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 rhabdomyolysis with myoglobinuria. Multiple urine organic acid analyses consistently revealed a markedly elevated excretion of lactic acid, 3-hydroxybutyric acid, and saturated and unsaturated C6-C16 dicarboxylic acids, with predominant C12-C16 species. Oxidation of [1-14C]octanoic acid in cultured skin fibroblasts was significantly reduced (0.59 nmol/h/mg of protein; controls, 1.93 +/- 0.65), [1-14C]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 substrate revealed a deficiency of a single enzyme not previously associated with a metabolic disorder, medium chain 3-ketoacyl-CoA thiolase (patient, 3.9 nmol/min/mg protein; controls (n = 6), 10.2 +/- 2.3). Immunoprecipitation with antibodies raised against medium chain 3-ketoacyl-CoA thiolase revealed a 60% decrease compared with controls.
Kamijo
T
T
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
Indo
Y
Y
Souri
M
M
Aoyama
T
T
Hara
T
T
Yamamoto
S
S
Ushikubo
S
S
Rinaldo
P
P
Matsuda
I
I
Komiyama
A
A
Hashimoto
T
T
D000102:Acetyl-CoA C-Acyltransferase / Q000172:deficiency*; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007231:Infant, Newborn; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D013379:Substrate Specificity
D005227:Fatty Acids; D000102:Acetyl-CoA C-Acyltransferase