ACADS – Short‐chain acyl-CoA dehydrogenase deficiency

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive mitochondrial fatty acid oxidation disorder caused by biallelic ACADS variants. Initial identification of compound heterozygous C136T (c.136C>T (p.Arg46Trp)) and C319T (c.319C>T (p.Arg107Cys)) alleles in a SCADD patient demonstrated a molecular basis for SCAD instability and reduced enzymatic activity (PMID:1692038). Biochemical hallmarks include elevated ethylmalonic acid and C4-carnitine, with clinical presentations spanning hypoglycaemia and metabolic acidosis in infancy to hypotonia and developmental delay (PMID:12061367; PMID:26110041).

Over 40 distinct ACADS variants—predominantly missense—have been reported, yet genotype–phenotype correlations remain inconsistent. Common polymorphisms c.625G>A (p.Gly209Ser) and c.511C>T (p.Arg171Trp) occur at high population frequencies and often confer biochemical SCAD deficiency without clinical disease, casting doubt on their pathogenicity (PMID:15902559). Functional studies reveal that pathogenic variants provoke SCAD misfolding, prolonged hsp60 association, proteolytic degradation, and aggregation in mitochondria, supporting a mechanism of loss-of-function and toxic gain-of-function (PMID:14506246).

Segregation data are limited, with asymptomatic homozygotes and variably affected relatives demonstrating incomplete penetrance. While dozens of probands have been molecularly characterized, robust family linkage and consistent clinical segregation are lacking. Functional assays provide moderate support but cannot reliably predict disease course.

Overall Clinical Validity: Limited. The ACADS–SCADD association has sparse segregation, variable expressivity, and common nonpathogenic variants, warranting cautious interpretation in the diagnostic setting.

Key take-home: Accurate diagnosis of SCADD requires integration of biochemical profiles, comprehensive ACADS sequencing, and functional validation; routine newborn screening inclusion is not currently supported.

References

• The Journal of clinical investigation • 1990 • Identification of two variant short chain acyl-coenzyme A dehydrogenase alleles, each containing a different point mutation in a patient with short chain acyl-coenzyme A dehydrogenase deficiency. PMID:1692038
• Acta paediatrica (Oslo, Norway : 1992) • 2002 • Hypoglycaemia and elevated urine ethylmalonic acid in a child homozygous for the short-chain acyl-CoA dehydrogenase 625G > A gene variation. PMID:12061367
• Biochemia medica • 2015 • A case report of short-chain acyl-CoA dehydrogenase deficiency (SCADD). PMID:26110041
• The Journal of biological chemistry • 2003 • Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. PMID:14506246
• Journal of inherited metabolic disease • 2005 • The 625G>A SCAD gene variant is common but not associated with increased C4-carnitine in newborn blood spots. PMID:15902559

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