Objective: To confirm the association between TMEM151A mutation and paroxysmal kinesigenic dyskinesia.

Background: Heterozygous mutations in TMEM151A, encoding a protein of undetermined function, have been very recently associated with paroxysmal kinesigenic dyskinesia (PKD) in the Chinese population (1). TMEM151A is highly expressed in the brain including the cerebral cortex and the thalamus and is highly conserved among species.

Method: We applied whole exome sequencing (WES) on 23 French patients with sporadic PKD who were tested negative for PRRT2 mutations, as well as their asymptomatic parents. PKD diagnosis was made by movement disorders specialists according to the consensus clinical criteria. WES, bioinformatic analysis and variant prioritization were performed as previously described (2). Variants were classified according to the American College of Human Genetics and Genomics (ACMG) criteria. All patients gave written informed consent before genetic testing and a local ethics committee approved the study.

Results: We identified a de novo missense variant (c.166G>C [p.Gly56Arg]) in TMEM151A in a single patient through trio-based exome sequencing. This variant, absent from public databases including Exac, 1000G and GnomAD, led to a substitution in the second transmembrane domain of the protein, near previously reported pathogenic variant such as (c.140T>C [p.Leu47Pro]) or (c.133T>G [p.Cys45Arg]). The patient had no history of infantile seizures and presented with brief attacks of dystonia triggered by voluntary movements, surprise, or stressful events beginning after age 16. The attacks totally ceased after the initiation of low doses of lamotrigine (50 mg/d). This variant was subsequently classified as Likely Pathogenic (class IV) according to the ACMG criteria (PS2 + PM1 + PM2 + PP2 + PP4).

Conclusion: We report on a de novo mutation in TMEM151A in a patient with PKD. Our findings confirm TMEM151A variants as a genetic cause of PKD and suggest that de novo mutations in this gene are infrequently responsible for sporadic PKD cases. Further works are warranted to refine the phenotype/genotype correlations among TMEM151A-related disorders. Whether TMEM151A is a transmembrane protein involved in synaptic function and whether TMEM151A-related PKD is underpinned by its loss of function also remain to be elucidated.

References: (1) Tian W-T, Zhan F-X, Liu Z-H, Liu Z, Liu Q, Guo X-N, et al. TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study. Mov Disord. 24 nov 2021;
(2) Wirth T, Tranchant C, Drouot N, Keren B, Mignot C, Cif L, et al. Increased diagnostic yield in complex dystonia through exome sequencing. Parkinsonism & Related Disorders. 1 mai 2020;74:50‑6

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MDS Abstracts - https://www.mdsabstracts.org/abstract/de-novo-mutation-in-tmem151a-and-paroxysmal-kinesigenic-dyskinesia/