GM17472

GM17472 Fibroblast

Description:

ACYL-CoA DEHYDROGENASE, SHORT-CHAIN, DEFICIENCY OF
ACYL-CoA DEHYDROGENASE, SHORT-CHAIN; ACADS

Affected:

Yes

Sex:

Male

Age:

13 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Lipid Metabolism

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Race

White

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; benign heart murmur; reactive airway disease; recurrent migraine headaches usually accompanied by a visual aura; noninflammatory myopathy; severe leg and calf pain after infections and exertion; acute episode of severe muscle cramping, contractions and pain associated with elevated CPK levels in serum occurred at age 8 years; at the time of this acute episode the total carnitine was 22.5 (normal 33.9-69) and free carnitine was 18.7 (normal 30.2-56.8); recurrent rhabdomyolysis; light microscopy performed on muscle biopsy was normal; 50% of normal carnitine palmitoyl transferase II activity; normal small-chain Acyl-CoA dehydrogenase activity in fibroblasts and muscle; fibroblast oxidation studies showed marked elevation of butylcarnitine; elevation of butyryl carnitine after MCT load consistent with a partial defect in short-chain acyl-Co-A dehydrogenase deficiency; ethylmalonic acid level was normal in urine; donor subject is a compound heterozygote: one allele has a G>A transition at nucleotide 625 of the ACADS gene [625G>A] resulting in a substitution of serine for glycine at codon 185 [Gly185Ser (G185S)] and a second allele has a C>T transition at nucleotide 511 of the ACADS gene [511C>T] resulting in a substitution of tryptophan for arginine at codon 147 [Arg147Trp (R147W)].

Characterizations

PDL at Freeze

0.88

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin confirmed by LINE assay

Gene

ACADS

Chromosomal Location

12q22-qter

Allelic Variant 1

606885.0007; SCAD DEFICIENCY

Identified Mutation

GLY185SER; Corydon et al (2001) studied 10 patients with ethylmalonic aciduria and SCAD deficiency (201470) in fibroblasts and found a 625G-A change in the SCAD gene, resulting in a gly185-to-ser (G185S) substitution, in 9 of the patients, 5 of whom were homozygous for this variation (3 had additional mutations). One patient with dysmorphic features and developmental delay was heterozygous for this mutation and for 511C-T (606885.0006), both of which have been referred to as 'variations,' because 14% of the general population has been found to be either homozygous or double heterozygous for them. Expression studies in E. coli showed that the G185S SCAD protein has 86% of wildtype activity.

Gene

ACADS

Chromosomal Location

12q22-qter

Allelic Variant 2

606885.0006; SCAD DEFICIENCY

Identified Mutation

ARG147TRP; Gregersen et al. (1998) found a 511C-T mutation (resulting in an arg147-to-trp amino acid substitution) in 13 of 130 and 15 of 67 625G polymorphic alleles, respectively, of normal controls and patients with elevated EMA excretion; they never found it in association with the 625A variant. This overrepresentation of the haplotype 511T-625G among the common 625G alleles in patients compared with controls was significant (P less than 0.02), suggesting that the allele 511T-625G, like 511C-625A, confers susceptibility to ethylmalonicaciduria. Gregersen et al. (1998) concluded that ethylmalonicaciduria, a commonly detected biochemical phenotype, is a complex multifactorial/polygenic condition where, in addition to the role of SCAD susceptibility alleles, other genetic and environmental factors are involved.