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. 2021 Mar;22(1):71-79.
doi: 10.1007/s10048-020-00633-2. Epub 2021 Jan 23.

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

Jean-Loup Méreaux  1   2   3 , Cristina Firanescu  4 , Giulia Coarelli  1   5 , Malin Kvarnung  6   7 , Rita Rodrigues  8 , Elena Pegoraro  9 , Meriem Tazir  10 , Frédéric Taithe  11 , Rémi Valter  1   3 , Vincent Huin  1 , Kristina Lidström  4 , Guillaume Banneau  12 , Sara Morais  1   3   13 , Livia Parodi  1   3   14 , Marie Coutelier  1   3 , Mélanie Papin  1   3 , Per Svenningsson  4   15 , Jean-Philippe Azulay  16 , Isabel Alonso  13   17 , Daniel Nilsson  6   7 , Alexis Brice  1 , Eric Le Guern  12 , Rayomand Press  4   15 , Giovanni Vazza  14 , José Leal Loureiro  8 , Cyril Goizet  18   19 , Alexandra Durr  1   5 , Martin Paucar  4   15 , Giovanni Stevanin  20   21   22   23
Affiliations

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

Jean-Loup Méreaux et al. Neurogenetics. 2021 Mar.

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.

Keywords: CAPN1; Cerebellar ataxia; Neurodegeneration; Spastic ataxia; Spastic paraplegia.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Pedigrees of CAPN1 families. Affected filled in black. Squares for men, circles for women, lozenges for men or women, small circles if stillborn. Numbers in squares and circles denote the number of people with similar characteristics to simplify the figure. Below the symbols are indicated the anonymous DNA sample identifier. Arrows show the probands
Fig. 2
Fig. 2
Calpain-1 with its 3 functional domains and all reported pathogenic variants (new in bold; truncating variants localized with a lozenge whereas a simple line for non-truncating variants. Below the protein are the corresponding CAPN1 coding exons)
Fig. 3
Fig. 3
Clinical summary of the 83 CAPN1-mutated cases reported in the literature, including our 21 cases (number at the end of each line indicates the number of cases with available data)
See this image and copyright information in PMC

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