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

Abstract

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.

TMEM151A variants associated with paroxysmal kinesigenic dyskinesia

“…Wirth et al [22] reported a de novo mutation in TMEM151A in a patient with PKD. Ma et al [14] reported two novel TMEM151A variants from two families, while Wang et al [20] also identi ed a novel variant in four individuals from one pedigree. They described the typical manifestations of PKD in a three-generation family and suggested that the TMEM151A gene may be associated with the disease spectrum of PKD-PKD/ICbenign familial infantile convulsions (BFIC).…”

“…TMEM151A, located at 11q13.2 and encoding transmembrane protein 151A, was rst reported as causative for PKD in 2021 [12]. Subsequent studies have shown that patients with TMEM151A variants are phenotypically different to patients with PRRT2 variants [2,13,14,16,20,22], the former more likely to be sporadic, have shorter attacks, and present with dystonia [2]. Like the PRRT2 protein, TMEM151A is also highly expressed in the brain, markedly increasing in expression postnatally, peaking at postnatal day 14, and then declining in adulthood.…”

The Pathogenesis of Paroxysmal Kinesigenic Dyskinesia: Current Concepts

“…PRRT2 mutations account for 77% to 93% of familial cases and 21% to 45% of sporadic cases in different cohorts 7,8 . In 2021, heterozygous transmembrane protein 151A ( TMEM151A ) variants were verified in both familial and sporadic cases in Chinese and French PKD cohorts 9‐14 . Variants of other genes, such as PNKD , SLC2A1 , KCNA1 , SCN8A , and DEPDC5 , were also detected in patients with PKD 15‐17 .…”

“…7,8 In 2021, heterozygous transmembrane protein 151A (TMEM151A) variants were verified in both familial and sporadic cases in Chinese and French PKD cohorts. [9][10][11][12][13][14] Variants of other genes, such as PNKD, SLC2A1, KCNA1, SCN8A, and DEPDC5, were also detected in patients with PKD. [15][16][17] However, there is still a large proportion of patients with PKD with unclear genetic causes.…”

TMEM151A Variants Associated with Paroxysmal Kinesigenic Dyskinesia

“…TMEM151A, located at 11q13.2 and encoding transmembrane protein 151A, was rst reported as causative for PKD in 2021 [12]. Subsequent studies have shown that patients with TMEM151A variants are phenotypically different to patients with PRRT2 variants [2,13,14,16,20,22], the former more likely to be sporadic, have shorter attacks, and present with dystonia [2]. Like the PRRT2 protein, TMEM151A is also highly expressed in the brain, markedly increasing in expression postnatally, peaking at postnatal day 14, and then declining in adulthood.…”