EEF2 – Spinocerebellar Ataxia Type 26

Autosomal dominant spinocerebellar ataxia type 26 (SCA26) is an ultra‐rare late-onset cerebellar ataxia originally described in a single six-generation Norwegian family segregating a missense variant in EEF2. Subsequent reports have identified de novo heterozygous EEF2 mutations in pediatric patients presenting with developmental delay and syndactyly, broadening the phenotypic spectrum beyond pure adult-onset ataxia. This body of evidence supports a strong gene-disease link for EEF2 and SCA26.

In the founding SCA26 pedigree, a missense variant in EEF2 co-segregated with cerebellar atrophy and progressive ataxia across six generations (PMID:35847164). More recently, four unrelated pediatric cases—three previously reported and one new eight-year-old boy—harbored the de novo variant c.2207C>T (p.Ala736Val) and presented with global developmental delay (HP:0001263) and syndactyly (HP:0001159) alongside ataxic features (PMID:35847164).

The variant spectrum in SCA26 is currently limited to missense substitutions affecting residues critical for translational fidelity. Key alleles include c.1787C>A (p.Pro596His), identified by targeted deep sequencing of the SCA26 interval (PMID:23001565), and the recurrent de novo c.2207C>T (p.Ala736Val).

Functional assays in yeast models have demonstrated that the p.Pro596His substitution impairs ribosomal translocation, increases –1 frameshifting, and heightens susceptibility to proteostatic stress, consistent with a toxic gain-of-function mechanism (PMID:23001565). These data concord with the neurodegenerative phenotype observed in patients and support pathogenicity.

No studies to date have refuted the association or described benign EEF2 variants in SCA26. Taken together, genetic segregation in a multi-generation pedigree, multiple unrelated de novo cases, and functional concordance in model systems satisfy ClinGen criteria for a strong gene–disease relationship.

Key take-home: Heterozygous missense variants in EEF2 cause SCA26 with an expanded phenotype including early‐onset developmental delay and limb anomalies, informing genetic diagnosis and counseling.

References

• Cureus • 2022 • A Comparison of Pathogenic Eukaryotic Elongation Factor 2 (EEF2) Variants in Spinocerebellar Ataxia 26 Versus De Novo Mutations. PMID:35847164
• Human molecular genetics • 2012 • A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult. PMID:23001565

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