Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene

Background: The human mitochondrial trifunctional protein (MTP) complex is composed,of 4 hydroacyl-CoA dehydrogenase-alpha (HADHA) and 4 hydroacyl-CoA dehydrogenase-beta (HADHB) subunits, which catalyze,the last 3 steps in the fatty acid beta-oxidation spiral of long-chain fatty acids. The HADHB gene encodes long-chain ketoacyl-CoA thiolase (LCTH) Activity, whereas the HADHA gene contains the information for the long-chain enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) functions, At present, 2 different biochemical phenotypes of defects in the mitochondrial trifunctional protein complex are known: isolated LCHAD deficiency and generalized MTP deficiency, with decreased activities of. all 3 enzymes. Isolated LCTH deficiency with mutations in the HADHB gene his not been reported. Patient and Results: We report a male newborn who presented with lactic acidosis, pulmonary edema, and cardiomyopathy leading to acute heart failure and death at the age of 6 weeks. Routine newborn screening by tandem mass spectrometry. Showed increased concentrations, of the acylcarnitines tetradecenoylcarnitine, hexadecenoylcarnitine, hydroxypalmitoylcarnitine, and hydroxyoctadecenoylcarnitine; suggesting LCHAD deficiency or complete MTP deficiency. Enzyme investigations revealed very low LCTH (4% of normal) and normal LCHAD activities, whereas molecular analysis showed compound heterozygosity for 185G>A (R62H) and 1292T>C (F431S) mutations in the HADHB gene. Conclusion: We describe the first case of isolated LCTH deficiency based on a mutation in the HADHB gene. (C) 2006 American Association for Clinical Chemistry.