Disorder of metabolism of branched-chain amino acids

Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of the enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis.

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Maple syrup disease

These are a group of autosomal recessive disorders caused by deficiency of one or more subunits of the decarboxylase active in the second step of branched-chain amino acid catabolism. Although relatively rare, they have a significant incidence among the Amish and Mennonites (probably 1/200 births).

Symptoms include a characteristic maple syrup-like body odor (especially strong in earwax) and a severe illness in the first few days of life, beginning with vomiting and lethargy and progressing to seizures, coma, and death if untreated. Patients with mild forms of the disease may only develop symptoms when stressed (e.g., infection, surgery).

Biochemical changes include marked ketonemia and acidemia. Diagnosis is based on elevated plasma levels of branched-chain amino acids (especially leucine).

In the acute phase, peritoneal dialysis or hemodialysis with simultaneous intravenous hydration and nutrition (including high-dose glucose) may be necessary. Long-term treatment involves dietary restriction of branched-chain amino acids; however, small amounts are necessary for normal metabolism. Thiamine is a cofactor for decarboxylation, and some patients respond to high-dose thiamine (up to 200 mg orally once daily).

Isovaleric acidemia

The third step in leucine metabolism is the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA, the dehydrogenation step. Deficiency of this dehydrogenase leads to elevated levels of isovaleric acid, the so-called "sweaty feet" syndrome, since the accumulated isovaleric acid smells like sweat.

Symptoms in the acute form develop in the first days of life and include low food intake, vomiting, and respiratory failure, occurring as the patient develops deep anion gap metabolic acidosis, hypoglycemia, and hyperammonemia. Bone marrow suppression often develops. The chronic intermittent form may not manifest for months or even years.

Diagnosis is based on detection of elevated levels of isovaleric acid and its metabolites in the blood or urine. In the acute form, treatment includes intravenous rehydration and parenteral nutrition (including high-dose glucose) and measures to increase the excretion of isovaleric acid; glycine and carnitine may increase its excretion. If these measures are insufficient, exchange transfusion and peritoneal dialysis may be necessary. Long-term treatment includes restriction of dietary leucine and continued supplementation with glycine and carnitine. The prognosis is excellent with treatment.

Propionic acidemia

Deficiency of propionyl-CoA carboxylase, the enzyme responsible for converting propionic acid to methyl malonate, leads to accumulation of propionic acid. Symptoms appear in the first days to weeks of life and include poor appetite, vomiting, and respiratory failure due to a deep anion gap metabolic acidosis, hypoglycemia, and hyperammonemia. Seizures may occur, and bone marrow suppression is common. Physiologic stress may precipitate repeated attacks. Patients may later develop mental retardation and neurologic dysfunction. Propionic acidemia may also be part of the disorder multiple carboxylase deficiency, biotin deficiency, or biotinidase deficiency.

Diagnosis is suggested by elevated levels of propionic acid metabolites, including methyl citrate and tiglate, and their glycine conjugates in urine and blood and confirmed by measuring propionyl-CoA carboxylase activity in leukocytes or cultured fibroblasts. Acute treatment includes intravenous hydration (including high-dose glucose) and parenteral nutrition; carnitine may be useful. If these measures are insufficient, peritoneal dialysis or hemodialysis may be required. Long-term treatment includes dietary restriction of precursor amino acids and extension-chain fatty acids and possibly continued carnitine supplementation. Some patients respond to high doses of biotin, as it is a cofactor for propionyl-CoA and other carboxylases.

Methyl malonic acidemia

This disorder results from deficiency of methylmalonyl-CoA mutase, which converts methylmalonyl-CoA (a product of the carboxylation of propionyl-CoA) to succinyl-CoA. Adenosylcobalamin, a metabolite of vitamin B12, is a cofactor; its deficiency can also cause methylmalonic acidemia (as well as homocystinuria and megaloblastic anemia). Accumulation of methylmalonic acid occurs. Age of onset, clinical manifestations, and treatment are similar to those of propionic acidemia, except that cobalamin rather than biotin may be effective in some patients.