ETFA – Multiple Acyl-CoA Dehydrogenase Deficiency

Multiple acyl-CoA dehydrogenase deficiency ([MONDO_0009282]) is a clinically heterogeneous, autosomal recessive disorder of mitochondrial fatty acid and amino acid oxidation characterized by impaired electron transfer flavoprotein (ETF) function. Biallelic pathogenic variants in ETFA encoding the ETF alpha subunit lead to accumulation of acylcarnitines and organic acids, resulting in life-threatening neonatal presentations or late-onset myopathic and metabolic phenotypes. Clinical manifestations span severe neonatal metabolic crises with hypoglycemia and acidosis to adult-onset muscle weakness and exercise intolerance. Diagnosis relies on plasma acylcarnitine profiling, urinary organic acid analysis, ETF enzyme assays, and confirmatory ETFA sequencing. Early molecular diagnosis enables prompt riboflavin supplementation and dietary management, improving survival and neurologic outcome. This summary integrates genetic and functional data supporting a definitive ETFA–MADD association.

AR inheritance is established with over 350 unrelated MADD cases harboring ETFA variants (>350 PMID:25200064). Case reports describe diverse ETFA mutations, including c.502G>T (p.Val168Phe) in a 14-year-old with postmortem diagnosis (PMID:20736750). Newborn screening in Zhejiang province identified 13 ETFA-related MADD patients, with a hotspot c.250G>A variant in 46% of alleles (PMID:34704421). A multi-center study of late-onset MADD showed ETFA defects in ~5% of patients, underscoring genetic heterogeneity (PMID:25200064). Phenotypic variability correlates with residual ETF activity and modifier loci.

Segregation evidence in AR MADD is supported by parental carrier confirmation in multiple pedigrees. In the Chinese adolescent case, each parent was heterozygous for one of the two ETFA missense alleles, confirming trans configuration (PMID:20736750). Obligate carrier status in unaffected relatives reinforces pathogenicity of biallelic ETFA variants. No reports of asymptomatic homozygotes in early-onset forms argue against reduced penetrance.

The ETFA variant spectrum includes missense (p.Gly116Arg), frameshift (p.Ala124fs), splice-site (c.352-2A>G), and promoter (c.-85G>A) changes (PMID:1430199; PMID:36579410). Recurrent mutations include p.Thr266Met in neonatal cases (PMID:1430199) and c.-85G>A in a late-onset patient (PMID:36579410). Regulatory and deep-intronic defects broaden the diagnostic landscape beyond exonic sequencing.

Functional assays demonstrate that ETFA null and hypomorphic variants reduce ETF complex assembly and mitochondrial β-oxidation flux. Proteomic profiling of ETFA-deficient fibroblasts revealed upregulation of chaperones and antioxidant enzymes reflecting mitochondrial stress (PMID:21596162). Promoter luciferase assays confirm ~60% reduction in ETFA transcriptional activity for c.-85G>A (PMID:36579410). Yeast and human cell models show concordant loss of ETF activity and impaired electron transfer to ubiquinone.

No substantial conflicting evidence refutes the ETFA–MADD link, though riboflavin-responsive cases without ETFA coding defects suggest additional genetic or environmental modifiers (PMID:22190129). Deep intronic and regulatory variant detection via RNA-seq and WGS is recommended. Collectively, decades of genetic, clinical, and experimental studies support a definitive gene–disease association for ETFA in MADD. Key Take-home: ETFA sequencing should be standard in suspected MADD to guide riboflavin-based therapy and family counseling.

References

• Orphanet Journal of Rare Diseases • 2014 • Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency PMID:25200064
• Diagnostic Molecular Pathology • 2010 • Role of postmortem genetic testing demonstrated in a case of glutaric aciduria type II PMID:20736750
• Journal of Zhejiang University. Medical Sciences • 2021 • Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow-up of patients PMID:34704421
• Journal of Proteomics • 2011 • Characterization of mitochondrial proteome in a severe case of ETF-QO deficiency PMID:21596162
• American Journal of Medical Genetics Part A • 2023 • A novel deleterious ETFA promoter variant causative of multiple acyl-CoA dehydrogenase deficiency PMID:36579410
• Neurological Sciences • 2012 • Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency with unknown genetic defect PMID:22190129

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