Role of Common Gene Variations in the Molecular Pathogenesis of Short-Chain Acyl-CoA Dehydrogenase Deficiency

Abstract

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is considered a rare inherited mitochondrial fatty acid oxidation disorder. Less than 10 patients have been reported, diagnosed on the basis of ethylmalonic aciduria and low SCAD activity in cultured fibroblast. However, mild ethylmalonic aciduria, a biochemical marker of functional SCAD deficiency in vivo, is a common finding in patients suspected of having metabolic disorders. Based on previous observations, we have proposed that ethylmalonic aciduria in a small proportion of cases is caused by pathogenic SCAD gene mutations, and SCAD deficiency can be demonstrated in fibroblasts. Another - much more frequent - group of patients with mild ethylmalonic aciduria has functional SCAD deficiency due to the presence of susceptibility SCAD gene variations, i.e. 625G>A and 511C>T, in whom a variable or moderately reduced SCAD activity in fibroblasts may still be clinically relevant. To substantiate this notion we performed sequence analysis of the SCAD gene in 10 patients with ethylmalonic aciduria and diagnosed with SCAD deficiency in fibroblasts. Surprisingly, only one of the 10 patients carried pathogenic mutations in both alleles, while five were double heterozygotes for a pathogenic mutation in one allele and the 625G>A susceptibility variation in the other. The remaining four patients carried only either the 511C>T or the 625G>A variations in each allele. Our findings document that patients carrying these SCAD gene variations may develop clinically relevant SCAD deficiency, and that patients with even mild ethylmalonic aciduria should be tested for these variations.

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…This suggests that there may be other factors, such as environmental or epigenetic, which can trigger the disease symptoms, resulting in the wide range of clinical variability associated with SCAD deficiency [116,117]. Similar to other FAO diseases, SCAD disease can be divided into subgroups based on age of presentation, which can either be in infancy/early childhood or in late adulthood.…”

“…In infants, developmental delay, hypotonia and myopathy are common [118]. In addition, ethylmalonic aciduria is a common feature of SCAD deficiency, and as such is a commonly used biomarker of the disease [116].…”

“…Pathogenic mutations in ACADS have been identified in patients with SCAD deficiency, whereas others carry two ACADS polymorphisms (G625A and C511T) that are considered susceptibility variants [116,117]. Newborn screening of SCAD has identified these variants in patients with ethylmalonic aciduria, however, they have also been detected in many asymptomatic individuals.…”

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

“…Modifier gene group Sixty patients presenting with ethylmalonic aciduria who carried either of two polymorphic SCAD missense variations conferring susceptibility to SCAD deficiency (Corydon et al 2001); although both variant SCAD proteins are functional, they have been shown to cause prolonged association of the variant SCAD proteins with the Hsp60 chaperonin (Pedersen et al 2003).…”

A Rare Case of Short-Chain Acyl-COA Dehydrogenase Deficiency: The Apparent Rarity of the Disorder Results in Under Diagnosis

“…Till date, 25 patients have been identified and 50 reported worldwide based upon reduced or absent SCAD activity in vitro [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Genotype-phenotype correlations have been inconsistent [8,18].…”