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-α (HADHA) and 4 hydroacyl-CoA dehydrogenase-β (HADHB) subunits, which catalyze the last 3 steps in the fatty acid β-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 has 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.