Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin

• Published in: Molecular genetics and metabolism Vol. 93; no. 2; pp. 179 - 189
• Main Authors: Tein, Ingrid, Elpeleg, Orly, Ben-Zeev, Bruria, Korman, Stanley H., Lossos, Alexander, Lev, Dorit, Lerman-Sagie, Tally, Leshinsky-Silver, Esther, Vockley, Jerry, Berry, Gerard T., Lamhonwah, Anne-Marie, Matern, Dietrich, Roe, Charles R., Gregersen, Niels
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2008
• Subjects: Abnormalities, Multiple - enzymology; Abnormalities, Multiple - genetics; Adolescent; Adult; Alleles; Animals; Ashkenazi; Base Sequence; Butyryl-CoA Dehydrogenase - deficiency; Butyryl-CoA Dehydrogenase - genetics; Child; Child, Preschool; Developmental delay; DNA Primers - genetics; Ethylmalonic aciduria; Fatty acid oxidation; Female; Founder Effect; Heterozygote; Homozygote; Humans; Infant; Infant, Newborn; Jews - genetics; Male; Metabolism, Inborn Errors - enzymology; Metabolism, Inborn Errors - genetics; Mice; Multicore myopathy; Muscular Diseases - enzymology; Muscular Diseases - genetics; Myopathy; Phenotype; Point Mutation; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Short-chain acyl-CoA dehydrogenase deficiency; Fatty acid oxidation; Ethylmalonic aciduria; Ashkenazi; Developmental delay; Myopathy; Multicore myopathy; Short-chain acyl-CoA dehydrogenase deficiency
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2007.09.021

We report 10 children (7 male, 3 female), 3 homozygous for c.319C>T mutation and 7 heterozygous for c.319C>T on one allele and c.625G>A variant on the other in the short-chain acyl-CoA dehydrogenase (SCAD) gene (
ACADS). All were of Ashkenazi Jewish origin in which group we found a c.319C>T heterozygote frequency of 1:15 suggesting the presence of a founder mutation or selective advantage. Phenotype was variable with onset from birth to early childhood. Features included hypotonia (8/10), developmental delay (8/10), myopathy (4/10) with multicore changes in two and lipid storage in one, facial weakness (3/10), lethargy (5/10), feeding difficulties (4/10) and congenital abnormalities (3/7). One female with multiminicore myopathy had progressive external ophthalmoplegia, ptosis and cardiomyopathy with pneumonia and respiratory failure. Two brothers presented with psychosis, pyramidal signs, and multifocal white matter abnormalities on MRI brain suggesting additional genetic factors. Two other infants also had white matter changes. Elevated butyrylcarnitine (4/8), ethylmalonic aciduria (9/9), methylsuccinic aciduria (6/7), decreased butyrate oxidation in lymphoblasts (2/4) and decreased SCAD activity in fibroblasts or muscle (3/3) were shown. Expression studies of c.319C>T in mouse liver mitochondria showed it to be inactivating. c.625G>A is a common variant in
ACADS that may confer disease susceptibility. Five healthy parents were heterozygous for c.319C>T and c.625G>A, suggesting reduced penetrance or broad clinical spectrum. We conclude that the c.319C>T mutation can lead to wide clinical and biochemical phenotypic variability, suggesting a complex multifactorial/polygenic condition. This should be screened for in individuals with multicore myopathy, particularly among the Ashkenazim.