Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis.
There are numerous disorders of branched-chain amino acid metabolism (see the table) as well as many other amino acid and organic acid metabolism disorders. See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism.
Branched-Chain Amino Acid* Metabolism Disorders
Disease (OMIM Number) | Defective Proteins or Enzymes | Comments |
|---|---|---|
Maple syrup urine disease, or branched-chain ketoaciduria (248600†) | Branched-chain alpha-ketoacid dehydrogenase complex (BCKD) | Biochemical profile: Elevated plasma valine, leucine, isoleucine, and alloisoleucine Clinical features (molecular forms do not correlate with clinical forms except that a high percentage of type II mutations are associated with thiamin responsiveness): In classic form, hypertonia, seizures, coma, death In intermediate form, intellectual disability, neurologic symptoms, full-blown picture developing with stress In intermittent form, symptoms only with stress (eg, fever, infection) In thiamin-responsive form, features similar to mild intermediate form In E3 subunit deficient form, features similar to intermediate form but accompanied by severe lactic acidosis because E3 is needed for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase Acute treatment: Chronic treatment: Dietary branched-chain amino acid restriction, thiamin supplementation as needed Emergency plan for acute illness, which may provoke a metabolic crisis Liver transplantation |
Type IA | BCKD E1alpha component | |
Type IB | BCKD E1beta component | |
Type II | BCKD E2 component | |
Type III | BCKD E3 component | |
Propionic acidemia (606054†) | Propionyl-CoA carboxylase | Biochemical profile: Clinical features: Hypotonia, vomiting, lethargy, coma, ketoacidosis, hypoglycemia, hyperammonemia, bone marrow suppression, growth delay, intellectual disability, physical disability Treatment: During acute episodes, high-dose glucose and aggressive fluid resuscitation, protein restriction For extreme hyperammonemia, may need hemodialysis or peritoneal dialysis. Intermittent courses of antibiotics considered for reduction of propionic acid load from intestinal bacteria Emergency plan for acute illness, which may provoke a metabolic crisis |
Type I | Alpha-subunit | |
Type II | Beta-subunit | |
Multiple carboxylase deficiency (253270†) | Holocarboxylase synthetase | Biochemical profile: Same as for propionic acidemia but also elevated lactate and 3-methylcrotonate Clinical features: Rash, alopecia, seizures, hypotonia, developmental delay, ketoacidosis, defective T- and B-cell immunity, hearing loss Treatment: |
Biotinidase deficiency (253260†) | Biotinidase | Clinical features similar to multiple carboxylase deficiency Treatment: |
Methylmalonic acidemia (mut defects; 251000†) | Methylmalonyl-CoA mutase Mut0 (no enzyme activity) Mut- (some residual enzyme activity) | Biochemical profile: Clinical features: Hypotonia, vomiting, lethargy, coma, ketoacidosis, hypoglycemia, hyperammonemia, bone marrow suppression, growth delay, intellectual disability, and physical disability Treatment: During acute episodes, high-dose glucose, aggressive fluid resuscitation, and protein restriction Close monitoring for stroke, renal failure, and acute pancreatitis For extreme hyperammonemia, may need hemodialysis or peritoneal dialysis For long-term management, controlled intake of threonine, valine, isoleucine, and methionine; carnitine supplementation; vitamin B12 for patients with mut- type Intermittent courses of antibiotics considered for reduction of propionic acid load from intestinal bacteria Emergency plan for acute illness, which may provoke a metabolic crisis |
Methylmalonic acidemia (cblA; 251100†) | Mitochondrial cobalamin translocase | Biochemical profile: Similar to methylmalonic acidemia due to mutase deficiency Clinical features: Similar to methylmalonic acidemia due to mutase deficiency Treatment: Responsive to high-dose hydroxycobalamin |
Methylmalonic acidemia (cblB; 251110†) | ATP:cob(I)alamin adenosyl transferase | Biochemical profile: Similar to methylmalonic acidemia due to mutase deficiency Clinical features: Similar to methylmalonic acidemia due to mutase deficiency Treatment: Responsive to high-dose hydroxycobalamin |
Methylmalonic acidemia-homocystinuria (cblC; 277400†) | Methylmalonyl-CoA mutase and methionine synthase | Biochemical profile: Similar to methylmalonic acidemia cblA and cblB but also homocystinemia, homocystinuria, low methionine, and high cystathionine; normal serum cobalamin Clinical features: Similar to cblA and cblB but also megaloblastic anemia Treatment: Protein restriction, high-dose hydroxycobalamin |
Methylmalonic aciduria and homocystinuria (cblD; 277410†) | Methylmalonyl-CoA mutase and methionine synthase | Similar to methylmalonic aciduria and homocystinuria cblC |
Methylmalonic aciduria and homocystinuria (cblF; 277380†) | Defective lysosomal release of cobalamin | Similar to methylmalonic aciduria and homocystinuria cblC |
Intrinsic factor deficiency (261000†) | Intrinsic factor | Megaloblastic anemia |
Megaloblastic anemia 1 (Imerslund-Grasbeck syndrome; 261100†) | Cubilin (intrinsic factor receptor) | Megaloblastic anemia |
Transcobalamin II deficiency (275350†) | Transcobalamin II | Methylmalonic aciduria, megaloblastic anemia, and pancytopenia |
Methylmalonate semialdehyde dehydrogenase deficiency with mild methylmalonic acidemia (603178†) | Methylmalonate semialdehyde dehydrogenase (see also disorders of beta- and gamma-amino acids, below) | Biochemical profile: Moderate urine methylmalonate Clinical features: Developmental delay, seizures Treatment: No effective treatment |
Isovaleric acidemia (243500†) | Isovaleryl-CoA dehydrogenase | Biochemical profile: Clinical features: Characteristic sweaty feet odor, vomiting, lethargy, acidosis, intellectual disability, bone marrow suppression, hypoglycemia; ketoacidosis, hyperammonemia, neonatal death Treatment: |
3-Methylcrotonyl-CoA carboxylase deficiency | 3-Methylcrotonyl CoA carboxylase | Biochemical profile: Elevated 3-hydroxyisovalerate, 3-methylcrontylglycine, and 3-hydroxyisovalerylcarnitine Clinical features: Episodic vomiting, acidosis, hypoglycemia, hypotonia, intellectual disability, coma; sometimes asymptomatic intellectual disability Treatment: Controlled leucine intake (See also Multiple carboxylase deficiency and Biotinidase deficiency, above) |
Type I (210200†) | Alpha-subunit | |
Type II (210210†) | Beta-subunit | |
3-Methylglutaconic aciduria type I (250950†) | 3-Methylglutaconyl-CoA hydratase | Biochemical profile: Elevated urine 3-methylglutaconate and 3-hydroxyisolvalerate Clinical features: Acidosis, hypotonia, hepatomegaly, speech delay Treatment: Carnitine; benefit of leucine restriction unclear |
3-Methylglutaconic aciduria type II (Barth syndrome; 302060†) | Tafazzin | Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Myopathy, dilated cardiomyopathy, mitochondrial abnormality, neutropenia, developmental delay Treatment: Elamipretide has shown positive effect in early clinical trials. |
3-Methylglutaconic aciduria type III (Costeff optic atrophy syndrome; 258501†) | Not determined | Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Optic atrophy, ataxia, spasticity, choreiform movement Treatment: No effective treatment |
3-Methylglutaconic aciduria type IV (250951†) | Not determined | Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Variable expression, growth and developmental delay, hypotonia, seizures, optic atrophy, deafness, cardiomyopathy, acidosis Treatment: No effective treatment |
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (246450†) | 3-Hydroxy-3-methylglutaryl-CoA lyase | Biochemical profile: Elevated urine 3-hydroxy-3-methylglutarate, 3-methylglutaconate, and 3-hydroxyisovalerate; elevated plasma 3-methylglutarylcarnitine Clinical features: Reye-like syndrome, vomiting, hypotonia, acidosis, hypoglycemia, lethargy, hyperammonemia without ketosis Treatment: Restricted leucine intake, control of hypoglycemia |
Mevalonic aciduria (610377†), Hyper-IgD syndrome (260920†) | Mevalonate kinase | Biochemical profile: Elevated creatine kinase, transaminase, leukotriene, and urinary mevalonic acid; decreased cholesterol Clinical features: In classic form, short stature, hypotonia, developmental delay, dysmorphic features, cataracts, vomiting, diarrhea, hepatosplenomegaly, arthralgia, lymphadenopathy, cerebral and cerebellar atrophy, anemia, thrombocytopenia, early death In hyper-IgD form, recurrent febrile episodes, vomiting, diarrhea, arthralgia, abdominal pain, rash, splenomegaly, elevated serum IgD and IgA levels Treatment: Corticosteroids during acute attacks; sometimes benefit from IL-1 blockade, tumor necrosis factor blockade, and stem cell transplantation |
Mitochondrial acetoacetyl-CoA thiolase deficiency (607809†) | Acetyl-CoA thiolase | Biochemical profile: Elevated urine 2-methyl-3-hydroxybutyrate and 2-methylacetoacetate, elevated plasma tiglylglycine Clinical features: Episodes of ketoacidosis, vomiting, diarrhea, coma, intellectual disability Treatment: Low-protein diet, controlled isoleucine intake |
Isobutyryl-CoA dehydrogenase deficiency (611283†) | Isobutyryl-CoA dehydrogenase | Biochemical profile: Elevated C-4 carnitine, low free carnitine Clinical features: Anemia, cardiomyopathy Treatment: Carnitine |
3-Hydroxyisobutyryl-CoA deacylase deficiency (methacrylic aciduria; 250620†) | 3-Hydroxyisobutyryl-CoA deacylase | Biochemical profile: Elevated SS Clinical features: Growth and developmental delay, dysmorphic feature, vertebral anomaly, central nervous system malformations, death Treatment: No effective treatment |
3-Hydroxyisobutyric aciduria (236795†) | 3-Hydroxyisobutyrate dehydrogenase | Biochemical profile: Elevated urine 3-hydroxyisobutyrate; in 50% patients, elevated lactate Clinical features: Dysmorphic features, central nervous system malformations, hypotonia, ketoacidosis Treatment: Low-protein diet, carnitine |
2-Methylbutyryl glycinuria (610006†) | Short branched-chain acyl-CoA dehydrogenase | Biochemical profile: Elevated urine 2-methylbutyrulglycine Clinical features: Hypotonia, muscular atrophy, lethargy, hypoglycemia, hypothermia Treatment: No effective treatment |
Ethylmalonic encephalopathy (602473†) | Mitochondrial protein of undetermined function | Biochemical profile: Elevated urine ethylmalonic and methylsuccinic acids, elevated serum lactate Clinical features: Retinopathy, acrocyanosis, diarrhea, petechiae, developmental delay, intellectual disability, extrapyramidal symptoms, ataxia, seizures, hyperintense lesions in the basal ganglia Treatment: No effective treatment |
Malonic aciduria (248360†) | Malonyl-CoA decarboxylase | Biochemical profile: Elevated lactate, malonate, methylmalonate, and malonylcarnitine Clinical features: Hypotonia, developmental delay, hypoglycemia, acidosis Treatment: No effective treatment; low-fat, high-carbohydrate diet Carnitine possibly helpful in some patients |
Hypervalinemia (277100†) | Valine transaminase | Biochemical profile: Elevated urine and serum valine Clinical features: Growth retardation Treatment: Controlled valine intake |
* The branched-chain amino acids are valine, leucine, and isoleucine. | ||
† For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man (OMIM) database. | ||
Maple Syrup Urine Disease
This is a group of autosomal recessive disorders caused by deficiency of 1 or more subunits of a dehydrogenase active in the second step of branched-chain amino acid catabolism. Although quite rare, incidence is significant (perhaps 1/200 births) in Mennonite populations (1).
Clinical manifestations include body fluid odor that smells like maple syrup (particularly strong in cerumen) and overwhelming illness in the first days of life, beginning with vomiting and lethargy, and progressing to seizures, coma, and death if untreated. Patients with milder forms of the disease may manifest symptoms only during stress (eg, infection, surgery).
Biochemical findings are profound ketonemia and acidemia. Diagnosis of maple syrup urine disease is by finding elevated plasma levels of branched-chain amino acids (particularly leucine) and confirmed by genetic testing. (See also testing for suspected inherited disorders of metabolism.)
Long-term management is restriction of dietary branched-chain amino acids; however, small amounts are required for normal metabolic function. Thiamin is a cofactor for the decarboxylation, and some patients respond favorably to high-dose oral thiamin. An emergency plan for how to manage acute illness, which may provoke a metabolic crisis, should be in place. Liver transplantation is curative.
Maple syrup urine disease reference
1. Puffenberger EG. Genetic heritage of the Old Order Mennonites of southeastern Pennsylvania. Am J Med Genet C Semin Med Genet. 2003;121C(1):18-31. doi:10.1002/ajmg.c.20003
Isovaleric Acidemia
The third step of leucine metabolism is the conversion of isovaleryl CoA to 3-methylcrotonyl CoA, a dehydrogenation step. Deficiency of this dehydrogenase results in isovaleric acidemia, also known as “sweaty feet” syndrome, because accumulated isovaleric acid emits an odor that smells like sweat.
Clinical manifestations of the acute form occur in the first few days of life with poor feeding, vomiting, and respiratory distress as infants develop profound anion gap metabolic acidosis, hypoglycemia, and hyperammonemia. Bone marrow suppression often occurs. A chronic intermittent form may not manifest for several months or years.
Diagnosis of isovaleric acidemia is made by detecting elevated levels of isovaleric acid and its metabolites in blood or urine. (See also testing for suspected inherited disorders of metabolism.)
Prognosis is excellent with treatment.
Propionic Acidemia
Propionic acid accumulation is caused by deficiency of the enzyme propionyl CoA carboxylase. This enzyme is responsible for metabolizing propionic acid to methylmalonate.
Illness begins in the first days or weeks of life with poor feeding, vomiting, and respiratory distress due to profound anion gap metabolic acidosis, hypoglycemia, and hyperammonemia. Seizures may occur, and bone marrow suppression is common. Physiologic stresses may trigger recurrent attacks. Survivors may have tubular nephropathies, intellectual disability, and neurologic abnormalities. Propionic acidemia can also be seen as part of multiple carboxylase deficiency, biotin deficiency, or biotinidase deficiency.
Diagnosis of propionic acidemia is suggested by elevated levels of propionic acid metabolites, including methylcitrate and tiglate and their glycine conjugates in blood and urine, and confirmed by measuring propionyl CoA carboxylase activity in white blood cells or cultured fibroblasts and/or genetic testing. (See also testing for suspected inherited disorders of metabolism.)
Methylmalonic Acidemia
This disorder is caused by deficiency of methylmalonyl CoA mutase, which converts methylmalonyl CoA (a product of the propionyl CoA carboxylation) into succinyl CoA. Adenosylcobalamin, a metabolite of vitamin B12, is a cofactor; its deficiency also may cause methylmalonic acidemia (and also homocystinuria and megaloblastic anemia). Methylmalonic acid accumulates.
Age of onset, clinical manifestations, and treatment are similar to those of propionic acidemia except that cobalamin, instead of biotin, may be helpful for some patients.
More Information
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Online Mendelian Inheritance in Man (OMIM) database: Complete gene, molecular, and chromosomal location information
