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.
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
