EEFSEC deficiency underlies a human selenopathy with primary neurodevelopmental origins via midbrain-hindbrain hypoplasia.

Abstract

Bi-allelic mutations in EEFSEC, a key factor in selenoprotein synthesis, cause a severe human selenopathy characterized by developmental delay, spasticity, and profound cerebellar atrophy. While previous studies in invertebrate models framed this condition as an early-onset neurodegenerative disorder, the contribution of primary developmental defects to the severe brain malformations in patients has remained a critical unanswered question. Here, we address this gap using a zebrafish model of EEFSEC deficiency. We discovered that loss of eefsec function does not impair global somatic growth but instead causes specific and significant hypoplasia of the midbrain and hindbrain-the embryonic precursors to the human cerebellum and brain stem. These structural defects directly correlate with robust behavioral impairments, including diminished locomotion and blunted escape responses, mirroring the severe motor dysfunction in patients. Critically, our findings provide the in vivo evidence from a vertebrate model that this disorder involves a primary neurodevelopmental defect, which underlies the severe brain malformations and creates a structurally vulnerable nervous system. This establishes a developmental basis for understanding this condition. We propose that this initial failure in brain construction, which we term a developmental selenopathy, creates a structurally vulnerable nervous system, providing a plausible mechanistic explanation for the human phenotype and proposing a framework for understanding this devastating condition.