EEFSEC deficiency: A selenopathy with early-onset neurodegeneration.

Summary

Across nine individuals from eight families, bi-allelic EEFSEC variants cause a selenoprotein deficiency syndrome with early-onset progressive neurodegeneration dominated by cerebellar pathology. Functional assays in fibroblasts and an eEFSec-RNAi Drosophila model validate reduced selenoprotein synthesis and link the genotype to synaptic and motor dysfunction.

Key Findings

• Six distinct bi-allelic EEFSEC variants identified in nine individuals cause a recessive selenoprotein deficiency disorder.
• Patient fibroblasts show reduced selenoprotein levels, confirming impaired EEFSEC function.
• An eEFSec-RNAi Drosophila model recapitulates progressive motor and synaptic defects, aligning with human cerebellar-dominant pathology.

Clinical Implications

Enables genetic diagnosis and counseling for selenopathy; suggests exploring targeted metabolic support (e.g., selenium status, antioxidant pathways) while future therapies could modulate selenoprotein synthesis.

Limitations

• Small sample size inherent to rare disease case series
• Limited therapeutic data; interventional strategies remain speculative

Future Directions

Elucidate tissue-specific selenoprotein deficits and test metabolic or gene-based interventions in models; establish natural history to inform trial endpoints.