ETFB – Multiple Acyl-CoA Dehydrogenase Deficiency

Electron transfer flavoprotein beta subunit (ETFB) deficiency is an autosomal recessive cause of multiple acyl-CoA dehydrogenase deficiency (MADD) (ETFB – Multiple acyl-CoA dehydrogenase deficiency). Patients present with a spectrum ranging from severe neonatal forms with congenital anomalies to mild late-onset lipid storage myopathy. Biochemical hallmarks include elevated urinary organic acids, low free carnitine, and impaired fatty acid oxidation in fibroblasts.

Genetic evidence derives from at least 5 unrelated probands with biallelic ETFB variants: a late-onset case with c.124T>C (p.Cys42Arg) and c.605_607delAGA (p.Lys205del) (PMID:12706375), a neonatal patient homozygous for c.143_145del (p.Glu48del) (PMID:27081516), two ETFB-mutant patients in a cohort of 16 with ETF deficiency (PMID:16510302), and additional cases in an eight-patient series with ETFB assembly defects (PMID:1430199, PMID:18289905). All reported variants segregate with disease in an autosomal recessive pattern.

The variant spectrum in ETFB includes missense changes (e.g., c.124T>C (p.Cys42Arg)), small in-frame deletions (c.143_145del (p.Glu48del)), frameshifts, and splice mutations. No recurrent founder alleles have been established. The predominant inheritance is autosomal recessive, and no population carrier frequencies have been described for ETFB variants to date.

Clinically, late-onset ETFB-related MADD manifests with exercise intolerance (HP:0003546), muscle weakness (HP:0001324), chronic fatigue (HP:0012432), and, in some cases, respiratory distress (HP:0002098). Neonatal forms may present with hypoglycemia, metabolic acidosis, and congenital anomalies. Riboflavin responsiveness is well documented for ETFDH mutations but is less predictable in ETFB-deficient patients.

Functional assays demonstrate markedly reduced ETF activity (<20% of control) in patient fibroblasts, with impaired oxidation of [9,10-3H]palmitate and myristate. Western blot and thermal stability studies show decreased ETFB protein levels and destabilized heterodimer assembly, consistent with a loss-of-function mechanism ([PMID:12706375], [PMID:16510302]).

Integration of genetic and functional data supports a strong gene–disease relationship. Early molecular diagnosis of ETFB deficiency allows prompt intervention, although riboflavin therapy shows variable benefit. Key take-home: ETFB mutations cause autosomal recessive MADD with consistent biochemical and functional defects, underscoring the importance of including ETFB in genetic panels for fatty acid oxidation disorders.

References

• Molecular genetics and metabolism • 2003 • Late-onset form of beta-electron transfer flavoprotein deficiency. PMID:12706375
• Human genome variation • 2015 • A novel ETFB mutation in a patient with glutaric aciduria type II. PMID:27081516
• Molecular genetics and metabolism • 2006 • Electron transfer flavoprotein deficiency: functional and molecular aspects. PMID:16510302
• The Journal of clinical investigation • 1992 • Glutaric acidemia type II. Heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha subunit of electron transfer flavoprotein in eight patients. PMID:1430199
• Molecular genetics and metabolism • 2008 • Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2. PMID:18289905

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