Paroxysmal kinesigenic dyskinesia (PKD, OMIM_128200), also called episodic kinesigenic dyskinesia 1 (EKD1) or paroxysmal kinesigenic choreoathetosis (PKC), is a rare movement disorder characterized by recurrent attacks of involuntary movements triggered by sudden initiation or modification of movements (1). Short episodes include dystonia, chorea, or ballism and usually last less than a minute.

The PKD most commonly occurs sporadically and also occurs as an autosomal-dominant familial trait with varying penetrance. 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).

The heterogeneity of phenotypes and genotypes is common in different types of movement disorders. PKD usually manifests itself in various movement patterns, such as dystonia, chorea, and ballism. Previous studies showed that some causative genes of PKD can also be related to other diseases. Patients with mutations in KCNA1 can present with PKD or Episodic Ataxia (10). CHRNA4 was reported to be associated with insular epilepsy (11) and PKD. Thus, it is important to reveal whether the TMEM151A gene is related to other disorders. To further explore the role of TMEM151A mutations in PKD and other movement disorders and broaden the clinical and genetic spectrum of TMEM151A mutations, we performed whole-exome sequencing (WES) in 181 patients with different movement disorders. Two additional novel pathogenic variants were identified. Clinical presentations of TMEM151A-related patients with PKD was also reviewed.

Paroxysmal dyskinesias are a group of movement disorders characterized by episodes of involuntary movements (dystonia, chorea, athetosis, ballismus, or combined symptoms). They are classified into three main categories: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal exercise-induced dyskinesia (PED), and paroxysmal non-kinesigenic dyskinesia (PNKD) (28). PKD, the most common type of paroxysmal dyskinesia, involves sudden attacks of dyskinesias induced by voluntary movements (28).

Gene PRRT2 was first confirmed as the causative gene of PKD. However, the prevalence of PRRT2 variants in patients with PKD ranges from 27 to 65% (2, 3), indicating that additional undiscovered causative genes are yet to be identified. With the help of next-generation sequencing, TMEM151A was identified as a causative gene for PKD (7–9). Li et al. (7) identified loss-of-function TMEM151A mutations, a frameshift and two missense variants, in three unrelated PKD families. They further screened TMEM151A variants in the WES data of 31 isolated Patients with PKD and found extra four truncated variants, three missense variants and a non-frameshift deletion in 8 isolated patients (25.8%, 8/31). Tian et al. (8) recruited a large cohort of patients with PKD and detected 24 heterozygous variants in TMEM151A in 25 probands (4.8%, 25/521), including 18 missense and 6 nonsense mutations, in which only one has been reported before. Li et al. (9) performed an exome-wide rare variant burden analysis in 86 PRRT2-negative PKD probands and identified 6 rare protein-altering TMEM151A variants (3 novel variants) in 10 unrelated probands. Chen et al. (29) also reported 7 variants (5 novel variants). So, a total of 44 TMEM151A mutations have been reported to be associated with PKD to date (Figure 2). Only mutations reported by Li et al. (7) have been recorded in Human Gene Mutation Database (HGMD) (30).

Currently, the function of TMEM151A is poorly understood. It is highly conserved among species. In mice, Tmem151a was highly expressed in the central nervous system (CNS), mainly in the cerebral cortex, hippocampus, spinal cord, brainstem, and thalamus (7). Until now, with our two patients added, 67 TMEM151A-related PKD cases were reported (7–9, 29) (see clinical manifestations of 67 cases in Supplementary Table). The mean age of onset of TMEM151A-related PKD is 11.99 ± 2.83 (mean ± SD), while male predominate (M: F = 2.53:1 [48:19]). Of these patients, 38.8% (26/67) had family history. There is no statistically significant difference in age of onset, family history, duration of attacks, laterality, and phenotype between genders (Table 1). When concerns to drug response, no statistical difference was found among patients with different drug reactions (complete relief, incomplete relief, and no treatment) (Table 2). However, a large percentage of female patients did not receive any treatments compared to their male counterparts, possibly because they had a mild condition. More male patients received treatment and regained their health.

As previously reported in the literature, no significant differences were found between PRRT2-positive and TMEM151A-positive PKD in terms of attack type and treatment outcome (8). However, patients with TMEM151A mutations were prone to have a later-onset age, shorter attack durations, and residual attacks/aura when treated with carbamazepine or oxcarbazepine (8, 29).

In this study, we identified two novel variants of the TMEM151A gene in two patients with PKD and summarized the clinical and genetic features of all patients reported, so far. We did not find any correlation between the TMEM151A gene and other movement disorders. Further studies on the function of the TMEM151A gene and protein are expected to determine the pathogenesis of PKD in the future.

The datasets presented in this study can be found in online repositories. The name of the repository and accession number can be found below: Genome Sequence Archive for Human (GSA-Human) in the National Genomics Data Center (NGDC), China National Center for Bioinformation (CNCB)/Beijing Institute of Genomics (BIG), Chinese Academy of Sciences (CAS), https://ngdc.cncb.ac.cn/gsa-human/, HRA001662.

The studies involving human participants were reviewed and approved by Beijing Tiantan Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

L-YM participated in the design of the study and drafted the manuscript. LH interpreted genetic data and contributed to the manuscript. TF and Y-ZY carried out the conceptualization of the study, reviewing, and critiquing the article at the same time. MN and LC collected the medical data of the patients. All authors have read and approved the final manuscript.

This research was supported by the Natural Science Foundation of China (Nos. 82071422 and 81571226) and Beijing Natural Science Foundation (Nos. 7164254 and 7212031).

LH was employed by Running Gene Inc. Beijing, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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