title: Complete deficiency of mitochondrial trifunctional protein due to a novel mutation within the beta-subunit of the mitochondrial trifunctional protein gene leads to failure of long-chain fatty acid beta-oxidation with fatal outcome.
abstract: The mitochondrial trifunctional protein (MTP) is a multienzyme complex which catalyses three of the four chain-shortening reactions in the beta-oxidation of long-chain fatty acids. Clinically, failure of long-chain fatty acid beta-oxidation leads to hypoketotic hypoglycaemia associated with coma, hepatopathy, skeletal myopathy and cardiomyopathy. We report on consanguineous parents with six children, four of whom had unexpectedly died in Egypt during the neonatal period due to cardiomyopathy of unknown aetiology and respiratory failure. After moving to Germany, two further children died at the age of 4 months and 12 h, respectively, with signs of respiratory and cardiac failure, hydrops fetalis and acidosis. Analysis of acylcarnitine profiles in dried blood spots of the last two children by electrospray tandem mass spectrometry was indicative of a long-chain fatty acid beta-oxidation disorder. Both infants were homozygous for a novel missense mutation (976G-->C) within a highly conserved region of the MTP beta-subunit gene. Immunoblot analysis in chorionic villi obtained during the subsequent pregnancy demonstrated absence of MTP. In fibroblasts and liver, activities of all three catalytic units of MTP were markedly decreased, further confirming the diagnosis of MTP deficiency.
  
  
  CONCLUSIONS
  the detected mutation (976G-->C) within the beta-subunit of the mitochondrial trifunctional protein gene destabilises the protein, leading to complete deficiency and a poor prognosis. Immunoblot analysis of mitochondrial trifunctional protein in chorionic villi may be a valuable tool for the prenatal diagnosis of the disorder when the molecular genetic defect is unknown.
authors.affiliation: Department of Paediatrics, Albert-Ludwigs-University Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany, Schwab@kikli.ukl.uni-freiburg.de
authors.forename: Karl Otfried
authors.initials: KO
authors.lastname: Schwab
authors.forename: Regina
authors.initials: R
authors.lastname: Ensenauer
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.forename: Gökhan
authors.initials: G
authors.lastname: Uyanik
authors.forename: Birgit
authors.initials: B
authors.lastname: Schnieders
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Wanders
authors.forename: Willy
authors.initials: W
authors.lastname: Lehnert
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics*; D000328:Adult; D003241:Consanguinity; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics; D008297:Male; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011296:Prenatal Diagnosis
chemical_list: D009097:Multienzyme Complexes; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063991:Mitochondrial Trifunctional Protein