FATTY-ACID OXIDATION ABNORMALITIES IN CHILDHOOD-ONSET SPINAL MUSCULAR-ATROPHY - PRIMARY OR SECONDARY DEFECT(S)

The purpose of this study was to further identify and quantify the fat ty acid oxidation abnormalities in spinal muscular atrophy, correlate these with disease severity, and identify specific underlying defect(s ), Fifteen children with spinal muscular atrophy (3 type I, 8 type II, 4 type III) were studied, Serum carnitine total/ free ratios demonstr ated a tendency toward an increased esterified fraction ranging 35-58% of total carnitine (normal: 25-30% of total) in younger children with types I and II, The remaining type II and III patients, older than 23 months of age at sampling, had normal esterified carnitine levels, Ur inary organic acid analysis demonstrated mild to moderate medium-chain dicarboxylic aciduria in type I patients and normal, mild, or moderat e increases in short-chain and medium-chain organic acids in type II p atients, In the type III group, the organic acids were normal except f or one patient with mild medium-chain dicarboxylic aciduria, Muscle in tramitochondrial P-oxidation was measured in 5 children (2 type I, 2 t ype II, and 1 type III) and a significant reduction in the activities of short-chain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3-hydro xyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase, and 3-ketoacyl-CoA thiolase were found; however, normal crotonase activity was documente d, Most strikingly, there was a marked increase (3- to 5-fold) in the activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase activities with both short- and long-chain substrates, The co mbined abnormalities suggest a defect in a mitochondrial multifunction al enzyme complex, distinct from the trifunctional enzyme. These abnor malities may be either primary or secondary and may respond to dietary measures to reduce the dependence on fatty acid oxidation.