Molecular basis of inherited medium‐chain acyl‐CoA dehydrogenase deficiency causing sudden child death

• DOI: 10.1007/bf01799626
• Publication Date: 2005-06-21T17:23:37Z
• Authors: D. P. Kelly; D. E. Hale; S. L. Rutledge; M. L. Ogden; A. J. Whelan; Z. Zhang; A. W. Strauss
• Keywords: Male; 0303 health sciences; Base Sequence; Molecular Sequence Data; Infant; DNA; Exons; Polymerase Chain Reaction; Acyl-CoA Dehydrogenase; 3. Good health; 03 medical and health sciences; Acyl-CoA Dehydrogenases; Liver; Humans; Amino Acid Sequence; Chromosome Deletion; Polymorphism, Restriction Fragment Length; Sudden Infant Death

SummaryDeficiency of medium‐chain acyl‐CoA dehydrogenase (MCAD) is an important cause of sudden death in children. The majority of surviving individuals with MCAD deficiency studied to date are homozygous for a single point mutation at bp 985 of the MCAD mRNA (A985G). We have now identified a four‐base‐pair deletion in exon 11 of one allele of the MCAD gene in an American child who died of MCAD deficiency. The deletion mutation results in a frameshift and premature termination codon in the mutant MCAD mRNA. The second mutant allele contained the common point mutation A985G, and thus the proband was a compound heterozygote. Protein immunoblot analysis of the child's liver proteins revealed that the mutant MCAD proteins were barely detectable. Allele‐specific oligonucleotide hybridization analysis performed on amplified exon 11 of the child's MCAD gene clearly identified both mutations. MCAD RFLP analysis of the patient's DNA revealed heterozygosity at the Taq I MCAD RFLP site, thus, the two mutations are associated with different haplotypes. Therefore, we have identified a new mutation in the MCAD gene and have developed a nucleic‐acid‐based screening approach which allows thepost mortem identification of MCAD deficiency.