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

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

Author information

1
Department of Human Genetics, McGill University, Montréal, QC, Canada.
2
Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
3
Faculty of Medicine, McGill University, Montréal, QC, Canada.
4
Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
5
Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.
6
Department of Pharmacology & Therapeutics, McGill University, Montréal, QC, Canada.
7
Centre for Structural Biology, McGill University, Montréal, QC, Canada.

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.

KEYWORDS:

ATP13A2 ; HSP; Neurodegeneration; Parkinsonism

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