SEPSECS – pontocerebellar hypoplasia type 2D

SEPSECS, a gene essential for selenoprotein biosynthesis, is robustly associated with pontocerebellar hypoplasia type 2D. Multiple independent studies have described affected individuals with autosomal recessive inheritance manifesting as neurodegeneration accompanied by cerebellar atrophy, microcephaly, and cognitive impairment (PMID:29464431). This association is supported by both early‐ and later‐onset cases, with some patients initially presenting with severe deficits in infancy, whereas others develop a milder progressive cerebellar ataxia in adulthood (PMID:36085396).

Genetic evidence is compelling. Several case reports and series have identified both homozygous and compound heterozygous variants – including missense and splice‐disrupting changes – in affected individuals. A representative pathogenic variant is c.1321G>A (p.Gly441Arg), which was identified in a 23‑year‑old affected woman and appears in multiple independent reports (PMID:29464431). Segregation analyses in extended family studies, with 19 additional affected relatives noted in multi‐patient investigations, further strengthen the link.

A broader review of the clinical literature highlights a total of 23 reported probands with pontocerebellar hypoplasia type 2D. These studies documented a range of variant types – from canonical loss‑of‑function to subtle synonymous variants impacting splicing – underscoring the diverse mutational spectrum in SEPSECS. The consistent recurrence of these variants across unrelated families provides robust genetic evidence for causation (PMID:35091508).

Functional studies complement the genetic findings. In vitro assays, animal models, and protein expression studies have demonstrated that altered SEPSECS activity leads to decreased selenoprotein synthesis, oxidative protein damage, and neuronal loss. These experimental results mirror the clinical neurodegenerative features seen in patients, providing moderate but essential functional support to the association (PMID:26115735, PMID:34794077).

Integrating the genetic and experimental findings establishes a coherent narrative where diverse pathogenic variants in SEPSECS lead to the neurodevelopmental and neurodegenerative features of pontocerebellar hypoplasia type 2D. The convergence of multiple case studies, segregation data and functional analyses exceeds the ClinGen scoring maximum and provides a strong evidence base that is directly applicable to diagnostic decision‑making and may further inform therapeutic strategies.

Key take‑home: The multi‐faceted evidence linking SEPSECS to pontocerebellar hypoplasia type 2D offers a high degree of clinical utility, ensuring that genetic testing for SEPSECS variants is a pivotal component in the diagnostic workup of patients with this neurodegenerative phenotype.

References

• Journal of inherited metabolic disease • 2018 • A SEPSECS mutation in a 23‑year‑old woman with microcephaly and progressive cerebellar ataxia PMID:29464431
• European journal of paediatric neurology • 2018 • Progressive cerebello‑cerebral atrophy and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy may be allelic syndromes PMID:30100179
• Cold Spring Harbor molecular case studies • 2022 • Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice‑disrupting synonymous variants in disease PMID:35091508
• Neurology • 2015 • Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate PMID:26115735

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