggests hepatic methionine adenosyltransferase deficiency. In affected patients, the presence of homocystine in the urine is a consistent finding, especially after early infancy. CBS enzyme activity can be measured in many tissues, including fibroblasts, lymphocytes, liver, amniocytes, and chorionic villi (biopsy or cultured cells). Deficient enzyme activity may be followed with DNA mutation analysis for the several known mutations in the CBS gene.

      Treatment
      Treatment of CBS deficiency usually begins with a trial of oral vitamin B6 (pyri- doxine) supplementation, with daily measurement of plasma amino acids. CBS requires pyridoxine as a coenzyme for enzymatic activity. Overall, about 25% of patients respond to large doses of pyridoxine, although the percentage may be lower for patients identi- fied through newborn screening. This pyridoxine response usually coincides with the presence of some residual enzyme activity. Dietary restriction of Methionine in conjunc- tion with Cystine supplementation reverses the biochemical abnormalities to some extent and appears to reduce the clinical symptoms. Special formulas are available commercially, but the diet is difficult to maintain long term. In an attempt to decrease Homocysteine levels, folic acid, and betaine can be supplemented to induce recycling of this amino acid to Methionine for alternate metabolism. Vitamin B12 (cobalamin) may also be helpful.
      Because the diagnosis and therapy of Homocystinuria is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Applegarth, D.A., Hardwick, D.F., et al. Excretion of S-adenosylmethionine and S- adenosylhomocysteine in Homocystinuria. New England J. Med. 285:1265, 1971.
      • Mudd, S.H., Levy, H.L., and Kraus, J.P. Disorders of Trans-sulferation. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 88, pg. 2007-2046.
      • Wong, P.W.K., Justice, P., et al. Folic acid non-responsive homocystinuria due to methylenetetrahydrofolate reductase deficiency. J Pediatrics 58:749-756, 1977.

  • Sindrome di Iperammonemia, Iperornitinemia, Omocitrullinuria
    • Hyperammonemia, Hyperornithinemia, Homocitrullinuria Syndrome (HHH)

      Background

      Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome was first described in 1969. In affected patients, plasma Ornithine is found to be dramatically elevated. Hyperammonemia is chronically present, but worsens postprandially. The etiology is a deficiency of a mitochondrial carrier protein that normally functions to transport Ornithine into the mitochondria as part of the urea cycle. When transport is defective, Ornithine accumulates in the cytosol and the urea cycle is impaired, resulting in hyperammonemia. The ORNT 1 gene that codes for the transport protein is located on chromosome 13, and several mutations have been identified in affected patients.

      Clinical
      HHH Syndrome may present at birth, during childhood or even adulthood. Newborns who are breast fed usually have an uneventful beginning with intermittent hyper- ammonemia. Infants on high protein formula or foods may vomit with feeding, refuse to eat, become lethargic or develop hyperammonemic coma. Most affected patients exhibit some symptoms, such as lethargy, vomiting, ataxia or chroeoathetosis, impaired growth and delayed development. Seizures are often reported. Mild to profound mental retarda- tion is usually apparent by childhood. Over time, patients will gravitate to a diet low in milk and meat during childhood.

      Testing
      Newborn screening of dried blood spots using tandem mass spectrometry (MS/MS) is capable of identifying and quantitating Ornithine. HHH Syndrome patients have Ornithine levels five to ten times normal. Alanine may be elevated. Hyperammonemia occurs postprandially and is chronically elevated on a high protein diet, but may be normal when fasting. Urine organic acid analysis will reveal elevated Orotic Acid while urine amino acid analysis finds elevated Homocitrulline, a metabolite of Ornithine. Elevated plasma Ornithine differentiates HHH Syndrome from other urea cycle defects. The disorder of Gyrate Atrophy of the Choroid and Retina, also with hyperornithinemia, is differentiated by its lack of hyperammonemia. Identification of mutations in the ORNT 1 gene allows for definitive diagnosis and carrier identification. Prenatal diagnosis is possible if the gene mutation has been identified in both parents.

      Treatment
      Few patients with HHH Syndrome have been treated from an early age, prior to onset of disabling symptoms. Dietary restriction of protein is the basic treatment, with supporting therapy to prevent and control the hyperammonemia. A trial of Ornithine, Arginine, or Citrulline supplementation may reduce plasma ammonia. Patient response is highly variable.
      Because the diagnosis and therapy of HHH Syndrome is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Camacho JA, Obie C, Biery B, et al. Hyperornithinaemia-hyperammonaemia- homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet. 22:151, 1999.
      • Lemay, J., Lambert, M., Mitchell, G., et al. HHH Syndrome: Neurologic, ophthalmologic and psychological evaluation of six patients. J Pediatrics 121:725, 1992.
      • Valle, D. and Simell, O. The Hyperornithinemias. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 83, pg. 1857 - 1895.

  • Iperornitinemia con Atrofia Girata
    • Hyperornithinemia with Gyrate Atrophy

      Background

      The first description of a patient with gyrate atrophy of the choroid and retina, as defined by the characteristic appearance of the ocular fundus and a typical history of visual deterioration, was probably made in 1888. Since that time numerous other case reports have confirmed this condition as a distinct entity. Hyperornithinemia and ornithinuria were recognized as the biochemical marker for this disorder in 1973. Elevations in Ornithine, a non-protein amino acid, are associated with complete or partial deficiency of Ornithine Aminotransferase (OAT) activity.

      Clinical
      The major clinical problem in these patients is a slowly progressive loss of vision leading to blindness, usually by the fifth decade of life. Myopia and decreased night vision are early symptoms, usually noted by the first or second decade. Reduced peripheral vision is typically present in the second decade, with nearly all patients ultimately developing cataracts. The combination of the cataracts and diminished visual fields results in progressive visual loss, which is frequently well established by the third decade of life in most patients. However, there is significant variability in vision and a few patients retain good visual function into their sixth or seventh decade.
      Younger patients often come to the attention of the ophthalmologist in late childhood or around the time of puberty for evaluation of myopia or decreased night vision. Aside from visual impairment, patients with gyrate atrophy are for the most part asymptomatic. Some patients have mild muscle weakness with associated abnormalities on muscle biopsy and in electromyograms, although creatine phosphokinase activity is normal. Affected patients are developmentally normal.

      Testing
      Newborn screening of dried blood spots using tandem mass spectrometry (MS/MS) is capable of identifying and quantitating Ornithine. Diagnostic evaluation can show abnormal levels of ornithine in plasma, cerebrospinal fluid and urine. An ornithine methyl ester is found in the urine of patients with gyrate atrophy and other conditions associated with hyperornithinemia.
      Deficiency of OAT has been documented in cultured skin fibroblasts, lymphocytes, skeletal muscle, and liver biopsy specimens. Activity of this enzyme is absent or markedly diminished and may explain the clinical heterogeneity of the disease. Numerous mutations have been found in the OAT gene in patients from around the world.

      Treatment
      A few gyrate atrophy patients will respond to pharmacologic doses of vitamin B6 (pyridoxine) with increase in residual enzyme activity, partial reduction in plasma Ornithine and stabilization of vision. The slow progression of the degenerative changes in vision and the difficulty in measuring small changes in ocular function make evalua- tion of any therapy difficult. Additional approaches to therapy may be efficacious, including dietary reduction in Ornithine and administration of creatine.
      Because the diagnosis and therapy of Hyperornithinemia with Gyrate Atrophy is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist.

      Inheritance
      Hyperornithinemia with Gyrate Atrophy is inherited as an autosomal recessive trait. Both parents are carriers of one normal gene and one abnormal Hyperornithinemia gene. An affected child is born when both parents pass along the Hyperornithinemia gene at conception, resulting in every cell of the body having the two abnormal genes. The risk for carrier parents having an affected pregnancy is one chance in four with every conception. If not screened at birth, all previous siblings should be tested to rule out Hyperornithinemia. This disease has been found in several ethnic groups around the world with a particularly high incidence in Finland.

      References:
      • Valle, D. and Simell, O. The hyperornithinemias. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al., eds. McGraw- Hill. Chapter 83:1857-1895.

  • Malattia delle Urine a Sciroppo d’Acero
    • Maple Syrup Urine Disease (MSUD)

      Background

      Maple Syrup Urine Disease (MSUD) was first described in 1954 in a family with four successive affected newborns. Each died with a progressive neurologic disease in the first weeks of life. MSUD is caused by a deficiency in the ability to decarboxylate branched-chain amino acids. This enzyme activity resides in the branched-chain a-ketoacid dehydrogenase complex in the mitochondrial membrane.

      Clinical
      The most common form of MSUD presents with overwhelming symptoms in the first days of life. Patients appear normal at birth, but begin to have feeding difficulties with vomiting, progressing to lethargy and coma. The infant may have a high-pitched cry and the odor of maple syrup may emanate from the diaper. Metabolic acidosis with increased anion-gap is typically present, and plasma branch-chain amino acids (leucine, isoleucine, and valine) are seen. Hypoglycemia may occur. Neurologic deterioration is progressive and rapid. Cerebral edema results in encephalopathy exhibited as alternating hyper- and hypotonia, scissoring of the legs, opisthotonos, abnormal respirations, coma, and death. If the patient survives this period, any infection or metabolic stress is life threatening. Other less acute presentations have been reported, including an intermittent form associated with episodic ataxia and acidosis, and a milder, more chronic intermediate form with less severe acidosis. With all forms of MSUD, neurologic symptoms are typically evident by two years of age. Variable phenotypes arise from different mutations in the branched-chain a-ketoacid dehydrogenase complex and the residual metabolic capacity of a given patient.

      Testing
      Newborn Screening of a dried blood spot specimen using tandem mass spectrometry measures valine and the sum of leucine, isoleucine, and alloisoleucine, the branched- chain amino acids. Leucine, isoleucine, and valine are nutritionally required amino acids. In MSUD, these amino acids are not metabolized (decarboxylated) and accumulate to very high levels, the highest being leucine. Oxidative decarboxylation is the second step in the degradative metabolic pathway, which is blocked in MSUD and results in the buildup of three organic acids - 2-oxoisocaproic acid from leucine, 2-oxo-3-methylvaleric acid from isoleucine, and 2-oxoisovaleric acid from valine - which are detected in high levels in the urine of affected patients. During a crisis, patients are acidotic from elevated organic acids and lactate, and are typically ketotic. The diagnosis of MSUD is based on measuring elevated plasma branched-chain amino acids along with alloisoleucine, and the abnormal urine organic acids. Deficiency of the branched-chain a-ketoacid dehydro- genase enzyme complex activity can be measured in cultured fibroblasts. Prenatal diag- nosis can be accomplished by measuring enzyme activity in chorionic villi cells or cultured amniocytes.

      Treatment
      Treatment often begins with aggressive intervention in an acute metabolic crisis. Hemo- dialysis, if available, can lower the levels of the branched-chain amino acids and organic acids in the plasma. Generous administration of IV fluids helps eliminate organic acids through renal loss. IV glucose provides an alternate energy source that reduces protein catabolism, which is a major source of branch-chain amino acids in acutely ill infants. Restriction of protein intake is usually a life-long requirement and commercial formulas that are depleted in branched-chain amino acids are available. Carnitine supplementa- tion is useful in removing organic acids and repleting carnitine stores. Some patients respond to high-dose thiamine supplementation, a cofactor of the enzyme complex, and all newly diagnosed critically ill infants should be treated with this vitamin. Close monitoring of patients who survive the newborn period or who have a later presentation is required to reduce morbidity and mortality.
      Because the diagnosis and therapy of MSUD is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Chuang, D.T. and Shih, V.E. Maple Syrup Urine Disease (Branched-Chain Ketoaciduria). In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 87, pg. 1971-2005.
      • Riviello, J.J., Rezvani, I., Degeorge, A.M., and Foley, C.M. Cerebral edema causing death in children with maple syrup urine disease. J Pediatrics 119:42, 1991.

  • Fenilchetonuria
    Classica
    Iperfenilalaninemia
    Deficit Cofattore Biopterina
    • Phenylketonuria (PKU)

      Background

      Phenylketonuria (PKU) is a disorder of amino acid metabolism that was recognized as a genetic defect as early as 1930. Phenylalanine is an essential amino acid that is converted to tyrosine by action of the enzyme phenylalanine hydroxylase. A block in this reaction due to deficient activity of phenylalanine hydroxylase causes PKU and results in severe central nervous system symptoms. Phenylalanine hydroxylase requires tetrahydrobiopterin as a cofactor and its deficiency, caused by an enzyme defect in the synthesis or recycling of tetrahydrobiopterin, can also result in PKU. The incidence of PKU is approximately 1 in 12,000 Caucasians. Historically, newborn screening originated with Dr. Robert Guthrie who developed a test for elevated phenylalanine (PKU) in dried blood spots.

      Clinical
      PKU babies typically appear normal at birth and in the neonatal period. Infants may later exhibit irritability, posturing, increased deep tendon reflexes, a peculiar “mousy” odor, and vomiting. Pale pigmentation develops in hair and skin, and seizures are sometimes present. Phenylalanine accumulates within the first days of life and tyrosine levels tend to be low. Although various phenylalanine metabolites are present, phenylalanine itself appears to be the toxic molecule in PKU. High phenylalanine levels prevent transport of other amino acids across the blood-brain barrier, inhibiting synthesis of key neurotransmitters and disrupting protein synthesis in the brain. This produces severe mental retardation and white matter disease.
      Women with untreated PKU who become pregnant are at high risk for having newborns with neurological damage. This is caused by the high phenylalanine levels in the untreated mother that cross the placenta during pregnancy and are toxic to the developing fetus. Mothers affected with PKU need to be on dietary control prior to conception to avoid the toxic effects of phenylalanine on their baby.

      Testing
      Newborn screening for PKU began with a bacterial bioassay and has progressed to the use of tandem mass spectrometry. This sensitive technology allows for measurement of both phenylalanine and tyrosine, showing elevated phenylalanine levels in conjunction with an increased phenylalanine to tyrosine ratio that is indicative of PKU. This methodology makes PKU screening effective, reliable, and efficient. Several hundred DNA mutations in the phenylalanine hydroxylase gene can cause PKU (98% of cases), as well as mutations in other genes necessary for tetrahydrobiopterin production (2% of cases). All newborns with PKU should be tested for tetrahydrobiopterin defects. Hyperalimentation with parenteral amino acid supplementation produces elevated phenylalanine levels in non-PKU infants, but the phenylalanine to tyrosine ratio is not elevated. Some infants have mutations in phenylalanine hydroxylase that result in mild hyperphenylalaninemia and no serious neurological disease.

      Treatment
      Patients with PKU need to maintain normal, physiological levels of phenylalanine and tyrosine for life. Studies have shown that periods of elevated Phenylalanine affect brain development and function. Newborns diagnosed with PKU should begin dietary treatment as soon as possible. Several commercial PKU formulas and various phenylalanine-restricted foods are available. Phenylalanine (and tyrosine) should be measured on a regular basis to follow dietary control.
      Because the diagnosis and therapy of PKU is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist and dietician. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Armstrong, M.D. and Tyler, F.H. Studies on phenylketonuria: I. Restriction phenylalanine intake in phenylketonuria. J Clin Invest 34:565, 1955.
      • Cockburn, F., Barwell, B.E., Brenton, D.P., et al. Recommendations on the dietary management of phenylketonuria. Arch Dis Child 68:426, 1993.
      • Koch, R., Moats, R., Guttler, F., Guldberg, P. and Nelson, M. Blood-brain phenylalanine relationships in persons with phenylketonuria. Pediatrics 106:1093-1096, 2000.
      • Scriver, C.R. and Kaufman, S. Hyperphenylalaninemia: Phenylalanine Hydroxylase Deficiency. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 77, pg. 1667-1724.
  • Tirosinemia
    Tirosinemia transitoria del neonato
    Tirosinemia Tipo I
    Tirosinemia Tipo II
    Tirosinemia Tipo III
    • Tyrosinemia

      Background

      Elevated blood Tyrosine levels are seen in three inherited disorders of Tyrosine metabolism. Tyrosinemia Type I was described in 1957 and is caused by deficiency of fumarylaceto- acetate hydrolase (FAH). While a predominance of patients are of French Canadian or Scandinavian decent, people from other ethnic groups have also been diagnosed. Tyrosinemia Type II, also known as Oculocutaneous Tyrosinemia, characteristically affects the cornea and skin, and is caused by deficiency of Tyrosine Aminotransferase, which acts at the first step in Tyrosine catabolism. Described in 1973, patients are predominately Italian, but other ethnic groups are represented as well. Tyrosinemia Type III is a rare disorder caused by deficiency of 4-hydroxyphenylpyruvate dioxygenase (4HPPD). Only a few patients have been described. In addition to the 3 inherited disorders, Transient Tyrosinemia
      of the Newborn is the major cause of tyrosine elevations detected on newborn screening.

      Clinical
      Tyrosinemia Type I usually presents in the first few months of life with progressive hepatorenal symptoms. Infants exhibit failure-to-thrive, hepatomegaly, liver dysfunction, together with metabolic acidosis and electrolyte disturbances due to renal tubular dysfunction (renal Fanconi syndrome). Diminished biosynthetic function of liver, which results in decreased clotting factors and a bleeding diathesis, often precedes large elevations in serum transaminases. Liver disease progresses to cirrhosis, hepatic failure, and death in undiagnosed patients. At any time, patients may develop acute hepatic crises with ascites, jaundice, and gastrointestinal bleeding. Neurologic episodes of painful paresthesias, weak- ness, paralysis, and respiratory insufficiency occur. There is a high risk for development of hepatic nodules and hepatocellular carcinoma. Most untreated patients die in infancy or early childhood. Patients with Type I disease do not have mental retardation.
      Oculocutaneous Tyrosinemia (Type II) is associated with corneal ulcers and painful hyperkeratotic plaques on the palms and soles. Mental retardation may be present in a minority of patients. Symptoms are thought to arise from accumulation of Tyrosine that crystallizes in cells and tissues.
      Patients with Tyrosinemia Type III develop neurologic problems, mental retardation and ataxia.
      Transient Tyrosinemia of the Newborn is chiefly a self-limited metabolic condition often found in premature infants. The disorder is due to immaturity of 4HPPD enzyme activity in the liver. It usually resolves spontaneously by two months of age.

      Testing
      Tyrosine is readily measured in a newborn screening dried blood spot using tandem mass spectrometry. Mild to moderate elevations of Tyrosine that decrease and become normal with follow-up testing is consistent with Transient Tyrosinemia of the Newborn. This transient elevation is a pattern associated with liver immaturity or dysfunction.
      Very high Tyrosine levels in the first screening specimen or high levels in a second specimen may point to an inherited metabolic defect. Workup of such patients includes measuring plasma amino acids and looking for succinylacetone on urine organic acid analysis. Elevations of plasma Tyrosine, often with methionine and perhaps a generalized aminoacidemia, are seen in Tyrosinemia Type I. The finding of succinylacetone in urine is pathognomonic for Type I disease. FAH activity is deficient in lymphocytes, erythrocytes, and liver tissue of Type I patients. Prenatal diagnosis for Type I can be accomplished by detecting succinylacetone in amniotic fluid and finding deficient FAH activity in chorionic villus cells or cultured amniocytes.
      Patients with Tyrosinemia Type II usually have an isolated elevation of Tyrosine only. Tyrosine Aminotransferase (Type II) activity can be measured in liver and kidney.
      Patients with Type III have 4-hydroxyphenylpyruvic and 4-hydroxyphenyllactic acids in their urine, which can be detected by organic acid analysis. 4HPPD enzyme activity is measured in liver.
      The genes for both Type I and II Tyrosinemia have been cloned and mutations identified. Mutation analysis can be informative for family counseling and prenatal testing.

      Treatment
      Patients with Transient Tyrosinemia can benefit from reducing the protein level in formula and usually do well on breast milk. Normalization of the Tyrosine level is hastened by dietary supplementation with vitamin C. Patients with Type I disease must be treated aggressively with dietary restriction of Tyrosine and Phenylalanine, and administration of 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). This drug inhibits 4HPPD and lowers Tyrosine metabolites that are responsible for much of the Type I morbidity. Liver transplantation is a cure for patients with Type I disease, providing normal FAH activity. Patients with Type II Tyrosinemia also require dietary restriction of Tyrosine and Phenylalanine, respond to vitamin A supplementation in clearing of the skin lesions and should be given a trial of pyridoxine phosphate. Patients with Type III benefit from dietary Tyrosine and Phenylalanine restriction.
      Because the diagnosis and therapy of Tyrosinemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      These disorders most often follow an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Cerone, R., Holme, E., Schiaffino, M.C., et al. Tyrosinemia type III: Diagnosis and ten- year follow-up. Acta Pediatrics 86:1013, 1997.
      • Kvittingen, E.A., Rootwelt, H., Brandtzaeg, P., et al. Hereditary Tyrosinemia type I. J Clinical Investigation 91:1816, 1993.
      • Mitchell, G.A., Larochelle, J., Lambert, M., et al. Neurologic crises in hereditary Tyrosinemia. New England J Medicine 322:432, 1990.
      • Mitchell, G.A., Grompe, M., Lambert, M., Tanguay, R.M. Hypertyrosinemia. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 79, pg. 1777 - 1805.
      • Sassa, S., Fujita, H. and Kappas, A. Succinylacetone and delta-aminolevulinic acid dehydratase in hereditary Tyrosinemia: Immunochemical study of the enzyme. J Pediatrics 86:84, 1990.
      • Shoemaker, L.R., Strife, C.F., Balistreri, W.F., and Ryckman, F.C. Rapid improvement in the renal tubular dysfunction associated with Tyrosinemia following hepatic replacement. J Pediatrics 89:251, 1992.

Altre analisi

  • Iperalimentazione
  • Malattia epatica
  • Somministrazione di Trigliceridi a catena media
  • Presenza di Anticoagulanti EDTA in campione ematico
  • Trattamento con Benzoato, Acido Pivalico, o Acido Valproico
  • Deficit di Ricaptazione Acido Carnitina
Malattie rilevabili mediante altre tecnologie

  • Deficit di Biotinidasi
    Deficit totale
    Deficit parziale
    • Biotinidase Deficiency

      Background

      Biotin is part of the vitamin B complex that functions as a cofactor for four carboxylase enzymes in man. When biotin is covalently linked to a key lysine residue in the carboxylases, the enzymes are activated. When the carboxylase enzymes are degraded, biotinyl-lysine is produced. Biotinidase subsequently hydrolyzes biotinyl-lysine to release free biotin, allowing it to be recycled and made available for activating newly synthesized carboxylase enzymes. In the absence of normal Biotinidase activity, the patient develops functional biotin deficiency and its clinical symptoms. Biotinidase deficiency is also known as late-onset multiple carboxylase deficiency, which distinguishes it from an earlier onset form caused by holocarboxylase synthetase deficiency.

      Clinical
      Newborns with Biotinidase Deficiency appear normal at birth. Biotin deficiency develops over time with clinical symptoms beginning at a few weeks to several years of age. If untreated, patients will develop metabolic ketoacidosis and organic aciduria. Symptoms include ataxia, hypotonia, developmental delay, conjunctivitis, skin rash and alopecia, seizures, hearing loss, breathing problems and optic atrophy. There is variable expression of these symptoms probably related to dietary biotin intake and the degree of residual Biotinidase enzyme activity. Partial Biotinidase Deficiency appears as a milder disease with most patients exhibiting chiefly the cutaneous symptoms, partiularly when the patient is under metabolic stress.

      Testing
      Newborn screening of Biotinidase activity from dried blood spots can identify affected patients shortly after birth. Both complete and partial deficiencies can be detected. The diagnosis is confirmed by measuring Biotinidase activity in serum or analyzing DNA to detect the most common genotypes. In clinically symptomatic cases, urine analysis by gas chromatograph/mass spectrometry will identify elevation of ß-hydroxyisovalerate, lactate, ß-methylcrotonylglycine, ß-hydroxypropionate and methyl citrate. These build up due to the inactivity of the four biotin requiring enzymes.

      Treatment
      Biotinidase deficiency is treated with oral biotin supplementation, which prevents development of the clinical symptoms.
      Because the diagnosis and therapy of metabolic disorders is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Wolf, B. Disorders of Biotin Metabolism. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 156, pg. 3935-3962.
      • Wolf, B., Grier, R.E., Allen, R.J., et al. Phenotypic variation in biotinidase deficiency. J Pediatrics 103:233, 1983.
      • Burton, B., Roach, E.S., Wolf, B. and Weissbecker, K.A. Sudden death associated with Biotinidase Deficiency. Pediatrics 79:482, 1987.
      • Lara, E.B., Sansaricq, C., Wolf, B., and Snyderman, S.E. Biotinidase Deficiency in black children. J Pediatrics 116:750, 1990.

  • Deficit di Glucosio-6-Fosfato Deidrogenasi
    • Glucose-6-Phosphate Dehydrogenase Deficiency

      Background

      Glucose-6-Phosphate Dehydrogenase (G6PD) functions throughout the body, but its deficiency is seen predominantly in its effects on the red blood cells. G6PD anchors the production of NADPH and glutathione to protect the body from oxidative insults. Erythrocytes are especially sensitive to oxidative damage. G6PD deficiency can result in neonatal jaundice and in life threatening reactions to several medications, foods and infections. G6PD deficiency affects 400 million people around the world and is the most common genetic enzyme deficiency in man. Population and epidemiology information point to G6PD deficiency as providing some resistance to malaria.

      Clinical
      Babies with G6PD deficiency appear normal at birth. They may experience neonatal jaundice and hemolysis that can be so serious as to cause neurologic damage or even death. Barring such severe complications in the newborn period, infants with G6PD deficiency generally experience normal growth and development. Exposure to certain antimalarial drugs and sulfonamides, infection stress (such as upper respiratory or GI infections), environmental agents (e.g. moth balls), and eating certain foods (e.g. fava beans), each of which impact the patient’s ability to handle oxidative reactions, can cause acute hemolytic anemia. Conversely, uniform testing for several years by the United States military found no significant adverse affects in G6PD deficient males with their health or military performance under proper care and avoidance.

      Testing
      Newborn screening for G6PD deficiency can be done by enzyme analysis or primary DNA screening. DNA analysis of the four most common mutations in the U.S. popula- tion will identify approximately 90% of individuals with G6PD Deficiency. Confirmatory testing using a quantitative assay should be performed for diagnosis of G6PD deficiency.

      Treatment
      Infants with G6PD deficiency may be at increased risk for pathological newborn jaundice and may warrant close monitoring for associated complications during the newborn period. Otherwise, treatment of G6PD deficiency is avoidance. For the infant, this means avoid- ance of several medications routinely prescribed for infections and illness. Strict atten- tion to the ingredients of prepared foods and restaurant meals is required as fava beans are a frequent addition to prepared foodstuffs. Patients should not be exposed to moth balls containing naphthalene. The adverse affects of infection on patients with G6PD Deficiency can be acute and life threatening. Over exertion from exercise and work leading to dehydration and hypoglycemia can precipitate clinical symptoms. As men- tioned above, patients mindful of these limitations can lead a normal life of exercise
      and choice of vocation.
      Because the diagnosis and therapy of this disorder is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric hema- tology specialist. It is recommended that parents travel with a letter of treatment guide- lines from the patient’s physician.

      Inheritance
      G6PD deficiency is inherited as an X-linked defect. Males with a G6PD deficiency mutation on their X chromosome are affected. Females with one G6PD deficiency mutation are carriers at a 50% risk to pass their G6PD deficiency X chromosome to a male child. As an X-linked disorder, G6PD deficiency would generally be thought to affect only males. However, females having a G6PD deficiency mutation on both of their X chromosomes also have clinical symptoms. Some carrier females have been reported to have symptoms. Therefore, all members of an identified family should have G6PD testing and genetic counseling. The risk for having an affected male pregnancy is one chance in two for a carrier female. G6PD deficiency is found in populations from areas of the world where malaria is prevalent.

      References:
      • Eshaghpour, E., Oski, F.A. and Williams, M. The relationship of erythrocyte glucose-6-phosphatae dehydrogenase deficiency to hyperbilirubineamia in Negro premature infants. J Pediatrics 70:595, 1967.
      • Kaplan, M., Rubaltelli, F.F., Hammerman, C., et al. Conjugated bilirubin in neonates with glucose-6-phosphatae dehydrogenase deficiency. J Pediatrics 128:695, 1996.
      • Luzzatto, L., Mehta, A. and Vulliamy, T. Glucose 6-Phosphate Dehydrogenase Deficiency. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 179, pg. 4517 - 4553.
      • Seidman, D.S., Shiloh, M., Stevenson, D.K., et al. Role of hemolysis in neonatal jaundice associated with glucose-6-phosphatae dehydrogenase deficiency. J Pediatr 127:804, 1995.
      • Valaes, T., Dokiadis, S. and Fessas, P.H. Acute hemolysis due to naphthalene inhalation. J Pediatrics 63:904, 1963

  • Iperplasia Adrenale Congenita
    Deficit di 21-Idrossilasi con perdita di sale
    Deficit di 21-Idrossilasi virilizzante semplice
    • Congenital Adrenal Hyperplasia

      Background

      The deficiency in one of the five enzymes required in the steroidogenic pathway for the biosynthesis of cortisol (hydrocortisone) results in a group of diseases known collectively as Congenital Adrenal Hyperplasia (CAH). The diseases are inherited as autosomal recessive disorders. As a result of impaired cortisol synthesis by the adrenal cortex, there is excessive secretion from the pituitary of adrenocorticotropic hormone (ACTH), or corticotrophin, which stimulates the adrenal cortex to synthesize and secrete more cortisol. ACTH stimulation causes diffuse hyperplasia of the adrenal gland, and usually the disease is recognized in infancy. Greater than 90% of cases of CAH are caused by reduced or absent activity of the steroid 21-hydroxylase enzyme, known as CYP21, or Classic CAH. This form of CAH presents in early infancy, early childhood or adoles- cence, depending upon the magnitude of the deficient enzyme activity. In severe cases, very low CYP21 activity causes low aldosterone secretion, salt loss and hypovolemia. Combined with hypotension and hypoglycemia from cortisol deficiency, this results in neonatal death during the first month of life if not recognized and adequately treated. Because the androgen synthetic pathway does not require CYP21 activity, there is excess androgen secretion, and virilization in the female fetus causing varying degrees of sexual ambiguity at birth.

      Clinical
      Male infants with CAH are normal at birth. In severe cases, salt wasting becomes evident within 7-10 days. By 2-3 weeks, failure to thrive, unexplained vomiting, poor feeding, hypovolemia and shock develop. The same sequence of symptoms develops in untreated female infants with CAH, but virilization with sexual ambiguity at birth leads to an early diagnosis of CAH and adequate treatment in many patients. However, complete female virulization presents at birth with the clinical phenotype of a male infant with bilateral cryptorchidism. In this presentation, the diagnosis of CAH may be missed and the incorrect sex assigned. Approximately 75% of children with classic CAH have the salt- losing CAH. Milder forms of CAH, the so-called Simple Virilizing CAH, have normal aldosterone secretion and present with virilization in infant girls, but the diagnosis in boys may not be evident until childhood when androgen excess causes sexual precocity without testicular enlargement. Late diagnosis is associated with markedly advanced skeletal maturation and accelerated linear growth initially, but early natural puberty and ultimately short stature. In the mildest form of CAH (attenuated, or late onset 21- hydroxylase deficiency), both cortisol and aldosterone secretion are normal, but at the expense of chronic mild-to-moderate excess production of androgenic hormones. These children present in childhood or adolescence with early onset of sexual hair (premature pubarche) and/or hirsuitism, oligomenorrhea and acne in females, or infertility in both sexes.

      Testing
      The immediate steroid precursor in classic CAH and the substrate for CYP21 is 17- hydroxyprogesterone (17-OHP). The measurement of 17-OHP in the newborn blood spot can discriminate infants with salt-wasting or Simple Virilizing CAH from non-affected infants. The newborn screening test usually does not detect attenuated or late onset non- classical CAH patients. When values exceed the normal range, 17-OHP analysis is repeated using organic extraction to remove interfering substances. The normal values for 17-OHP vary with birth weight and gestational age, and cutoffs should be adjusted accordingly.
      Serum confirmation tests include a repeat 17-OHP value, other steroid precursors to be certain that a mildly elevated 17-OHP is not caused by another form of CAH (e.g.,11-hydroxylase deficiency), and tests related to salt loss, such as serum Na and K, and renin activity. Confirmatory DNA testing is also available.

      Treatment
      Oral hydrocortisone in a physiologic replacement dose is the treatment of choice for CAH. The more potent glucocorticoids are contraindicated in the growing child and adolescent because of the difficulty in determining a physiologic versus pharmacologic dose. In children with salt-losing CAH, 9·-fluorohydrocortisone should maintain normal electrolyte balance without excessive natriuretic or glucocorticoid effects. Monitoring plasma 17-OHP and androstenedione levels, growth velocity, and an occasional bone age offer the basic tools for adequate, effective therapy.
      Because the tests to select and interpret at the time of initial diagnosis and during therapy are often complex, the pediatrician is advised to manage the patient with CAH in close collaboration with a consulting pediatric endocrine specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician, and the child should wear a bracelet or necklace for emergency identification that they are Cortisol deficient.

      Inheritance
      The forms of CAH are each inherited as autosomal recessive diseases. DNA carrier testing of families and prenatal diagnostic testing is available. Early identification of affected fetuses is important to avoid virilization of female infants. For families at risk for an affected child, oral dexamethasone is started as early in pregnancy as possible after pregnancy is diagnosed. If started before 6 weeks of fetal life, virilization is prevented or considerably limited. Once the sex of the fetus is determined, maternal therapy can be discontinued for a male fetus; once DNA tests of the female infant are known, maternal therapy can be discontinued for an unaffected female fetus.

      References:
      • Donohoue PA, Parker KL, Migeon CJ. Congenital Adrenal Hyperplasia. In, Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 8th edition, volume III, part 18, hormones, chapter 159, 2001:4077-4113.
      • MacLaughlin DT, Donohue PA. Sex determination and differentiation. N Engl J Med 2004;350(4):367-378.
      • Speiser PW, White PC. Congenital Adrenal Hyperplasia. N Engl J Med 2003;349(8):776-88.
      • Speiser PW, The genetics of steroid 21-hydroxylase deficiency. The Edocrinologist 2005;15(1):37-43.
      • Pang S. Newborn screening for congenital adrenal hyperplasia. Pediatr Ann 2003;32:516-523.
      • Working Group on Neonatal Screening of the European Society for Paediatric Endocrinology. Procedure for neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency Horm Res 2001;55:201-5.
      • Honour JW, Torresani T. Evaluation of neonatal screening for congenital adrenal hyperplasia 2. Horm Res 2001;55:206-11.
      • Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab ClinNorth Am 2001;30:15-30.
      • Steigert M, Schoenle EJ, Biason-Lauber A, Torresani T. High reliability of neonatal screening for congenital adrenal hyperplasia in Switzerland. J Clin Endocrinol Metab 2002;87:4106-10.
      • Joint LWPES/ESPE CAH Working Group. Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 2002;87(9):4048-53.
      • MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med 2004;350:367-78.

  • Fibrosi Cistica (non valido dopo 3 mesi di età)
    • Cystic Fibrosis

      Background

      Cystic Fibrosis (CF) was first recognized as a clinical entity in 1938. Its genetic nature and autosomal recessive inheritance pattern were described in 1946. In 1948, patients with CF were observed to lose excess salt in their sweat which led to development of the chloride sweat test (a diagnostic test still in use). Documentation of clinical manifesta- tions (pancreatic insufficiency and bacterial endobronchial infections) over the next 3 decades resulted in earlier diagnosis. In the 1980s, problems in epithelial chloride transport were linked to CF. In the late 1980s, elevations in pancreatic immunoreactive trypsinogen (IRT) in newborn blood were associated with CF. Finally, in 1989, DNA mutations associated with CF were identified on chromosome 7. The gene product was called the cystic fibrosis transmembrane conductance regulator (CFTR). During the 1990s, major insights were gained into the function of CFTR and the pathophysiology
      of CF. Dramatic improvements in early diagnosis and treatment have followed close behind.

      Clinical
      More than 1,600 mutations within the CFTR gene have been identified, and while some mutations are often associated with severe sequelae, even siblings with identical CF mutations may have dramatically different clinical courses. CF may affect the lung and upper respiratory tract, GI tract, pancreas, liver, sweat glands, and genitourinary tract. Nutritional abnormalities secondary to pancreatic insufficiency also have predictable consequences for growth and development. Organ dysfunction can occur at widely different ages and progression of the disease is highly variable. Although CF is a multi-system disease, lung involvement is ultimately the major cause of morbidity and mortality.

      Testing
      Initial screening of newborn bloodspots measures IRT. This pancreatic exocrine product is significantly elevated in over 90% of affected newborns. An elevated IRT should prompt additional genetic evaluation or sweat testing to confirm the diagnosis. If the patient being screened had meconium ileus or other bowel obstruction, IRT screening is not reliable and additional screening or diagnostic tests should be considered as indicated.

      Treatment
      Early diagnosis by newborn screening has allowed earlier combined anti-inflammatory and antibiotic therapies to combat upper respiratory infections and nutritional supple- mentation to avoid nutritional deficits. Dramatic progress has been made in improving quality of life for these newborns.
      Because the diagnosis and therapy of cystic fibrosis is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric pulmonologist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Welsh MJ, Ramsey BW, Accurso F, and Cutting GR, “Cystic Fibrosis” in The Metabolic and Molecular Bases of Inherited Disease, 8th edition, 2001. Scriver, Beaudet, et. al., McGraw-Hill, vol. III, Chapter 201, p.5121-5188.
      • Farrell PM, Kosorok MR, et.al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long term growth. Paediatrics 2001; 107: 1-13.
      • Siret D, Bretaudeau G, et al. Comparing the clinical evolution of cystic fibrosis screened neonatally to that of cystic fibrosis diagnosed from clinical symptoms: A 10 year retrospective study in a French region (Brittany). Pediatric Pulmonology 2003; 35: 342-349.

  • Ipotiroidismo congenito (non valido dopo 2 mesi di età)
    • Congenital Hypothyroidism

      Background

      The deficiency of thyroid hormones in the neonate has been known since antiquity. Most cases prior to the 20th century were caused by iodine deficiency. Though still a prevalent nutritional disease world wide, iodine deficiency rarely causes Congenital Hypothyroidism (CH) in western countries. Permanent neurodevelopmental deficits were known to occur when CH was not recognized and adequately treated by 2 to 3 months of postnatal age. Since the advent of newborn screening for CH in 1973, mental retardation as a consequence of CH has been virtually eradicated among affected infants detected by screening within the first 2-3 weeks of age. The incidence is approximately 1:4,000 in iodine sufficient populations. The etiology in 70 to 80% of the non-familial cases is unknown. Maternal hypothyroidism may adversely affect the fetus to rarely cause findings of CH, or to be associated with mildly decreased IQ outcomes when maternal hypothyroidism occurs during the first half of pregnancy despite normal
      fetal and neonatal thyroid function.

      Clinical
      In greater than 95% of newborn infants with CH, there are no symptoms or signs of CH when the diagnosis is suspected by newborn screening. During the first 2 to 6 months of life, an affected, untreated infant with moderate to severe hypothyroidism may have persistent hyperbilirubinemia, edema, an umbilical hernia, enlarged fontanelles, and an absent, hypoplastic, normal or enlarged thyroid gland; then gradually develops lethargy, poor feeding, macroglossia, hypothermia, constipation, dry and sallow skin, hoarse cry, circumoral pallor, and mottling of the skin.

      Testing
      There are two newborn screening tests performed in blood to detect hypothyroidism: Thyroid Stimulating Hormone (TSH) and Thyroxine (T4). When the thyroid gland is defective, known as Primary CH, TSH values are elevated and T4 values usually are low, although T4 values may be within the normal range in mild CH. Primary CH accounts for > 95% of cases. When there is defective hypothalamic or pituitary regulation of the thyroid gland, known as Central CH, T4 values are low; the TSH values may be low, normal, or mildly elevated.
      Serum confirmatory tests usually are limited to 2 tests: TSH and Free Thyroxine, or FT4 (the small fraction of T4 that is not bound to serum proteins and represents the more biologically relevant measurement). An elevated serum TSH test is diagnostic of primary CH, the most common form of CH. A low serum FT4 with a normal or low TSH is diagnostic of central CH. Infants with central CH should have other tests to evaluate hypothalamic-pituitary function since ACTH/Cortisol, Growth Hormone and/or Gonadotropin deficiencies are associated with hypoglycemia (typically within hours of birth), and in male neonates, hypogonadism (micropenis, small testicles, cryptorchidism).
      An image of the thyroid gland is often obtained by thyroid ultrasound and/or a radionuclide thyroid scan. These tests determine whether it is enlarged (goiter), absent (athyreosis), small (hypoplasia), or malformed and not in the normal location in the neck (ectopia). In these situations, the infant most often has a permanent form of primary CH. The thyroid gland may be normal in size and in the normal location in the neck (eutopic) on ultrasound, especially in familial causes of CH and transient CH.

      Treatment
      Treatment of hypothyroidism is relatively uncomplicated. As soon as tests to confirm the diagnosis of CH are obtained, Levothyroxine (L-thyroxine) should be started promptly. Central CH may require additional management based on associated findings. Evaluation and monitoring should be performed in conjunction with a pediatric endocrine specialist.

      Inheritance
      Approximately 15 to 20% of affected infants with CH have one of several inherited forms of CH collectively known as Familial Thyroid Dyshormonogenesis. These diseases are caused by mutations in the enzymes that are required for thyroid hormone synthesis, metabolism and end organ responsiveness, and are inherited as autosomal recessive traits. With similar inheritance patterns the mutations in genes for the synthesis of hypothalamic-pituitary hormones and their receptors infrequently cause CH. There are very rare mutations in genes that regulate thyroid and pituitary gland embryogenesis. The mode of inheritance is unknown. Though not a cause of CH, Thyroxine Binding Globulin (TBG) deficiency is caused by mutations in the gene that is required for the synthesis of this major plasma binding protein for T4. The mode of inheritance usually is X-linked, though autosomal recessive forms of TBG deficiency have been reported.

      References:
      • Refetoff S, Dumont JE, Vassart G. Thyroid disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 8th edition, volume III, part 18, hormones, chapter 158, 2001:4029-4075.
      • AAP Committee on Genetics; AAP Section on Endocrinology; and Public Health Committee of the American Thyroidism Association. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2005 (in press)
      • Fisher DA, Brown RS. Thyroid physiology in the perinatal period and during childhood. In: Braverman LE, Utiger RD, eds. Werner & Ingbar's The Thyroid. 8th ed. Philadelphia. Lippincott Williams & Wilkins: Part VIII, Chapter 81, 2000, pp 959-972.
      • Foley TP, Jr. Congenital hypothyroidism. In, Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid. 8th ed. Philadelphia: Lippincott Williams & Wilkins, Part VIII, Chapter 82, 2000, pp. 977-83.

  • Anemia falciforme e altre emoglobinopatie
    (Emoglobina S, S/C, S/Beta-Talassemia, C, & E)
    • Sickle Cell and Other Hemoglobinopathies

      Background

      Sickle cell disease was the first hemoglobinopathy to be linked to an inherited structural defect in the beta globin gene, and the first in which the point mutation resulting in the defect was identified and characterized. The scope of newborn screening for sickle cell disease, which began over 30 years ago, has evolved to include other hemoglobin diseases.
      Today, evaluation of newborns for hemoglobinopathies encompasses detection of point mutations which lead to structural defects in the alpha or beta globin chains (hemoglobino- pathies) such as sickle cell disease, and detection of defects in rate of production of either alpha or beta globin chains (thalassemias). Taken together, the inherited disorders of hemoglobin are some of the most common genetic disorders in the world. Because the different hemoglobin disorders coexist at a high frequency in many populations and because individuals may inherit more than one type, hemoglobin disorders present a complex series of clinical phenotypes.

      Clinical
      In the newborn period, a transition occurs from primarily fetal hemoglobin (HbF) production to adult hemoglobin (HbA). This transition temporarily masks symptoms of disease. As a result, diseases associated with red blood cell sickling (Hb S, C, S/C, S/O, and S/D diseases) usually present during the first or second year of life, although milder cases may present much later. Usual presenting features are failure to thrive, repeated infection in infancy, painful dactylitis, and pallor. At this stage typical hematologic findings are established. Heterozygotes (e.g., Sickle cell trait) are carriers with no clinical symptoms.
      Thalassemias present with a wide clinical diversity depending upon the degree to which the alpha or beta chains are being synthesized. In beta thalassemia major, or complete absence of beta chain production, newborns are asymptomatic. But as HbF declines, affected infants present with severe anemia (usually within the first two years). Beta thalassemia minor (partial synthesis) has a variable clinical course. In alpha thalassemia, absence of alpha chains is uniformly fatal to the newborn within days of birth, whereas partial production, as in hemoglobin H disease, may produce variable clinical symptoms.

      Testing
      Primary screening for hemoglobinopathies is by isoelectric focusing (IEF) of blood eluted from a dried blood spot. IEF separates the hemoglobins and identifies most common variants by band mobility. DNA probes which specifically identify HbS, HbC, HbE, HbO Arab and HbD are used to confirm abnormal findings by IEF. Reduced HbA and second tier DNA testing for common beta thalassemia mutations help to identify beta thalas- semias. The presence of Hb Barts and/or Hb H in the IEF pattern detects alpha thalassemia.

      Treatment
      Apart from bone marrow transplantation, there is no curative treatment for hemoglobin disorders. Management for newborns affected with sickling diseases typically involves oral penicillin given daily and maintained throughout childhood, and vaccination against Pneumococcus, Meningococcus, and H influenzae.
      Because the diagnosis and therapy of this disorder is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric hematology specialist.

      Inheritance
      Structurally abnormal hemoglobins follow autosomal recessive inheritance. Most abnormal hemoglobins cause little or no clinical manifestations in heterozygotes (one copy of the mutation), including Hb S, C, D, E, and O Arab. Because the production of alpha chains is controlled by four gene loci (two on each pair of chromosomes), each gene controls only about 25% of total alpha chain production, and hemoglobinopathies due to alpha chain abnormalities are uncommon compared to beta chain abnormalities.

      References:
      • Weatherall DJ, Clegg JB, Higgs DR and Wood WG. “The Hemoglobinopathies” in The Metabolic and Molecular Bases of Inherited Disease, 8th edition, 2001. Scriver, Beaudet, et al. McGraw-Hill, Vol III, Chapter 181, p. 4571-4626.

  • Galattosemia
    Deficit di Galattochinasi
    Deficit di Galattosio-1-Fosfato Uridiltransferasi
    Deficit di Galattosio-4-Epimerasi
    • Galactosemia

      Background

      Individuals intolerant to ingested galactose were described as early as 1908, but it wasn’t until 1935 that elimination of galactose from the diet was shown to reverse the acute toxicity syndrome associated with galactosemia. The Leloir pathway, the main pathway of galactose metabolism, was elucidated in the early 1950s. In 1955, the accumulation of galactose-1-phosphate in red blood cells of infants with impaired galactose metabolism was demonstrated. Methods were subsequently developed to measure galactose-1- phosphate uridyl transferase (GALT) and galactose-1-phosphate in newborn blood spots.
      GALT deficiency accounts for about 95% of galactosemias. Although many mutations in the GALT gene have been documented, most cases of GALT deficiency are accounted for by a few high frequency mutations. In about 5% of cases of galactosemia, the metabolic defect is in galactokinase (GALK), and very rarely, the defect is found to be in uridyl diphosphate galactose epimerase (GALE).

      Clinical
      GALT deficiency most often presents as a life threatening illness within the first two weeks after birth. Poor feeding, poor weight gain, vomiting and diarrhea, lethargy, and hypotonia are initial symptoms. On physical examination, infants are jaundiced with hepatomegaly, may have a full fontanelle and show prolonged bleeding after venous or arterial sampling. Cataracts are often present. Lab tests revealing liver disease, renal tubular dysfunction, and hematologic abnormalities are common. Hemolytic anemia and septicemia may occur. Long-term complications include impaired neuropsychological development and late neurologic complications. Ovarian failure due to prenatal toxic effects of galactosemia is common in females and not reversible.
      In GALK deficiency, the only consistent clinical finding is cataracts. In GALE deficiency, patients are, with very rare exceptions, asymptomatic, with normal growth and development.

      Testing
      Screening for galactosemia includes testing for elevated total galactose (galactose plus galactose-1-phosphate), and measuring GALT enzyme activity. Elevated total galactose and/or reduced GALT activity should trigger additional evaluation of the patient. The galactose level can be fractionated into free galactose and galactose-1-phosphate, and DNA analysis for the common mutations associated with GALT deficiency can be performed on the initial blood spot specimen. This combined approach quickly reveals from a single blood spot whether the galactosemia is a GALT deficiency, or is due to GALK or GALE deficiency. Confirmatory testing usually includes serum studies of galactose and the associated enzyme activity to characterize the patient's phenotype.

      Treatment
      Immediate exclusion of dietary galactose (breast feeding, cow’s milk) should be instituted at the first suspicion of galactosemia. Infant soy formulas are recommended unless there is significant liver disease. For the newborn who is seriously ill at the time of diagnosis, supportive care may include treatment with vitamin K and fresh-frozen plasma to correct clotting abnormalities. Gram-negative sepsis should be assumed and appropriate IV antibiotics given.
      Because the diagnosis and therapy of this disorder is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

      Inheritance
      This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

      References:
      • Holton JB, Walter JH, and Tyfield LA. “Galactosemia” in The Metabolic and Molecular Bases of Inherited Disease, 8th edition, 2001. Scriver, Beaudet, et.al., McGraw-Hill , vol I, chapter 72, p. 1553-1587.
  • Immunodeficienze combinate gravi (SCID)

    • Background
      Severe Combined Immunodeficiency (SCID) is a group of disorders characterized by the absence of both humoral and cellular immunity. Infants with SCID die of infections by age 2 years unless immunity is reconstituted by treatment. The defining characteristic for SCID is always a severe defect in T cell production and function, with defects in B-lymphocytes as a primary or secondary problem and, in some genetic types, in NK cell production as well. SCID is also commonly known as the “bubble boy” disease.

      Clinical
      Infants generally have a normal physical examination result before the onset of infection. The pathophysiology and molecular biology vary among different forms of SCID, however, the lack of T-cell and B-cell function is the common endpoint in all forms of SCID. Lymphopenia usually occurs from the absence of T cell, and sometimes from the absence of natural killer cells. Functional antibodies are decrease or absent. Infections are usually serious, and may include pneumonia, meningitis or bloodstream infections with average age at the onset of symptoms at 2 months.

      Testing
      T-cell Receptor Excision circles (TRECs) are circular DNA fragments generated during T-cell receptor rearrangement. In healthy neonates, TRECs are made in large numbers, while in infants with SCID they are barely detectable. Real-time quantitative PCR assay is used to determine the TREC copy number in blood, which can be used to distinguish T-cell lymphopenic SCID infants from healthy babies. However, low TRECs copy numbers can also be the results of other immunodeficiency, such as DiGeorge Syndrome, and sometimes as a result of the use of Immunosuppression drugs. Confirmatory tests are needed for the diagnosis of SCID and for the determination of the form of SCID.

      Treatment
      Infections are treated with specific antibiotic, antifungal, and antiviral agents and administration of intravenous immunoglobulin. Restoration of a functional immune system is essential. The preferred treatment is bone marrow/stem cell transplantation. Early detection and treatment can result in markedly improved survival rates. Enzyme replacement therapy is available for adenosine deaminase deficiency (a form of SCID). Gene therapy is still in the experimental phase.

      Inheritance
      SCID occurs in approximately 1 in 50,000-100,000 live births. Over 10 different genetic defects have been identified that account for SCID in humans. The most common type is linked to the X chromosome, making this form affect only males. This X-linked form accounts for approximately 50% of SCID cases. Other forms of SCID usually follow an autosomal recessive inheritance pattern or are the result of spontaneous mutations. Approximately 25% of the patients with an autosomal recessive SCID are JAK3 deficient, and 40% are adenosine deaminase deficient.

Fonte:

PerkinElmer Genetics, StepOne® Newborn Screening - Handbook of Metabolic and Other Inherited Disorders, 2008
Page created on: 21/03/2011
Last modified on: 03/09/2012
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