Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy

Abstract

Mutations in the SQSTM1 gene have recently been identified as rare causes of progressive childhood neurodegenerative diseases. To date, only 27 cases have been reported, with 11 different mutations affecting SQSTM1. Here, we describe two new cases of progressive childhood-onset cerebellar ataxia with gaze palsy, in whom clinical exome sequencing identified a novel pathogenic variant. The first patient was a 12-year-old boy of Iraqi and Iranian descent, who presented with a 3-year history of recurrent falls, swaying while walking, and difficulties with writing and speech. Physical examination revealed frozen eye movements, gait ataxia, and dysarthria. The second patient was a 9-year-old Iranian boy, who developed involuntary movements, gait instability, and tremor at the age of 8 years. On examination, cerebellar ataxia and dysarthria were observed. In both cases, initial workup was unremarkable, but whole-exome sequencing revealed a novel homozygous pathogenic truncating mutation, SQSTM1 (c.838G>T, p. Glu280Ter). During 2 years of follow-up, the second patient developed gaze palsy. This report highlights the importance of considering SQSTM1 mutations in the differential diagnosis of patients presenting with both cerebellar ataxia and ophthalmological manifestations.