MEDIUM-CHAIN 3-KETOACYL-COENZYME A THIOLASE DEFICIENCY - A NEW DISORDER OF MITOCHONDRIAL FATTY-ACID BETA-OXIDATION

A Japanese male neonate died at 13 d of age after presenting at 2 d of age with vomiting, dehydration, metabolic acidosis, liver dysfunction , and terminal rabdhomyolysis with myoglobinuria. Multiple urine organ ic acid analyses consistently revealed a markedly elevated excretion o f lactic acid, 3-hydroxybutyric acid, and saturated and unsaturated C- 6-C-16 dicarboxylic acids, with predominant C-12-C-16 species; Oxidati on of [1-C-14]octanoic acid in cultured skin fibroblasts was significa ntly reduced (0.59 nmol/h/mg of protein; controls, 1.93 +/- 0.65), [1- C-14]palmitic acid oxidation was 1.11 nmol/h/mg of protein (controls, 1.63 +/- 0.41). A systematic study of the catalytic activities of nine enzymes of the beta-oxidation cycle using the respective optimal subs trate revealed a deficiency of a single enzyme not previously associat ed with a metabolic disorder, medium chain 3-ketoacyl-CoA thiolase (pa tient, 3.9 nmol/min/mg protein; controls (n = 6), 10.2 +/- 2.3). Immun oprecipitation with antibodies raised against medium chain 3-ketoacyl- CoA thiolase revealed a 60% decrease compared with controls.