SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

Eur J Hum Genet. 2016 Jul;24(7):1016-21. doi: 10.1038/ejhg.2015.240. Epub 2015 Dec 2.

Abstract

Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed whole-exome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adult
  • Exome
  • Female
  • Genes, Recessive
  • Heterozygote
  • Humans
  • Intellectual Disability / epidemiology
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Metalloendopeptidases / genetics*
  • Middle Aged
  • Muscle Spasticity / epidemiology
  • Muscle Spasticity / genetics*
  • Muscle Spasticity / pathology
  • Mutation, Missense*
  • Optic Atrophy / epidemiology
  • Optic Atrophy / genetics*
  • Optic Atrophy / pathology
  • Prevalence
  • Quebec
  • Spinocerebellar Ataxias / epidemiology
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / pathology

Substances

  • Metalloendopeptidases
  • SPG7 protein, human
  • ATPases Associated with Diverse Cellular Activities

Supplementary concepts

  • Spastic Ataxia