Superior Cerebellar Atrophy: An Imaging Clue to Diagnose ITPR1-Related Disorders

Abstract

The inositol 1,4,5-triphosphate receptor type 1 (<i>ITPR1</i>) gene encodes an InsP₃-gated calcium channel that modulates intracellular Ca²⁺ release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the <i>ITPR1</i> gene are associated with different types of autosomal dominant spinocerebellar ataxia: SCA15 (adult onset), SCA29 (early-onset), and Gillespie syndrome. Cerebellar atrophy/hypoplasia is invariably detected, but a recognizable neuroradiological pattern has not been identified yet. With the aim of describing <i>ITPR1</i>-related neuroimaging findings, the brain MRI of 14 patients with <i>ITPR1</i> variants (11 SCA29, 1 SCA15, and 2 Gillespie) were reviewed by expert neuroradiologists. To further evaluate the role of superior vermian and hemispheric cerebellar atrophy as a clue for the diagnosis of <i>ITPR1</i>-related conditions, the <i>ITPR1</i> gene was sequenced in 5 patients with similar MRI pattern, detecting pathogenic variants in 4 of them. Considering the whole cohort, a distinctive neuroradiological pattern consisting in superior vermian and hemispheric cerebellar atrophy was identified in 83% patients with causative <i>ITPR1</i> variants, suggesting this MRI finding could represent a hallmark for <i>ITPR1</i>-related disorders.