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Birth prevalence of MSUD is estimated at around 1/150,000. Classic MSUD may account for 50-75% of cases.

Onset of classic MSUD occurs in the neonatal period (usually 12 hours after birth) with the presence of a maple syrup odor in the cerumen and later in urine, poor feeding and drowsiness. Progressive encephalopathy with lethargy, intermittent apnea, stereotyped movements (described as "fencing" and bicycling") and opisthotonus occur in the first few days of life. Without treatment, coma and central respiratory failure occur by days 7 to 10. Later, catabolic stress, infection or injury may cause acute, potentially fatal, leucine intoxication with vomiting, altered consciousness, ataxia and acute dystonia in toddlers and hallucinations, hyperactivity, focal dystonia, ataxia and choreoathetosis in children and adults.

MSUD is due to mutations in genes encoding 3 of the 4 subunits of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to accumulation of branched-chain amino acids (especially leucine) and branched-chain alpha-ketoacids. In classic MSUD, mutations in BCKDHA predominate.

Classical MSUD is readily diagnosed by tandem mass-spectrometry population newborn screening. Otherwise, isolated ketosis and encephalopathy or maple syrup odor are suggestive. Plasma leucine is greatly elevated, with a ratio of leucine/valine/isoleucine of approximately 4/2/1. Plasma allo-isolucine >5umol/L is diagnostic. Urine branched chain 2-ketoacids (BCKAs) are elevated on gas chromatopgraphy-mass spectrometry. Molecular genetic testing can identify causal mutations, and perhaps suggest a sub-type.

Differential diagnoses include other inborn errors of metabolism associated with predominant neurological deterioration such as urea cycle defects, organic acidemias (i.e. propionic or isovaleric acidemias, methylmalonic academia with homocystinuria, multiple carboxylase deficiency), and beta-ketothiolase deficiency (see these terms). In infants, ketosis, with the absence of significant metabolic acidosis, hyperammonaemia and hypoglycaemia, rules out many inborn errors of metabolism. In older children with diabetic ketoacidosis, plasma valine is higher than leucine.

Prenatal diagnosis is possible in families with a known disease-causing mutation.

Inheritance is autosomal recessive and genetic counseling is possible.

Classic MSUD in neonates is a medical emergency. Acute management requires aggressive enhancement of protein anabolism using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements. Hemodialysis is often required. Stabilized infants need high calorie BCAA-free formulas, dietary leucine restriction and close outpatient monitoring at a metabolic clinic. Patients require a strict life-long diet and special monitoring during pregnancy. Orthotopic liver transplantation is also an effective treatment.

Prognosis is good for those who are diagnosed early, treated promptly and who follow a strict lifelong diet.