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Two Novel HADHB Gene Mutations in a Korean Patient with Mitochondrial Trifunctional Protein Deficiency

Address correspondence to Won-Soon Park, M.D., Ph.D., Department of Pediatrics, Samsung Medical Center, 50 Ilwon-dong, Gangnam-gu, Seoul, 135-710, Korea; tel 82 2 3410 3523; fax 82 2 3410 0043; e-mail wonspark{at}skku.edu.

Mitochondrial trifunctional protein (MTP) is a heterocomplex composed of 4 -subunits containing LCEH (long-chain 2,3-enoyl-CoA hydratase) and LCHAD (long-chain 3-hydroxyacyl CoA dehydrogenase) activity, and 4 β-subunits that harbor LCKT (long-chain 3-ketoacyl-CoA thiolase) activity. MTP deficiency is an autosomal recessive disorder that causes a clinical spectrum of diseases ranging from severe infantile cardiomyopathy to mild chronic progressive polyneuropathy. Here, we report the case of a Korean male newborn who presented with severe lactic acidosis, seizures, and heart failure. A newborn screening test and plasma acylcarnitine profile analysis by tandem mass spectrometry showed an increase of 3-hydroxy species: 3-OH-palmitoylcarnitine, 0.44 nmol/ml (reference range, RR <0.07); 3-OH-linoleylcarnitine, 0.31 nmol/ml (RR <0.06); and 3-OH-oleylcarnitine, 0.51 nmol/ml (RR <0.04). These findings suggested either long-chain 3-hydroxyacyl-coA dehydrogenase deficiency or complete MTP deficiency. By molecular analysis of the HADHB gene, the patient was found to be a compound heterozygote for c.358dupT (p.A120CfsX8) and c.1364T>G (p.V455G) mutations. These 2 mutations of the HADHB gene were novel and inherited. Although the patient was treated by reduction of glucose administration and supplementation of a medium-chain triglyceride-based diet with L-carnitine, he died 2 mo after birth due to advanced cardiac failure.

Keywords: mitochondrial trifunctional protein (MTP) deficiency, HADHB gene mutations