Genetic updates on paroxysmal dyskinesias

Liao, James; Salles, Philippe A.; Shuaib, Umar; Fernández, Hubert H.

doi:10.1007/s00702-021-02335-x

Cited by 13 publications

(10 citation statements)

References 155 publications

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“…PKD is the most common phenotype of paroxysmal dyskinesia, which is a diverse group of genetic disorders that manifest as recurrent episodes of dystonia, chorea, or ballism, with specific triggers, attack frequency, and duration. 1,10,26 Although PKD is inherited in an autosomal dominant manner, sporadic patients are more common, which causes difficulties in family-based strategies for the identification of causative gene. Here, GRIPT was applied to identify new causative genes, which was different to the method of the meantime research by Li and colleagues.…”

Section: Discussionmentioning

confidence: 99%

“…1,7 In addition, multiple genes related to the pathogenesis of PKD, including PNKD, SLC2A1, KCNMA1, DEPDC5, KCNA1, SCN8A, and CHRNA4, have also been reported. [8][9][10][11][12] However, nearly two-thirds of PKD patients still have no clearly defined genetic etiology, indicating that additional culprit genes are yet to be identified or that genotypic overlap between PKD and other paroxysmal disorders might exist. Due to the episodic clinical features and the function of PKD-related genes, the underlying mechanism of PKD is assumed to be associated with the disturbance in cellular excitability.…”

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confidence: 99%

“…Hitherto, more than 80 mutations, most of which are truncated variants, have been documented in approximately 34% patients of PKD 1,7 . In addition, multiple genes related to the pathogenesis of PKD, including PNKD , SLC2A1 , KCNMA1 , DEPDC5 , KCNA1 , SCN8A , and CHRNA4 , have also been reported 8‐12 . However, nearly two‐thirds of PKD patients still have no clearly defined genetic etiology, indicating that additional culprit genes are yet to be identified or that genotypic overlap between PKD and other paroxysmal disorders might exist.…”

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TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large‐Sample Study

et al. 2021

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Background Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one‐third of PKD patients are attributed to proline‐rich transmembrane protein 2 (PRRT2) mutations. Objective We aimed to explore the potential causative gene for PKD. Methods A cohort of 196 PRRT2‐negative PKD probands were enrolled for whole‐exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case–control analysis, was applied to identify the candidate genes. Another 325 PRRT2‐negative PKD probands were subsequently screened with Sanger sequencing. Results Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A‐related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A‐positive and PRRT2‐positive groups. Conclusions We consolidated mutations in TMEM151A causing PKD with the aid of case–control analysis of a large‐scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A‐related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A‐related PKD. © 2021 International Parkinson and Movement Disorder Society

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TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large‐Sample Study

et al. 2021

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“…In 2011, the gene proline-rich transmembrane protein 2 ( PRRT2 ) was first identified to be associated with PKD, which accounts for 77–93% familial and 21–45% isolated PKD ( 2 , 3 ). Other genes, such as PNKD (paroxysmal nonkinesigenic dyskinesia protein), SLC2A1 (solute carrier family 2 members 1), KCNA1 (potassium voltage-gated channel subfamily A member 1), and CHRNA4 (cholinergic receptor nicotinic alpha 4 subunits), have been proved to be associated with PKD as well ( 4 – 6 ). In recent studies, three research teams identified mutations of the TMEM151A gene (transmembrane protein 151A) as causative factors of PKD ( 7 – 9 ).…”

Section: Introductionmentioning

confidence: 99%

Screening of the TMEM151A Gene in Patients With Paroxysmal Kinesigenic Dyskinesia and Other Movement Disorders

Lin²,

Niu

et al. 2022

Front. Neurol.

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BackgroundParoxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent involuntary movements usually triggered by sudden movements. Mutations in the TMEM151A gene were found to be the causative factor of PKD in recent studies. It has also been revealed that loss-of-function is the mechanism by which TMEM151A mutations cause PKD.MethodsTo investigate the genetic basis of PKD and broaden the clinical spectrum of the TMEM151A mutations, we recruited 181 patients of Chinese origin with movement disorders (MDs), including 39 PRRT2-negative PKD, 3 paroxysmal exercise-induced dyskinesia (PED), 2 paroxysmal non-kinesigenic dyskinesia (PNKD), 127 isolated dystonia, 8 choreas, and 2 myoclonus-dystonia syndromes. Whole-exome sequencing was applied to identify their possible disease-causing mutations. Then, Sanger sequencing was performed for validation and co-segregation analysis. Genetic analysis was also performed on additional family members of patients with TMEM151A mutations. Clinical manifestations of all PKD cases with mutations in TMEM151A reported, so far, were reviewed.ResultsTwo novel variants of the TMEM151A gene (NM_153266.4, NP_694998.1), c.627_643dup (p.A215Gfs*53) and c.627delG (p.L210Wfs*52), were identified in 2 patients with PKD by whole-exome sequencing and further Sanger sequencing. Both variants were inherited by the patients from their respective mothers. No mutation of the TMEM151A gene was found in the other type of movement disorders. In reviewing the clinical presentation of TMEM151A-related PKD, no statistically significant difference in the age of onset, family history, duration of attacks, laterality, and phenotype was found between genders. More male patients received treatment and had a good response. A higher proportion of female patients did not receive any treatment, possibly because they had a milder condition of the disease.ConclusionsThis study further validated the role of TMEM151A in PKD. Future studies on protein function will be needed to ascertain the pathogenesis of TMEM151A in PKD.

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“…The introductory article updates on the definition and nomenclature of dystonia as well as on the two classification axes (clinical and etiological) (Grütz and Klein 2021). The following contributions focus on genetic aspects of dystonia by reviewing the present knowledge of hereditary isolated (Domingo et al 2020), combined (Weissbach et al 2020), complex (Herzog et al 2020), and paroxysmal disease forms (Liao et al 2021), and the relevance of genetic testing (Pozojevic et al 2021). Importantly, through the expedite uncovering of the genetic basis of monogenic dystonias, new molecular mechanisms underlying the disease process have emerged and indicated several areas of functional convergence among the relevant proteins (Gonzalez-Latapi et al 2021).…”

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confidence: 99%