Disease characteristics of SEPSECS deficiency: an international, retrospective, multicenter cohort study.

Biallelic SEPSECS variants disrupt selenoprotein biosynthesis; variants in the conserved N- and C-termini and catalytic site cause misfolding, aggregation, thermal instability and loss of function, with oxidative stress and possible neuronal ferroptosis.

This international retrospective multicenter study describes 27 individuals with biallelic SEPSECS variants, including 13 previously unreported variants. Broad biochemical correlation, focused metabolomics, and structural and in vitro activity analyses delineate three clinical courses: severe early-onset with cerebellar or cerebral atrophy, milder early-onset with gradual deterioration, and late-onset mild disease. Involvement is primarily cerebral: in only one of eight individuals assessed did thyroid hormone measurements suggest defective T4 to T3 conversion, whereas increased plasma glutathione and sulfur metabolites indicated elevated oxidative stress. For differential diagnosis and monitoring of therapeutic attempts, the authors recommend measuring plasma selenium, glutathione and sulfur metabolites, GPX activity, and SELENOP. Because pontine involvement was present in fewer than half of cases, they propose renaming PCH2D as SEPSECS-related neurodevelopmental disorder.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The proposed renaming is not cosmetic: using pontocerebellar hypoplasia as the radiological entry point misses more than half of cases, and this study should prompt reconsideration of SEPSECS variants dismissed on an unsuggestive MRI. The proposed biochemical panel (selenium, glutathione, sulfur metabolites, GPX, SELENOP) is the real operational contribution, but it still needs prospective validation as a differential diagnostic aid, since here it is derived from the cohort itself. With 27 patients spread across three trajectories, individual prognosis cannot yet be given from variant position alone.

Analysis by Dr Thibaut Benquey