METHYLMALONIC SEMIALDEHYDE DEHYDROGENASE-DEFICIENCY - PSYCHOMOTOR DELAY AND METHYLMALONIC ACIDURIA WITHOUT METABOLIC DECOMPENSATION

A patient presenting with developmental delay but no episodes of metab olic acidosis was found to excrete significant amounts of methylmalona te (MMA) without any associated increased excretion of malonate, ethyl malonate, S-hydroxypropionate, or beta-alanine. In contrast to patient s with methylmalonic aciduria due to deficient mutase or impaired coba lamin metabolism, there was no increase of propionylcarnitine in blood or urine. The activity of methylmalonyl-CoA mutase and the pathway fo r cobalamin metabolism were also intact. The quantitative levels of th e various labeled enantiomers of 3-hydroxyisobutyric (3-HIBA), 3-amino isobutyric (3-AIBA), MMA, and propionylcarnitine were compared followi ng separate intravenous infusions of equimolar doses of [H-2(8)]-valin e or [H-2(4)]thymine in this patient and another with methylmalonyl-Co A mutase deficiency. Levels of labeled S- and R-3-HIBA and S- and R-3- AIBA indicated an isolated defect in methylmalonic semialdehyde dehydr ogenase in this patient. This condition can be recognized by plasma MM A levels of similar to 8.5 mu M (cf, 400 mu M in mutase deficiency), u rine MMA of 20-55 mu mol/kg/24 h (cf. 1150 mu mol/kg/24 h), no increas e in propionylcarnitine following an oral carnitine load, and increase d excretion of S-3-AIBA-nearly 10 times that observed in mutase defici ency. The ratio of R-AIBA to S-AIBA of <1 also reflects this disorder. (C) 1998 Academic Press.