Isolated Mitochondrial Long-Chain Ketoacyl-CoA Thiolase Deficiency Resulting from Mutations in the HADHB Gene

• Published in: Clinical chemistry (Baltimore, Md.) Vol. 52; no. 3; pp. 530 - 534
• Main Authors: Das, Anibh M, Illsinger, Sabine, Lucke, Thomas, Hartmann, Hans, Ruiter, Jos P.N, Steuerwald, Ulrike, Waterham, Hans R, Duran, Marinus, Wanders, Ronald J.A
• Format: Journal Article
• Language: English
• Published: Washington, DC Am Assoc Clin Chem 01.03.2006; American Association for Clinical Chemistry; Oxford University Press
• Subjects: Acetyl-CoA C-Acyltransferase - deficiency; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Dehydrogenase; Edema; Fatal Outcome; Fatty acids; Fundamental and applied biological sciences. Psychology; Humans; Infant, Newborn; Investigative techniques, diagnostic techniques (general aspects); Male; Mass spectrometry; Medical sciences; Mitochondrial Trifunctional Protein; Mitochondrial Trifunctional Protein, alpha Subunit; Mitochondrial Trifunctional Protein, beta Subunit; Multienzyme Complexes - genetics; Mutation; Protein Subunits - deficiency; Protein Subunits - genetics; Mitochondria; Gene; Long chain; Deficiency; Clinical biology; Genetics; Biochemistry; Mutation; Molecular biology
• ISSN: 0009-9147; 1530-8561
• DOI: 10.1373/clinchem.2005.062000

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 has not been reported. 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. We describe the first case of isolated LCTH deficiency based on a mutation in the HADHB gene.