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Genetic and phenotypic analyses of PRRT2 positive and negative paroxysmal kinesigenic dyskinesia
Yingying Zhang1, Jiechuan Ren2, Tianhua Yang1
1Department of Neurology, West China Hospital of Sichuan University, Chengdu, China.
Background:
Paroxysmal 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.
Objective:
The objective was to investigate the clinical and genetic characteristics of PKD and to establish genotype-phenotype correlations.
Methods:
We 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.
Results:
Among 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.
Conclusion:
These 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.
Insights
Paroxysmal kinesigenic dyskinesia (PKD) is often caused by PRRT2 gene variants. Truncated PRRT2 variants may lead to more severe symptoms and bilateral attacks in PKD patients.
Area of Science:
- Genetics and Neurology
- Rare Neurological Disorders
- Molecular Genetics
Background:
- Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by involuntary movements triggered by sudden action.
- Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene are the most frequent genetic cause of PKD.
Purpose of the Study:
- To investigate the clinical and genetic characteristics of paroxysmal kinesigenic dyskinesia (PKD).
- To establish genotype-phenotype correlations in PKD patients.
- To expand the spectrum of genetic variants associated with PKD.
Main Methods:
- Enrolled 219 PKD patients, documenting clinical information.
- Performed PRRT2 gene screening using Sanger sequencing.
- Conducted whole exome sequencing on 49 PRRT2-negative probands and performed genotype-phenotype correlation analyses.
Main Results:
- Identified 16 PRRT2 variants (7 novel) in 219 PKD patients; mean diagnostic delay was 7.94 years.
- Patients with PRRT2 variants showed a positive family history, earlier onset, and higher fall prevalence compared to those without.
- Truncated PRRT2 variants were associated with bilateral attacks; TMEM151A variants were found in PRRT2-negative PKD cases.
Conclusions:
- Findings offer insights into PKD clinical characteristics, diagnosis, and treatment.
- Truncated PRRT2 variants may indicate more severe paroxysmal symptoms in PKD patients.
- Carbamazepine and oxcarbazepine are effective first-line treatments for PKD.
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