Complete deficiency of mitochondrial trifunctional protein due to a novel mutation within the β-subunit of the mitochondrial trifunctional protein gene leads to failure of long-chain fatty acid β-oxidation with fatal outcome

Karl Otfried Schwab, Regina Ensenauer, Dietrich Matern, Gökhan Uyanik, Birgit Schnieders, Ronald J A Wanders, Willy Lehnert

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The mitochondrial trifunctional protein (MTP) is a multienzyme complex which catalyses three of the four chain-shortening reactions in the β-oxidation of long-chain fatty acids. Clinically, failure of long-chain fatty acid β-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 β-oxidation disorder. Both infants were homozygous for a novel missense mutation (976G→C) within a highly conserved region of the MTP β-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. Conclusion: the detected mutation (976G→C) within the β-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.

Original languageEnglish (US)
Pages (from-to)90-95
Number of pages6
JournalEuropean Journal of Pediatrics
Volume162
Issue number2
StatePublished - Feb 1 2003

Fingerprint

Mitochondrial Trifunctional Protein
Fatal Outcome
Fatty Acids
Mutation
Genes
Chorionic Villi
Cardiomyopathies
Respiratory Insufficiency
Multienzyme Complexes
Hydrops Fetalis
Egypt
Protein Subunits
Muscular Diseases
Missense Mutation
Coma
Tandem Mass Spectrometry
Acidosis
Prenatal Diagnosis
Hypoglycemia
Germany

Keywords

  • Hydrops fetalis
  • Mitochondrial fatty acid β-oxidation
  • Mitochondrial trifunctional protein
  • Sudden infant death

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Complete deficiency of mitochondrial trifunctional protein due to a novel mutation within the β-subunit of the mitochondrial trifunctional protein gene leads to failure of long-chain fatty acid β-oxidation with fatal outcome. / Schwab, Karl Otfried; Ensenauer, Regina; Matern, Dietrich; Uyanik, Gökhan; Schnieders, Birgit; Wanders, Ronald J A; Lehnert, Willy.

In: European Journal of Pediatrics, Vol. 162, No. 2, 01.02.2003, p. 90-95.

Research output: Contribution to journalArticle

Schwab, Karl Otfried ; Ensenauer, Regina ; Matern, Dietrich ; Uyanik, Gökhan ; Schnieders, Birgit ; Wanders, Ronald J A ; Lehnert, Willy. / Complete deficiency of mitochondrial trifunctional protein due to a novel mutation within the β-subunit of the mitochondrial trifunctional protein gene leads to failure of long-chain fatty acid β-oxidation with fatal outcome. In: European Journal of Pediatrics. 2003 ; Vol. 162, No. 2. pp. 90-95.
@article{3d9406ee78014e59afbef73ef76de7a5,
title = "Complete deficiency of mitochondrial trifunctional protein due to a novel mutation within the β-subunit of the mitochondrial trifunctional protein gene leads to failure of long-chain fatty acid β-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 β-oxidation of long-chain fatty acids. Clinically, failure of long-chain fatty acid β-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 β-oxidation disorder. Both infants were homozygous for a novel missense mutation (976G→C) within a highly conserved region of the MTP β-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. Conclusion: the detected mutation (976G→C) within the β-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.",
keywords = "Hydrops fetalis, Mitochondrial fatty acid β-oxidation, Mitochondrial trifunctional protein, Sudden infant death",
author = "Schwab, {Karl Otfried} and Regina Ensenauer and Dietrich Matern and G{\"o}khan Uyanik and Birgit Schnieders and Wanders, {Ronald J A} and Willy Lehnert",
year = "2003",
month = "2",
day = "1",
language = "English (US)",
volume = "162",
pages = "90--95",
journal = "Acta Paediatrica Academiae Scientiarum Hungaricae",
issn = "0943-9676",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - Complete deficiency of mitochondrial trifunctional protein due to a novel mutation within the β-subunit of the mitochondrial trifunctional protein gene leads to failure of long-chain fatty acid β-oxidation with fatal outcome

AU - Schwab, Karl Otfried

AU - Ensenauer, Regina

AU - Matern, Dietrich

AU - Uyanik, Gökhan

AU - Schnieders, Birgit

AU - Wanders, Ronald J A

AU - Lehnert, Willy

PY - 2003/2/1

Y1 - 2003/2/1

N2 - The mitochondrial trifunctional protein (MTP) is a multienzyme complex which catalyses three of the four chain-shortening reactions in the β-oxidation of long-chain fatty acids. Clinically, failure of long-chain fatty acid β-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 β-oxidation disorder. Both infants were homozygous for a novel missense mutation (976G→C) within a highly conserved region of the MTP β-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. Conclusion: the detected mutation (976G→C) within the β-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.

AB - The mitochondrial trifunctional protein (MTP) is a multienzyme complex which catalyses three of the four chain-shortening reactions in the β-oxidation of long-chain fatty acids. Clinically, failure of long-chain fatty acid β-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 β-oxidation disorder. Both infants were homozygous for a novel missense mutation (976G→C) within a highly conserved region of the MTP β-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. Conclusion: the detected mutation (976G→C) within the β-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.

KW - Hydrops fetalis

KW - Mitochondrial fatty acid β-oxidation

KW - Mitochondrial trifunctional protein

KW - Sudden infant death

UR - http://www.scopus.com/inward/record.url?scp=0037323578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037323578&partnerID=8YFLogxK

M3 - Article

C2 - 12548384

AN - SCOPUS:0037323578

VL - 162

SP - 90

EP - 95

JO - Acta Paediatrica Academiae Scientiarum Hungaricae

JF - Acta Paediatrica Academiae Scientiarum Hungaricae

SN - 0943-9676

IS - 2

ER -