TY - JOUR
T1 - 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
AU - Tein, Ingrid
AU - Elpeleg, Orly
AU - Ben-Zeev, Bruria
AU - Korman, Stanley H.
AU - Lossos, Alexander
AU - Lev, Dorit
AU - Lerman-Sagie, Tally
AU - Leshinsky-Silver, Esther
AU - Vockley, Jerry
AU - Berry, Gerard T.
AU - Lamhonwah, Anne Marie
AU - Matern, Dietrich
AU - Roe, Charles R.
AU - Gregersen, Niels
N1 - Funding Information:
We thank the patients and their families for their generous cooperation in these studies. This work was supported in part by a grant from the Physicians’ Services Incorporated Foundation of Ontario, the Danish Medical Research Council, Aarhus University Hospital Research Initiative, Institute of Clinical Science, Aarhus University, and Karen Elise Jensens Foundation, Denmark. J.V. was supported in part by NIH Grants RO1DK45482 and RO1DK54936, and the Pennsylvania Department of Health, Tobacco Formula Funding.
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
KW - Ashkenazi
KW - Developmental delay
KW - Ethylmalonic aciduria
KW - Fatty acid oxidation
KW - Multicore myopathy
KW - Myopathy
KW - Short-chain acyl-CoA dehydrogenase deficiency
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U2 - 10.1016/j.ymgme.2007.09.021
DO - 10.1016/j.ymgme.2007.09.021
M3 - Article
C2 - 18054510
AN - SCOPUS:38049177259
SN - 1096-7192
VL - 93
SP - 179
EP - 189
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 2
ER -