Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia

Background and Aim : Hereditary spastic paraplegia (HSP) is an umbrella name for a group of heterogenous neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, which are known to cause a form of atypical parkinsonism called Kufor-Rakeb syndrome (KRS), were recently suggested to also cause HSP in five families (SPG78).Methods : Whole-exome sequencing was done in CanHSP, a Canada-wide network for HSP which includes 696 patients.Results : We identified three additional patients from three different families with homozygous ATP13A2 mutations, representing 0.4% of all HSP patients and 0.7% of all HSP families. Spastic paraplegia was the most predominant feature in all three patients. The three patients presented with psychiatric symptoms which have been reported in only one SPG78 patient prior to the current study. One of the patients has developed seizure, spinocerebellar ataxia and dysmetria which have not been reported in SPG78. Of the three 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 to cause KRS but not HSP. Structural analysis of the missense mutations suggested a disruptive effect, and enrichment analysis suggested specific pathways potentially involved in HSP.Conclusion : Our study highlights the clinical variability of SPG78, and suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms. Additional studies are required to understand why there is such large phenotypic variability, even among carriers of the same mutation.

Keywords:

HSP , SPG78 , ATP13A2 , Parkinsonism , Neurodegeneration