Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype

Mol Genet Genomic Med. 2020 Mar;8(3):e1052. doi: 10.1002/mgg3.1052. Epub 2020 Jan 15.


Background: Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP.

Methods: Whole-exome sequencing was done in a Canada-wide HSP cohort.

Results: Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways.

Conclusion: Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.

Keywords: ATP13A2; HSP; Neurodegeneration; Parkinsonism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Enzyme Stability
  • Female
  • Gene Frequency
  • Homozygote
  • Humans
  • Male
  • Mutation
  • Paraplegia / genetics*
  • Paraplegia / pathology
  • Phenotype*
  • Proton-Translocating ATPases / chemistry
  • Proton-Translocating ATPases / genetics*


  • ATP13A2 protein, human
  • Proton-Translocating ATPases