Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: A novel inborn error of branched-chain fatty acid and isoleucine metabolism

We report a novel inborn error of metabolism identified in a child with an unusual neurodegenerative disease. The mate patient was born at term and re covered well from a postnatal episode of metabolic decompensation and lacti c acidosis. Psychomotor development in the first year of life was only mode rately delayed. After 14 mo of age, there was progressive loss of mental an d motor skills; at 2 years of age, he was severely retarded with marked res tlessness, choreoathetoid movements, absence of directed hand movements, ma rked hypotonia and little reaction to external stimuli. Notable laboratory findings included marked elevations of urinary 2-methyl-3-hydroxybutyrate a nd tiglylglycine without elevation of 2-methylacetoacetate, mild elevations of lactate in CSF and blood, and a slightly abnormal acylcarnitine profile . These abnormalities became more apparent after isoleucine challenge, Enzy me studies showed absent activity of 2-methyl-3-hydroxybutyryl-CoA dehydrog enase (MHBD) in the mitochondrial oxidation of 2-methyl branched-chain fatt y acids and isoleucine. Under dietary isoleucine restriction, neurologic sy mptoms stabilized over the next 7 months.