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

PURPOSE: Protein-altering gene variants in SEPSECS disrupt the biosynthesis of selenoproteins, leading to a spectrum of neurological diseases.

METHODS

We studied 27 individuals with biallelic SEPSECS variants and identified 13 unreported gene variants. To better understand and diagnose the disorder, broad biochemical correlations of neurological symptoms, focused metabolomics, and structural and in vitro activity analyses were deployed.

RESULTS

Our results suggest 3 general clinical courses: (i) severe early onset with cerebellar or cerebral atrophy, (ii) milder early onset with gradual deterioration, and (iii) late-onset, mild disease. SEPSECS variants primarily affect the brain. In only 1 individual out of 8, thyroid hormone measurements suggested a defect in T4 to T3 conversion. An accompanied increase in glutathione and sulfur metabolites in plasma indicates elevated oxidative stress. Variants mapping to conserved N- and C-termini and the catalytic site elicit SEPSECS misfolding, aggregation, thermal instability, and loss of function, which could ultimately lead to ferroptosis of neurons and perhaps oligodendrocytes. For differential diagnosis and monitoring therapeutic attempts, we recommend measuring the levels of plasma selenium, glutathione, and sulfur metabolites, GPX activity, and SELENOP. Given the pontine involvement in less than half of the cases, we suggest renaming the syndrome from pontocerebellar hypoplasia type 2D to SEPSECS-related neurodevelopmental disorder.

CONCLUSION

Our study expands the understanding of SEPSECS-related neurodevelopmental disorders, highlighting the need for updated diagnostic criteria and potential treatment strategies.