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

Int J Mol Sci. 2022 Jun 16;23(12):6723. doi: 10.3390/ijms23126723.

Abstract

The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene encodes an InsP3-gated calcium channel that modulates intracellular Ca2+ release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the ITPR1 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 ITPR1-related neuroimaging findings, the brain MRI of 14 patients with ITPR1 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 ITPR1-related conditions, the ITPR1 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 ITPR1 variants, suggesting this MRI finding could represent a hallmark for ITPR1-related disorders.

Keywords: MRI; ataxia; cerebellar atrophy.

MeSH terms

  • Adult
  • Atrophy
  • Cerebellum / abnormalities
  • Developmental Disabilities
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol*
  • Nervous System Malformations
  • Pedigree
  • Spinocerebellar Ataxias
  • Spinocerebellar Degenerations

Substances

  • ITPR1 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Inositol

Supplementary concepts

  • Cerebellar Hypoplasia
  • Spinocerebellar Ataxia 15
  • Spinocerebellar Ataxia 29

Grants and funding

The work was supported by funds from the Italian Ministry of Health (grant # RC2021 265 and RC2022 to IRCCS Medea and IRCCS Mondino, Ricerca Finalizzata grant number RF-2019-266 12369368 to E.M.V.), 5X MILLE (to R.R.), Fondazione Mariani (Neuropediatric Network project to E.M.V. 267 and R.B.) and funds from the Fondazione Regionale Lombarda per la Ricerca Biomedica FRRB (grant 268 # Care4NeuroRare to M.T.B.). E.B. and G.Z. are members of the European Reference Network for Rare 269 Neurological Diseases—Project ID No 739510.