Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations

Jean-Loup Méreaux,Vincent Huin,Elena Pegoraro,Mélanie Papin,Rémi Valter,Kristina Lidström,Rita Rodrigues,Giovanni Vazza,Frédéric Taithe ,Guillaume Banneau,Giulia Coarelli,Daniel Nilsson,Livia Parodi,Cyril Goizet,José Loureiro ,Per Svenningsson,Mériem Tazir ,Cristina E Firanescu ,Alexandra Dürr ,Martin Paucar,Alexis Brice,Malin Kvarnung,Marie Coutelier,Sara Morais,E Le Guern ,Rayomand Press,Isabel Alonso,Jean‐Philippe Azulay ,Giovanni Stevanin

doi:10.1007/s10048-020-00633-2

Abstract

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.

Highlights

Spastic ataxias are rare neurodegenerative genetic disorders involving spinocerebellar and pyramidal tracts
We diagnosed a series of 21 cases of spastic ataxia with CAPN1 causative variants from 13 new families (Fig. 1)
We described a large series of 21 patients from 13 families with CAPN1 pathogenic variants causing various degrees of spastic ataxia, including nine novel variants

Summary

Introduction

Spastic ataxias are rare neurodegenerative genetic disorders involving spinocerebellar and pyramidal tracts. They belong to the clinical spectrum of hereditary spastic paraplegias (HSPs) and hereditary cerebellar ataxias (HCAs). Variants in more than a hundred genes have been implicated in their etiology [1, 2]. All classical transmission modes have been described. CAPN1 variants were initially associated with an autosomal recessive (AR) form of complex HSP (SPG76) or spastic ataxia in 2016 [3, 4]. An increasing number of patients have been described (n > 50). CAPN1 encodes the calpain-1 protein, a calcium-activated intracellular proteinase, Extended author information available on the last page of the article with numerous biological roles, including in synaptic plasticity and neuroprotection [5]

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Discussion

Conclusion