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


ABSTRACT: 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.

SUBMITTER: Estiar MA 

PROVIDER: S-EPMC7057081 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Estiar Mehrdad A MA   Leveille Etienne E   Spiegelman Dan D   Dupre Nicolas N   Trempe Jean-François JF   Rouleau Guy A GA   Gan-Or Ziv Z  

Molecular genetics & genomic medicine 20200115 3


<h4>Background</h4>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.<h4>Methods</h4>Whole-exome sequencing was done in a Canada-wide HSP cohort.<h4>Results</h4>Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic para  ...[more]

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