Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Ann Clin Transl Neurol. 2020 Oct;7(10):1862-1869. doi: 10.1002/acn3.51169. Epub 2020 Aug 29.


Objective: Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia-spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity.

Methods: We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high-throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases.

Results: Six unreported CAPN1-associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs* 103, c.759+1G>A, and p.R285* ), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain-1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015).

Interpretation: Our study supports the clinically heterogeneous inter- and intra-family variability of SPG76 patients, and demonstrates that gender and calpain-1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia / genetics
  • Calpain / genetics*
  • Cerebellar Ataxia / genetics*
  • Female
  • Humans
  • Intellectual Disability / virology
  • Male
  • Muscle Spasticity / virology
  • Mutation / genetics*
  • Optic Atrophy / virology
  • Paraplegia / genetics
  • Pedigree
  • Phenotype*
  • Spastic Paraplegia, Hereditary / genetics*
  • Spinocerebellar Ataxias / virology


  • Calpain
  • CAPN1 protein, human

Supplementary concepts

  • Spastic Ataxia

Grants and funding

This work was funded by National Natural Science Foundation of China grants 81771230, 81801130, and U1905210; Joint Funds for the Innovation of Science and Technology of Fujian Province grants 2017Y9094 and 2018Y9082; Key Clinical Specialty Discipline Construction Program of Fujian grant ; Natural Science Foundation of Fujian Province grant 2019J05076; Startup Fund for scientific research of Fujian Medical University grants 2017XQ1072 and 2018QH2033.