Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms

Overview

Journal Neurosci Bull

Specialty Neurology

Date 2023 Dec 13

PMID 38091244

Authors

Jiao-Jiao Xu

Hong-Fu Li

Zhi-Ying Wu

Affiliations

Soon will be listed here.

Abstract

Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal movement disorder, is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements. PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene. The exact pathophysiological mechanisms of PKD remain unclear, although the function of PRRT2 protein has been well characterized in the last decade. Based on abnormal ion channels and disturbed synaptic transmission in the absence of PRRT2, PKD may be channelopathy or synaptopathy, or both. In addition, the cerebellum is regarded as the key pathogenic area. Spreading depolarization in the cerebellum is tightly associated with dyskinetic episodes. Whereas, in PKD, other than the cerebellum, the role of the cerebrum including the cortex and thalamus needs to be further investigated.

Citing Articles

Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment.

Spoto G, Ceraolo G, Butera A, Di Rosa G, Nicotera A Curr Issues Mol Biol. 2024; 46(6):5632-5654.

PMID: 38921008 PMC: 11202702. DOI: 10.3390/cimb46060337.

Narrative Review of Brivaracetam: Preclinical Profile and Clinical Benefits in the Treatment of Patients with Epilepsy.

Klein P, Bourikas D Adv Ther. 2024; 41(7):2682-2699.

PMID: 38811492 PMC: 11213745. DOI: 10.1007/s12325-024-02876-z.

References

Kertesz A . Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology. 1967; 17(7):680-90. DOI: 10.1212/wnl.17.7.680. View

Chen W, Lin Y, Xiong Z, Wei W, Ni W, Tan G . Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet. 2011; 43(12):1252-5. DOI: 10.1038/ng.1008. View

Li H, Chen Y, Zhuang L, Chen D, Ke H, Luo W . TMEM151A variants cause paroxysmal kinesigenic dyskinesia. Cell Discov. 2021; 7(1):83. PMC: 8437987. DOI: 10.1038/s41421-021-00322-w. View

Wang H, Li H, Liu G, Wen X, Wu Z . Mutation Analysis of MR-1, SLC2A1, and CLCN1 in 28 PRRT2-negative Paroxysmal Kinesigenic Dyskinesia Patients. Chin Med J (Engl). 2016; 129(9):1017-21. PMC: 4852666. DOI: 10.4103/0366-6999.180529. View

Yin X, Lin J, Cao L, Zhang T, Zeng S, Zhang K . Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene. Hum Mol Genet. 2018; 27(4):625-637. DOI: 10.1093/hmg/ddx430. View

Li H, Chen W, Ni W, Wang K, Liu G, Wang N . PRRT2 mutation correlated with phenotype of paroxysmal kinesigenic dyskinesia and drug response. Neurology. 2013; 80(16):1534-5. DOI: 10.1212/WNL.0b013e31828cf7e1. View

Valtorta F, Benfenati F, Zara F, Meldolesi J . PRRT2: from Paroxysmal Disorders to Regulation of Synaptic Function. Trends Neurosci. 2016; 39(10):668-679. DOI: 10.1016/j.tins.2016.08.005. View

Fruscione F, Valente P, Sterlini B, Romei A, Baldassari S, Fadda M . PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity. Brain. 2018; 141(4):1000-1016. PMC: 5888929. DOI: 10.1093/brain/awy051. View

Meneret A, Grabli D, Depienne C, Gaudebout C, Picard F, Durr A . PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology. 2012; 79(2):170-4. DOI: 10.1212/WNL.0b013e31825f06c3. View

10.

Huang X, Wang S, Guo X, Tian W, Zhan F, Zhu Z . The Phenotypic and Genetic Spectrum of Paroxysmal Kinesigenic Dyskinesia in China. Mov Disord. 2020; 35(8):1428-1437. DOI: 10.1002/mds.28061. View

11.

Li H, Ni W, Xiong Z, Xu J, Wu Z . PRRT2 c.649dupC mutation derived from de novo in paroxysmal kinesigenic dyskinesia. CNS Neurosci Ther. 2012; 19(1):61-5. PMC: 6493561. DOI: 10.1111/cns.12034. View

12.

Chen Y, Chen D, Ke H, Zhao S, Li H, Wu Z . Paroxysmal Kinesigenic Dyskinesia Caused by 16p11.2 Microdeletion and Related Clinical Features. Neurol Genet. 2022; 8(2):e659. PMC: 8855691. DOI: 10.1212/NXG.0000000000000659. View

13.

Tsai M, Nian F, Hsu M, Liu W, Liu Y, Liu C . PRRT2 missense mutations cluster near C-terminus and frequently lead to protein mislocalization. Epilepsia. 2019; 60(5):807-817. DOI: 10.1111/epi.14725. View

14.

Zhao S, Li L, Chen Y, Chen Y, Liu G, Dong H . Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2-related disorders. CNS Neurosci Ther. 2019; 26(1):39-46. PMC: 6930815. DOI: 10.1111/cns.13147. View

15.

Tan G, Liu Y, Wang L, Li K, Zhang Z, Li H . PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by regulating synaptic transmission in cerebellum. Cell Res. 2017; 28(1):90-110. PMC: 5752836. DOI: 10.1038/cr.2017.128. View

16.

Huang X, Wang T, Wang J, Liu X, Che X, Li J . Paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 110 patients. Neurology. 2015; 85(18):1546-53. DOI: 10.1212/WNL.0000000000002079. View

17.

Heron S, Grinton B, Kivity S, Afawi Z, Zuberi S, Hughes J . PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet. 2012; 90(1):152-60. PMC: 3257886. DOI: 10.1016/j.ajhg.2011.12.003. View

18.

Lee H, Huang Y, Bruneau N, Roll P, Roberson E, Hermann M . Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep. 2012; 1(1):2-12. PMC: 3334308. DOI: 10.1016/j.celrep.2011.11.001. View

19.

Riant F, Roos C, Roubertie A, Barbance C, Hadjadj J, Auvin S . Hemiplegic Migraine Associated With Variations: A Clinical and Genetic Study. Neurology. 2021; 98(1):e51-e61. DOI: 10.1212/WNL.0000000000012947. View

20.

Liu Q, Qi Z, Wan X, Li J, Shi L, Lu Q . Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression. J Med Genet. 2012; 49(2):79-82. DOI: 10.1136/jmedgenet-2011-100653. View