title: Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency.
abstract: Patients with long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency manifest hypoketotic hypoglycemia, hepatomegaly, hypotonia, lactic acidemia, acute renal failure, cardiomyopathy, and sudden death. We describe four novel mutations of the alpha- and beta-subunits of the mitochondrial trifunctional protein in four patients from three unrelated families. Their plasma acylcarnitine profiles suggested the presence of LCHAD deficiency by demonstrating highly elevated 3-hydroxyacyl carnitines by tandem mass spectrometry (MS/MS). Patients 1 and 2 had siblings who had died of lactic acidemia during the neonatal period. These patients also manifested lactic acidemia and died in the neonatal period. Patient 3 had a family history of Reye-like syndrome. She exhibited acute renal failure, rhabdomyolysis, pericardial effusion, and myopathy at the age of 12 years. DNA analysis of patients 1 and 2 revealed homozygosity for a c.1689+2T>G mutation of the HADHA gene, resulting in the skipping of exon 16 with an in-frame 69-bp deletion. Patient 3 was a compound heterozygosity of the HADHB gene, N307D/N389D. Patient 4, a 25-month-old baby, manifested recurrent episodes of lethargy, metabolic acidosis, elevated liver enzymes, and dark urine from the age of 10 months. Mutation analysis of the HADHB gene of patient 4 identified compound heterozygosity of N114D/N307D.
authors.affiliation: Department of Pediatrics, Chungnam National University Hospital, College of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Hye-Ran
authors.initials: HR
authors.lastname: Yoon
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Seong-Jong
authors.initials: SJ
authors.lastname: Park
authors.forename: Young-Lim
authors.initials: YL
authors.lastname: Shin
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002331:Carnitine / Q000031:analogs & derivatives / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D063991:Mitochondrial Trifunctional Protein; D063992:Mitochondrial Trifunctional Protein, alpha Subunit; D063993:Mitochondrial Trifunctional Protein, beta Subunit; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics*; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D053719:Tandem Mass Spectrometry
chemical_list: D009097:Multienzyme Complexes; C116917:acylcarnitine; C576205:HADHA protein, human; D063992:Mitochondrial Trifunctional Protein, alpha Subunit; C576206:HADHB protein, human; D063991:Mitochondrial Trifunctional Protein; D063993:Mitochondrial Trifunctional Protein, beta Subunit; D002331:Carnitine