SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia

Abstract

Background: Deletions in ITPR1, coding for the inositol-triphosphate receptor type 1, have been recently identified in spinocerebellar ataxia type 15 (SCA15).

Objective: To determine the frequency and the phenotypical spectrum of SCA15.

Design: Taqman polymerase chain reaction (258 index cases) or single-nucleotide polymorphism genome-wide genotyping (75 index cases).

Setting: A collaboration between the Centre de Recherche de l'Institut de Cerveau et de la Moelle Epinière of the Salpêtrière Hospital (Paris, France) and the Molecular Genetics Unit of the National Institute of Aging (Bethesda, Maryland). Patients Index cases of 333 families with autosomal dominant cerebellar ataxia negative for CAG repeat expansions in coding exons.

Main outcome measures: Detection of ITPR1 copy number alterations.

Results: A deletion of ITPR1 was found in 6 of 333 families (1.8%), corresponding to 13 patients with SCA15. Age at onset ranged from 18 to 66 years (mean [SD] age, 35 [16] years). The symptom at onset was cerebellar gait ataxia, except in 1 patient with isolated upper limb tremor. Although families were tested irrespective of their phenotype, patients with SCA15 had a homogeneous phenotype and were characterized by a slowly progressive cerebellar ataxia. However, pyramidal signs (2 patients) and mild cognitive problems (2 patients) were occasionally present. Radiologic findings showed global or predominant vermian cerebellar atrophy in all patients.

Conclusions: In this series, ITPR1 deletions were rare and accounted for approximately 1% of all autosomal dominant cerebellar ataxias. The SCA15 phenotype mostly consists of a slowly progressive isolated cerebellar ataxia with variable age at onset; an additional pyramidal syndrome and problems in executive functions may be present.

Figure 1

pedigree of the six SCA15 families. The asterisks indicate that DNA was available for genetic analysis

Figure 2

Brain MRI of patient BOR-279-1 at 63 years. Sagittal T1-weighted images (A, B) showing global cerebellar atrophy, mainly involving cerebellar vermis; axial T2Flair-weighted image (C) and T2-weighted image (D) showing involvement of cerebellar hemispheres.

Figure 3. Brain MRI of patient EPI-21-5 at 51 years

Sagittal T1-weighted images showing upper and dorsal cerebellar vermis atrophy with sparing of the pons (A) and cerebellar hemispheres (B); axial T1-weighted image (C) and T2-weighted image (D) showing relative sparing of cerebellar hemispheres.