Metabolic Disorders Of Branched Chain Amino Acids

Valine, leucine and isoleucine are branched chain amino acids; an enzyme deficiency can affect their metabolism and lead to an accumulation of organic acids with a severe metabolic acidosis.

There are many disorders of branched-chain amino acid metabolism (see table) and many other amino acid and organic acid metabolism disorders. See also approach in a patient with suspected congenital metabolic disorder

Valine, leucine and isoleucine are branched chain amino acids; an enzyme deficiency can affect their metabolism and lead to an accumulation of organic acids with a severe metabolic acidosis. There are many disorders of branched-chain amino acid metabolism (see table) and many other amino acid and organic acid metabolism disorders. See also procedure in a patient suspected of having a congenital metabolic disorder, congenital metabolic disorders of branched chain amino acids disease (OMIM number) defects proteins or enzymes defective gene or genes (chromosomal location) Remarks maple syrup urine disease or branched ketoaciduria (248600) Branched ?-keto acid dehydrogenase complex (BCKD) Biochemistry profile: Elevated valine, leucine, isoleucine and alloisoleucine in blood Clinical characteristics: Molecular forms do not correlate with Klinis Chen shapes, except that a high percentage of Type II mutations is associated with a thiamine-responsiveness. In the classic form: hypertension, seizures, coma, death At the intermediate form: (, infection such as fever.) Symptoms only stress When: mental retardation, neurological symptoms, the full picture is obtained for increased stress In the mean shape thiamine-sensitive form are the symptoms similar to the mild to moderate form in the E3 subunit deficiency form of the symptoms are similar to the mean shape, but they are accompanied by severe lactic acidosis because E3 is needed for pyruvate dehydrogenase and ?-ketoglutarate Acute treatment: peritoneal dialysis, hemodialysis, or both; strict diet control including high doses of glucose, insulin and special hyperalimentation; strict observation in terms of cerebral edema and acute pancreatitis, chronic treatment: prevention of branched-chain amino acid in the food intake, thiamine supplementation as needed contingency plan for an acute disease which can cause a metabolic crisis liver transplantation type IA BCKD E1alpha component BCKDHA (19q13) † type IB BCKD E1?- component BCKDHB (6p22-p21) † type II BCKD E2 component DBT (1p31) † Type III BCKD E3 component DLD (7q31-q32) † propionic acidemia (606054) propionyl-CoA carboxylase biochemical profile: Elevated glycine in the blood, methylcitrate, 3-hydroxypropionate, Propionylglyzin and Tiglylglyzin in urine Clinical features: hypotension, vomiting, lethargy, coma, ketoacidosis, hypoglycemia, hyperammonemia, bone marrow suppression, growth retardation, mental retardation, physical disability treatment: During the acute incidents, high-dose glucose and increased fluid intake, protein restriction In extreme hyperammonemia hemodialysis or peritoneal dialysis may be required. For long-term treatment, a controlled intake of threonine, valine, isoleucine, and methionine is displayed; Carnitine supplementation; Biotin in patients who responded to it (s. Also multiple carboxylase deficiency and biotinidase, below) Periodic courses of antibiotics for the reduction of propionic acid exposure to intestinal bacteria emergency plan for an acute condition that can trigger a metabolic crisis type I ? subunit PCCA (13q32) † type II ?-subunit PCCB (3q21-q22) † multiple Pyruvatcarboxylasemangel (253270) holocarboxylase synthetase HLCS (21q22.1) † Biochemical profile : As with propionic acidemia, but in addition increased lactate and 3-Methycrotonatester Clinical features rash, hair loss, convulsions, hypotension, developmental delay, ketoacidosis, defective T and B cell immunity, hearing loss treatment: biotin, carnitine biotinidase (253260) biotinidase BTD (3p25) † Similar multiple carboxylase deficiency methylmalonic (mut deficiencies; 251000) methylmalonyl CoA mutase Mut0 (no enzyme activity) parent (some residual enzyme activity) MUT (6p21) † biochemical profile: Elevated glycine in the blood, increased methylmalonate, 3-hydroxypropionate, methylcitrate and Tiglylglyzin in urine Clinical features: hypotension, vomiting, lethargy, coma, ketoacidosis, hypoglycemia, hyperammonemia, bone marrow suppression, growth retardation, mental retardation and physical disability treatment: during the acute incidents, high-dose glucose, increased fluid intake and protein restriction Close monitoring of stroke, kidney failure and acute pancreatitis in extreme hyperammonemia are possibly hemodialysis or peritoneal dialysis requires long-term treatment: controlled intake of threonine, valine, isoleucine and methionine; Carnitine, vitamin B12 for patients with mut-type periodic courses of antibiotics for the reduction of propionic acid exposure to intestinal bacteria emergency plan for an acute condition that can trigger a metabolic crisis methylmalonic (CBLA; 251100) Mitochondrial cobalamin translocase MMAA (4q31.1- q31.2) † biochemical profile: Similar to the methylmalonic, due to the Mutasemangels Clinical features: Similar to the methylmalonic because of Mutasemangels treatment: responsive to a high dose of hydroxycobalamin at methylmalonic (CBLB; 251110) ATP: cob (1) alamin-adenosyl-transferase MMMB (12q24) † biochemical profile: Similar to the methylmalonic, due to the Mutasemangels Clinical features: Similar to the methylmalonic because of Mutasemangels treatment: responsive to a high dose of hydroxycobalamin at methylmalonic-homocystinuria-megaloblastic anemia (CBLC; 277,400) methylmalonyl-CoA mutase, and methylenetetrahydrofolate: homocysteine ??methyltransferase genetically heterogeneous biochemical profile: Similar to methylmalonic CBLA and CBLB, but additionally Homocystinemie, homocystinuria, low and high methionine cystathionine; normal serum cobalamin Clinical features: Similar to CBLA and CBLB, but additionally megaloblastic anemia Treatment: avoidance of protein in the food intake, high doses of hydroxycobalamin methylmalonic-homocystinuria-megaloblastic anemia (cblD; 277410) Not determined genetically heterogeneous Similarly, the methylmalonic CBLC methylmalonic-homocystinuria-megaloblastic anemia ( CBLF; 277380) Defective lysosomal release of cobalamin genetically heterogeneous Similarly, the methylmalonic CBLC Methylmalonic-homocystinuria-megaloblastic (intrinsic factor deficiency; 261000) intrinsic factor GIF (11q13) † Like the methylmalonic CBLC methylmalonic-homocystinuria-megaloblastic (Imerslund-Gräsbeck syndrome; 261100) cubilin (intrinsic factor receptor) CUBN (10p12.1) † Like the methylmalonic CBLC methylmalonic-Homocystinurie- megaloblastic anemia (transcobalamin II deficiency; 275,350) transcobalamin II TC2 (22q11.2) † Similarly, the methylmalonic CBLC Methylmalonischer semialdehyde dehydrogenase deficiency with mild methylmalonic (603178) methylmalonic semialdehyde (s. also diseases of the ?- and ?-amino acids, below) ALDH6A1 (14q24.1) Biochemical profile: Moderate methylmalonate in urine Clinical features: developmental delay, seizures Treatment: There is no effective therapy. Methylmalonic-homocystinuria (cblH; 606,169) Not determined genetically heterogeneous Similarly, the methylmalonic CBLA isovaleric (243500) isovaleryl-CoA dehydrogenase IVD (15q14-q15) † biochemical profile: isovaleryl glycine, 3-Hydroxyisovalerate Clinical characteristics: Characteristic Schweißfußgeruch, vomiting, lethargy, acidosis, mental retardation, bone marrow suppression, hypoglycemia, ketoacidosis, hyperammonemia, neonatal treatment: controlled supply of leucine, glycine, carnitine 3-methylcrotonyl-CoA carboxylase deficiency 3-methylcrotonyl CoA carboxylase biochemical profile: Elevated 3-Hydroxyisovalerat, 3-methylcrontylglyzin and 3-Hydroxyisovalerylcarnitin Clinical features: episodic vomiting, acidosis, hypoglycemia, hypotension, mental retardation, coma and sometimes symptomatic mental retardation treatment: Control leucine intake (s , also multiple carboxylase deficiency and biotinidase, supra) Type I (210200) ?-subunit MCCC1 (3q25-q27) † type II (210210) ?-subunit MCCC2 (5q12-q13) † 3-Methylglutaconische aciduria type I (250950) 3 -Methylglutaconyl-CoA hydratase AUH (9) † biochemical profile: Elevated 3-Methylglutaconat and 3-Hydroxyisolvalerat in urine Clinical features: acidosis, hypotension, hepatomegaly, slowing of speech treatment: carnitine; Use of leucine restriction unclear 3-Methylglutaconische aciduria type II (Barth syndrome; 302060) Tafazzin TAZ (Xq28) † biochemical profile: Elevated 3-methylglutaconat and 3-methylglutarate in urine Clinical features: myopathy, cardiomyopathy, mitochondrial abnormality, neutropenia, developmental delay treatment: pantothenic acid 3-Methylglutaconische aciduria type III (Costeff -Optikusatrophie; 258501) Not determined OPA3 (19q13) † biochemical profile: Elevated 3-methylglutaconat and 3-methylglutarate in urine Clinical features: Optikusatrop here, ataxia, spasticity, chorea political movements Treatment: There is no effective therapy. 3-Methylglutaconische aciduria type IV (250951) Not determined Not determined biochemical profile: Elevated 3-methylglutaconat and 3-methylglutarate in urine Clinical features: Various forms of expression, growth and developmental delay, hypotension, seizures, Optic Atrophy, Deafness, cardiomyopathy, acidosis treatment: There is no effective therapy. 3-hydroxy-3-methyl-CoA lyase deficiency (246450) 3-Hydroxy-3-methyl-CoA lyase HMGCL (1pter-p33) † biochemical profile: Elevated 3-hydroxy-3-methylglutarate in urine, 3- Methylglutaconat and 3-Hydroxyisovalerat; increased 3-Methylglutarylcarnitin in blood Clinical features: Reye’s syndrome, vomiting, hypotension, acidosis, hypoglycemia, lethargy, hyperammonemia without ketosis treatment: Restriction of leucine incorporation, control of hypoglycemia Mevalonazidurie (251170, 260920) mevalonate kinase MVK (12q24) † Biochemistry profile: Increased creatine kinase, transaminase, leukotriene and mevalonic acid in the urine; reduced cholesterol Clinical features: In the classic form of short stature, hypotonia, developmental delay, facial dysmorphism, cataract, vomiting, diarrhea, hepatosplenomegaly, joint pain, lymph nodes, brain and cerebellar atrophy, anemia, thrombocytopenia, early death In the Hyper IgD form of recurrent bouts of fever, vomiting , diarrhea, joint pain, abdominal pain, rash, splenomegaly, elevated serum IgD and IgA levels treatment: No effective treatment; Corticosteroids may be helpful Mitochondrial acetoacetyl-CoA thiolase deficiency during acute attacks (607,809) Acetyl-CoA thiolase ACAT1 (11q22.3-a23.1) † biochemical profile: Elevated 2-methyl-3-hydroxy and 2-methyl acetoacetate in Urine; increased Tiglylglyzin in blood Clinical features: incidents with ketoacidosis, vomiting, diarrhea, coma, mental retardation treatment: low protein diet, controlled administration of isoleucine isobutyryl-CoA dehydrogenase isobutyryl-CoA dehydrogenase Not determined biochemical profile: Elevated C-4 carnitine , degraded free carnitine Clinical features: anemia, cardiomyopathy treatment: carnitine 3-hydroxyisobutyryl-CoA Deacylasemangel (methacrylic acid aciduria; 250620) 3-hydroxyisobutyryl-CoA deacylase Not determined biochemical profile: Elevated S- (2-Carboxypiperidin ropyl) -Zystein and S- (2-carboxypropyl) -Zysteamin Clinical features: growth and developmental delay, facial dysmorphism function vertebral anomaly, CNS malformations, death treatment: There is no effective therapy. 3-Hydroxyisobutyrische aciduria (236795) 3-hydroxyisobutyrate dehydrogenase hibadh (chromosomal location not determined) Biochemistry profile: Elevated 3-hydroxyisobutyrate in the urine; in 50% of patients increased lactate Clinical features: facial dysmorphism, CNS malformations, hypotension, ketoacidosis treatment: low-protein diet, carnitine 2-Methylbutyrylglyzinurie Biochemistry (600301) Short branched acyl-CoA dehydrogenase ACADSB (10q25-q26) † Profile : Increased 2-Methylbutyrulglyzin in urine Clinical features: hypotension, muscle atrophy, lethargy, hypoglycemia, hypothermia treatment: There is no effective therapy. Ethylmalonic encephalopathy (602473) mitochondrial protein undetermined function ETHE1 (19q13.32) † biochemical profile: Elevated ethylmalonic, and methylsuccinic acid in the urine, increased serum lactate Clinical features: retinopathy, acrocyanosis, diarrhea, petechiae, developmental delay, mental retardation, extrapyramidal symptoms, ataxia, seizures, hyperintense lesions in the basal ganglia treatment: There is no effective therapy. Malonische aciduria (248360) malonyl-CoA decarboxylase mlycd (16q24) † biochemical profile: Increased lactate, malonate, methylmalonate and Malonylcarnitin Clinical features: hypotension, developmental delay, hypoglycemia, acidosis Treatment: No effective treatment; low-fat, high-carbohydrate diet carnitine may be in some patients helpful Hypervalinämie or Hyperisoleucine-Hyperleucinämie (277100) Mitochondrial branched aminotransferase 2 BCAT2 (19q13) Biochemistry profile: Elevated valine in urine and serum Clinical features: growth retardation treatment: controlled delivery of valine The branched chain amino acids valine , leucine and isoleucine. † The gene was identified and the molecular basis has been elucidated. OMIM = Online Mendelian Inheritance in Man (see OMIM database). Maple syrup syndrome This disorder belongs to a group of autosomal recessive disorders caused by the lack of one or more subunits of the dehydrogenase. It activates the second step of the branched-chain amino acid catabolism. Although the disease is rare, the incidence is (1 in 200 births) significantly in the population of Amish and Mennonites. The clinical signs include an odor of body fluids, especially of cerumen, which smells strongly of maple syrup. The children are very sick in the first days of life, suffering from vomiting and lethargy, which go untreated in seizures, coma and death. In patients with milder forms, symptoms show only under stress (eg. As infection, surgery). Biochemical findings are a strong ketosis and acidemia. The diagnosis of Leuzinose is provided by the increased serum levels of branched-chain amino acids (especially leucine). (See also check on suspicion of inherited metabolic disorders.) The acute therapy of Leuzinose includes a peritoneal dialysis or hemodialysis, an i.v. Hydrogenation and Food (einschl.Proteinrestriktion and high doses of dextrose). Patients should be closely monitored for cerebral edema and acute pancreatitis. The long-term treatment consists in a restriction of the orally supplied branched-chain amino acids; However, small quantities are needed for normal metabolic function. Thiamine is the cofactor for the decarboxylase, and some patients respond favorably to high doses of thiamine (up to 200 mg p.o. once daily). An emergency plan as acute illness that can trigger a metabolic crisis are treated should be present. A liver transplant affects curative. The third step in isovaleric acidemia Isoleucinstoffwechsel is the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA, a dehydrogenase step. A lack of this dehydrogenase leads to isovaleric, also known as the “sweaty foot” syndrome, because the accumulation of isovaleric leads to a sweat smell. The clinical manifestations of acute form (bad eating habits, vomiting and shortness of breath) can be seen in the first few days, when the babies develop a strong anion gap metabolic acidosis with, hypoglycemia, and hyperammonemia. A bone marrow suppression frequently occurs. A chronic intermittent form can for months and years do not exist. The diagnosis of isovaleric is delivered in the blood or urine due to increased levels of isovaleric acid and its metabolites. (See also check on suspicion of inherited metabolic disorders.) The acute treatment of isovaleric consists of i.v. Hydration and nutrition (incl. High-dose dextrose) and measures to increase the excretion of isovaleric by conjugation with glycine. If these measures are not sufficient, exchange transfusion and peritoneal dialysis may be necessary. The long-term treatment is the restriction of Isoleucinzufuhr and a supplementary dose of glycine and carnitine. The prognosis is excellent with treatment. Propionic acidemia A lack of propionyl-CoA carboxylase, an enzyme which is responsible for the metabolism of the propionic acid to methylmalonate, causes an accumulation of propionic acid. The disease begins in the first days of life with poor eating habits, vomiting and shortness of breath when patients develop a strong anion gap metabolic acidosis with, hypoglycemia, and hyperammonemia. Seizures may occur and a bone marrow is often found. Physiological stress can trigger repeated attacks. The survivors can tubular nephropathy, develop mental retardation and other neurological pathologies. The propionic acidemia can also serve as part of a carboxylase – be seen or Biotinidasemangels – biotin. The diagnosis of propionic acidemia is the increased levels of Propionsäuremetabolite, including methylcitrate and -tiglat and, provided their glycine conjugates in the blood and urine, and by measuring the propionyl-CoA carboxylase activity in the leukocytes or cultured fibroblasts bestätigt.p.p1 { margin: 0.0px 0.0px 0.0px 0.0px; font: Arial 13.0px; color: # 6a6a6a; -webkit-text-stroke: # 6a6a6a} span.s1 {font-kerning: none} (See also check on suspicion of inherited metabolic disorders.) The acute treatment of propionic acidemia consists in i.v. Hydrogenation (incl. High-dose dextrose) and Food, the administration of carnitine can be helpful. If these measures are not sufficient, peritoneal dialysis or hemodialysis should be initiated. The long-term treatment of a Propionazedämie consists in a restriction of the precursor amino acids and odd fatty acids and a continuation of Karnitinsupplementierung. A few patients respond to high doses of biotin, because it is the cofactor of propionyl-CoA carboxylase and others. The temporary administration of antibiotics should be considered for reducing Propionsäurebelastung due to intestinal bacteria. An emergency plan as acute illness that can trigger a metabolic crisis are treated should be present. Methylmalonic This disorder is caused by a lack of CoA mutase which the methylmalonyl-CoA is converted (a product of propionyl-CoA carboxylation) in succinyl-CoA. Cofactor is adenosylcobalamine, a metabolite of vitamin B12. A lack of it can also be a methylmalonic (and homocystinuria and megaloblastic anemia) cause. Methylmalonic acid accumulates in itself. The onset of the disease, the onset of clinical manifestations and treatment are similar to those of propionic acidemia, except that helps some patients instead of biotin cobalamin.

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