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A Novel Truncation Mutation of the PRRT2 Gene Resulting in a 16-Amino-Acid Protein Causes Self-inducible Paroxysmal Kinesigenic Dyskinesia.

ABSTRACT: Paroxysmal kinesigenic dyskinesia (PKD) is a sporadic or autosomal-dominant, hereditary disorder characterized by brief, recurrent attacks of involuntary movements triggered by sudden, voluntary movement that generally develops during childhood and adolescence and is typically treated with carbamazepine. The proline-rich transmembrane protein 2 (PRRT2) gene contains 4 exons that encode 340 amino acids as the major isoform, and recent research has identified PRRT2 as the primary causative gene in PKD, benign familial infantile epilepsy (BFIE), and infantile convulsions with PKD (PKD/IC). Here, the authors report the phenotype of a family with a novel p.E16X (c.46G>T) nonsense mutation of the PRRT2 gene that lacked almost a full allele. In this family, none of the individuals in the pedigree exhibited evidence of cognitive impairment: the elder brother had PKD/IC with migraine; the younger brother had PKD with ataxia; the father had PKD; both siblings experienced a sensory aura; and all 3 had a history of febrile seizures. This is the first report of a short nonsense mutation in PRRT2 and indicates that the manifestations of the disease, including other mutations to date, can be explained by haploinsufficiency and that 1 intact PRRT2 allele can allow normal cognitive development.

SUBMITTER: Kita M

PROVIDER: S-EPMC6353529 | biostudies-literature | 2017 Jul-Aug

REPOSITORIES: biostudies-literature

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A Novel Truncation Mutation of the PRRT2 Gene Resulting in a 16-Amino-Acid Protein Causes Self-inducible Paroxysmal Kinesigenic Dyskinesia.

Kita Makoto M Kuwata Yasuhiro Y Murase Nagako N Akiyama Yuichi Y Usui Takeshi T

Movement disorders clinical practice 20170523 4

Paroxysmal kinesigenic dyskinesia (PKD) is a sporadic or autosomal-dominant, hereditary disorder characterized by brief, recurrent attacks of involuntary movements triggered by sudden, voluntary movement that generally develops during childhood and adolescence and is typically treated with carbamazepine. The proline-rich transmembrane protein 2 (PRRT2) gene contains 4 exons that encode 340 amino acids as the major isoform, and recent research has identified PRRT2 as the primary cau ...[more]

PMID: 30713971

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Project description:BackgroundParoxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder, characterized by attacks of involuntary movements triggered by sudden action. Variants in proline-rich transmembrane protein 2 (PRRT2) are the most common genetic cause of PKD.ObjectiveThe objective was to investigate the clinical and genetic characteristics of PKD and to establish genotype-phenotype correlations.MethodsWe enrolled 219 PKD patients, documented their clinical information and performed PRRT2 screening using Sanger sequencing. Whole exome sequencing was performed on 49 PKD probands without PRRT2 variants. Genotype-phenotype correlation analyses were conducted on the probands.ResultsAmong 219 PKD patients (99 cases from 39 families and 120 sporadic cases), 16 PRRT2 variants were identified. Nine variants (c.879+4A>G, c.879+5G>A, c.856G>A, c.955G>T, c.884G>C, c.649C>T, c.649dupC, c.649delC and c.696_697delCA) were previously known, while seven were novel (c.367_403del, c.347_348delAA, c.835C>T, c.116dupC, c.837_838insC, c.916_937del and c.902G>A). The mean interval from onset to diagnosis was 7.94 years. Compared to patients without PRRT2 variants, patients with the variants were more likely to have a positive family history, an earlier age of onset and a higher prevalence of falls during pre-treatment attacks (27.14% versus 8.99%, respectively). Patients with truncated PRRT2 variants tend to have bilateral attacks. We identified two transmembrane protein 151A (TMEM151A) variants including a novel variant (c.368G>C) and a reported variant (c.203C>T) in two PRRT2-negative probands with PKD.ConclusionThese findings provide insights on the clinical characteristics, diagnostic timeline and treatment response of PKD patients. PKD patients with truncated PRRT2 variants may tend to have more severe paroxysmal symptoms. This study expands the spectrum of PRRT2 and TMEM151A variants. Carbamazepine and oxcarbazepine are both used as a first-line treatment choice for PKD patients.

Dataset Information

A Novel Truncation Mutation of the PRRT2 Gene Resulting in a 16-Amino-Acid Protein Causes Self-inducible Paroxysmal Kinesigenic Dyskinesia.

Publications

A Novel Truncation Mutation of the <i>PRRT2</i> Gene Resulting in a 16-Amino-Acid Protein Causes Self-inducible Paroxysmal Kinesigenic Dyskinesia.

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