A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death.
Open Access
- 1 October 1994
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 94 (4), 1477-1483
- https://doi.org/10.1172/jci117486
Abstract
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common known genetic disorder of fatty acid oxidation. Most (approximately 80%) cases are homozygous for a single mutation: A to G replacement at nucleotide 985 (A985G). MCAD deficiency typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Prompt diagnosis and management may prevent long-term sequelae. MCAD deficiency was verified by analysis of urinary acylglycine and serum acylcarnitine species from two neonates referred for diagnosis. Full-length cDNA and MCAD exon 7 and 11 genomic clones were prepared for sequence analysis. Normal and mutant cDNAs were expressed in bacteria, and enzymatic activity was assayed by the ferricenium hexaflurophosphate method. Four compound heterozygote individuals from two unrelated families with A985G on one allele and a novel G to A mutation at nucleotide 583 (G583A) as the second mutant allele presented with MCAD deficiency in the first week of life. The expressed G583A mutant protein lacks enzymatic activity. This novel mutation, G583A, is associated with severe MCAD deficiency causing hypoglycemia or sudden, unexpected neonatal death. This previously unrecognized phenotype of MCAD deficiency may contribute significantly to preventable infant deaths.Keywords
This publication has 32 references indexed in Scilit:
- Intramitochondrial folding and assembly of medium-chain acyl-CoA dehydrogenase (MCAD). Demonstration of impaired transfer of K304E-variant MCAD from its complex with hsp60 to the native tetramer.1994
- Medium-Chain Acyl-Coenzyme a Dehydrogenase Deficiency and Sudden Infant DeathNew England Journal of Medicine, 1991
- Neonatal onset of medium-chain Acyl-CoA dehydrogenase deficiency in two siblingsBrain & Development, 1988
- Medium-Chain Acyl-CoA Dehydrogenase DeficiencyNew England Journal of Medicine, 1988
- Structure of the medium-chain acyl-CoA dehydrogenase from pig liver mitochondria at 3-A resolution.Proceedings of the National Academy of Sciences, 1988
- Medium-chain and long-chain acyl CoA dehydrogenase deficiency: Clinical, pathologic and ultrastructural differentiation from Reye's syndrome†Hepatology, 1986
- Genetic Deficiency of Medium-Chain Acyl Coenzyme A Dehydrogenase: Studies in Cultured Skin Fibroblasts and Peripheral Mononuclear LeukocytesPediatric Research, 1985
- Purification of DNA from formaldehyde fixed and paraffin embedded human tissueBiochemical and Biophysical Research Communications, 1985
- Defects of metabolism of fatty acids in the sudden infant death syndrome.BMJ, 1985
- Isolation of biologically active ribonucleic acid from sources enriched in ribonucleaseBiochemistry, 1979