Branched-Chain Amino Acid Metabolism Disorders

This is a group of autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more disorders caused by deficiency of one or more subunits of a dehydrogenase active in the 2nd step of branched-chain amino acid catabolism. Although quite rare, incidence is significant (perhaps 1/200 births) in Mennonite populations.

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. (Also see testing for suspected inherited disorders of metabolism Initial testing Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more .)

Acutely, treatment of maple syrup urine disease with peritoneal dialysis or hemodialysis may be required, along with IV hydration and nutrition (including protein restriction and high-dose dextrose). Patients should be closely monitored for cerebral edema and acute pancreatitis.

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 thiamin (up to 200 mg orally once a day). An emergency plan for how to manage acute illness, which may provoke a metabolic crisis, should be in place. Liver transplantation is curative.

The 3rd 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 High anion gap acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3⁻), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more , 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. (Also see testing for suspected inherited disorders of metabolism Initial testing Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more .)

Acute treatment of isovaleric acidemia is with IV hydration and nutrition (including high-dose dextrose) and measures to increase renal isovaleric acid excretion by conjugation with glycine. If these measures are insufficient, exchange transfusion and peritoneal dialysis may be needed. Long-term treatment is with dietary leucine restriction and continuation of glycine and carnitine supplements. Prognosis is excellent with treatment.

Deficiency of propionyl CoA carboxylase, the enzyme responsible for metabolizing propionic acid to methylmalonate, causes propionic acid accumulation.

Illness begins in the first days or weeks of life with poor feeding, vomiting, and respiratory distress due to profound anion gap metabolic acidosis High anion gap acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3⁻), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more , hypoglycemia, and hyperammonemia. Seizures may occur, and bone marrow suppression is common. Physiologic stresses may trigger recurrent attacks. Survivors may have tubular nephropathies Overview of Tubulointerstitial Diseases Tubulointerstitial diseases are clinically heterogeneous disorders that share similar features of tubular and interstitial injury. In severe and prolonged cases, the entire kidney may become... read more , 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. (Also see testing for suspected inherited disorders of metabolism Initial testing Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more .)

Acute treatment of propionic acidemia is with IV hydration (including high-dose dextrose), nutrition, and protein restriction; carnitine may be helpful. If these measures are insufficient, peritoneal dialysis or hemodialysis may be needed. Long-term propionic acidemia treatment is dietary restriction of precursor amino acids and odd-chain fatty acids and possibly continuation of carnitine supplementation. A few patients respond to high-dose biotin because it is a cofactor for propionyl CoA and other carboxylases. Intermittent courses of antibiotics should be considered for reducing a propionic acid load resulting from intestinal bacteria. An emergency plan for how to manage acute illness, which may provoke a metabolic crisis, should be in place.

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 Classic homocystinuria A number of defects in methionine metabolism lead to accumulation of homocysteine (and its dimer, homocystine) with adverse effects including thrombotic tendency, lens dislocation, and central... read more and megaloblastic anemia Megaloblastic Macrocytic Anemias Megaloblastic anemias result most often from deficiencies of vitamin B12 and folate. Ineffective hematopoiesis affects all cell lines but particularly red blood cells. Diagnosis is usually based... read more ). 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.