ETFDH – Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II, is an autosomal recessive inborn error of fatty acid and amino acid metabolism. Patients present with a broad spectrum of manifestations including exercise intolerance, muscle weakness, metabolic acidosis, hypoglycemia and hepatopathy. Late-onset MADD typically responds to riboflavin, carnitine or coenzyme Q10 supplementation, underscoring the therapeutic importance of accurate molecular diagnosis.

Genetic evidence demonstrates biallelic loss-of-function and missense variants in ETFDH across unrelated families, with >350 cases reported in the literature ([PMID:25200064]). Autosomal recessive segregation is supported by compound heterozygosity and homozygosity in sib pairs, often with parental carrier status confirmed by segregation analysis. No affected carriers have been reported, consistent with complete penetrance in the recessive state.

The variant spectrum includes frequent missense alterations (e.g., c.250G>A (p.Ala84Thr)) and splice or frameshift mutations leading to truncated proteins. c.250G>A (p.Ala84Thr) is a founder allele in southern Chinese and Taiwanese cohorts with an estimated carrier frequency of ~1:125 ([PMID:20138856]). Splice variants (e.g., c.1690+1G>T) abolish ETFDH expression, while deep intronic changes (c.35-959A>G) introduce pseudo-exons, highlighting the necessity for RNA‐based assays in unresolved cases.

Mechanisms of pathogenicity include protein instability, impaired FAD binding, and defective electron transfer to CoQ10. Patient-derived cells and ETFDH knock-in mice exhibit reduced ETFDH levels, mitochondrial bioenergetic deficits, lipid droplet accumulation, and clinical phenotypes that are rescued by riboflavin or CoQ10 supplementation ([PMID:30232818], [PMID:30709034]). In vitro, mutant ETFDH proteins show accelerated ubiquitin-proteasome degradation via CHIP, confirming a chaperone-mediated clearance pathway.

No significant conflicting evidence has been reported. Rare missense variants predicted benign by sequence alone (e.g., c.158A>G) have been shown experimentally to cause exon skipping and loss of ETFDH, emphasizing the importance of functional validation ([PMID:24123825]).

Integration of genetic and experimental data yields a consistent disease model: biallelic deleterious ETFDH variants disrupt electron transfer flavoprotein dehydrogenase activity, leading to impaired fatty acid oxidation and secondary CoQ10 deficiency. Riboflavin-responsive MADD displays robust genotype–phenotype correlations, with early diagnosis enabling life-saving intervention.

Key take-home: ETFDH testing is essential in individuals with unexplained lipid storage myopathy or recurrent metabolic crises, as riboflavin and coenzyme Q10 therapy can dramatically improve outcomes.

References

• Orphanet Journal of Rare Diseases • 2014 • Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency PMID:25200064
• Neuropathology • 2018 • Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency PMID:34066864
• Annals of Neurology • 2018 • FLAD1-associated multiple acyl-CoA dehydrogenase deficiency identified by newborn screening PMID:30232818
• Cells • 2019 • ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency PMID:30709034
• Frontiers in Pediatrics • 2020 • A Synonymous Variant c.579A>G in the ETFDH Gene Caused Exon Skipping in a Patient With Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report PMID:32292771

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