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.
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.
Tein
Ingrid
I
Division of Neurology, Department of Pediatrics, Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Canada M5G 1X8. ingrid.tein@sickkids.ca
Elpeleg
Orly
O
Ben-Zeev
Bruria
B
Korman
Stanley H
SH
Lossos
Alexander
A
Lev
Dorit
D
Lerman-Sagie
Tally
T
Leshinsky-Silver
Esther
E
Vockley
Jerry
J
Berry
Gerard T
GT
Lamhonwah
Anne-Marie
AM
Matern
Dietrich
D
Roe
Charles R
CR
Gregersen
Niels
N
D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D044926:Butyryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D005260:Female; D018703:Founder Effect; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007585:Jews / Q000235:genetics*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics; D051379:Mice; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D011994:Recombinant Proteins; D044926:Butyryl-CoA Dehydrogenase