A number sign (#) is used with this entry because of evidence that episodic kinesigenic dyskinesia-3 (EKD3) is caused by heterozygous mutation in the TMEM151A gene (620108) on chromosome 11q13.

Episodic kinesigenic dyskinesia-3 (EKD3) is an autosomal dominant form of paroxysmal kinesigenic dyskinesia (PKD), an episodic involuntary movement disorder characterized by dystonia, chorea, athetosis, and other hyperkinetic movements. The age at onset is around 9 to 12 years of age and symptoms are usually triggered by sudden movement or stress. Most patients have spontaneous resolution of episodes in their early twenties or later. Brain imaging is normal. There is a favorable response to treatment with carbamazepine (Li et al., 2021; Tian et al., 2022; Wang et al., 2022).

For a general phenotypic description and a discussion of genetic heterogeneity of episodic kinesigenic dyskinesia (EKD), see EKD1 (128200).

Li et al. (2021) reported 9 individuals from 3 unrelated Chinese families (families 1-3) with paroxysmal kinesigenic dyskinesia transmitted in an autosomal dominant pattern. Eight unrelated Chinese patients with sporadic occurrence of the disorder were also identified. The patients, who ranged from 18 to 58 years of age, had onset of symptoms between ages 9 and 15 years. The episodes were triggered by sudden movement and were characterized by stiffness and twisting of the limbs, with dystonic posturing and no loss of consciousness. Other manifestations included frequent falls associated with the episodes, difficulty walking, choreic movements, grimacing, and torticollis. Almost all patients reported an aura; brain MRI was normal in those tested. Six individuals had remission of the disorder between 18 and 30 years of age, whereas the others had persistent symptoms. There was a good treatment response to carbamazepine.

Tian et al. (2022) reported 29 Chinese patients from 25 families with PKD ascertained from large cohorts of patients who underwent genetic studies. The mean age of symptoms onset was 12.93 years, and 13 patients reported spontaneous remission of the disease around 21 years of age. Most of the patients reported a premonition or aura prior to the episodes. The episodes were triggered by sudden movement, as well as speed changes, emotional stress, intentional movements, and fatigue. The transient involuntary movements were characterized as dystonia (100%), chorea (28%), ballism (10%), and facial involvement (86%). Most reported decreased frequency of the attacks after age 20 years. There was a favorable response to treatment with carbamazepine.

Wirth et al. (2022) reported a French man with EKD3. He presented with brief attacks of dystonia after 16 years of age. Symptoms could be triggered by voluntary movements, surprise, or stressful events. Attacks could be focal or generalized, affecting speech or involving the face or upper and lower limbs subsequently or simultaneously. Treatment with lamotrigine resulted in symptom resolution.

Wang et al. (2022) reported a family in which 4 patients spanning 2 generations had EKD3. The proband was a 14-year-old boy who had a 3-year history of paroxysmal limb stiffening and involuntary movements of the limbs, trunk, and face. Limb twisting was consistent with dystonia; chorea and ballism were not observed. Aura was reported, and triggers included sudden movement or long-distance running. The attacks were completely relieved by carbamazepine. Family history showed symptom resolution around 20 years of age. Of note, 1 of the mutation carriers in this family also demonstrated afebrile infantile convulsions in infancy, which spontaneously resolved at 18 months of age; this feature expanded the phenotypic spectrum associated with TMEM151A mutations.

Huang et al. (2023) described 3 unrelated Chinese patients, aged 18 to 26 years, with EKD3. Patient 1 had dystonia episodes of her face 5 to 10 times daily that were triggered by movement. The episodes were relieved by treatment with carbamazepine. Patient 2 had a history of dyskinetic movements in the left limb and trunk triggered by voluntary movements or emotional stress. Patient 3 developed dystonic episodes at 8 years of age. The episodes occurred about 10 times per day and were triggered by sudden movement. The episodes were relieved by treatment with carbamazepine.

The transmission pattern of EKD3 in the families reported by Li et al. (2021) and Tian et al. (2022) was consistent with autosomal dominant inheritance with incomplete penetrance.

In affected members of 3 unrelated Chinese families with EKD3, Li et al. (2021) identified heterozygous mutations in the TMEM151A gene (620108.0001-620108.0003). In addition, heterozygous TMEM151A mutations were found in 8 unrelated patients with sporadic occurrence of the disorder. The 11 mutations identified were nonsense, frameshift, and missense, as well as a small intragenic deletion. Mutations in the PRRT2 gene (614386) had been excluded in all patients. The TMEM151A mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, although there was evidence of incomplete penetrance in 3 of the sporadic cases, since they inherited the mutations from an unaffected parent. Western blot analysis of HEK293 cells transfected with some of the mutations showed that they caused a significant decrease in TMEM151A protein levels, suggesting a loss-of-function effect with haploinsufficiency as a pathogenic mechanism.

In 25 Chinese probands with EKD3, Tian et al. (2022) identified 24 different heterozygous mutations in the TMEM151A gene (see, e.g., 620108.0002 and 620108.0004). The mutations, which were found by whole-exome sequencing or direct Sanger sequencing, segregated with the disorder in a few families from whom information was available, although there was also evidence for incomplete penetrance. There were 18 missense and 6 nonsense mutations. Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from large cohorts totaling 521 individuals with PRRT2-negative EKD; TMEM151A mutations accounted for 4.80% of cases.

In 10 Chinese probands, all male, with EKD3, Li et al. (2022) identified heterozygous mutations in the TMEM151A gene (see, e.g., 620108.0002 and 620108.0005). The mutations, which were found by exome sequencing, were not present in the ExAC database. There were 3 missense variants, 1 nonsense, and 2 frameshift, including 1 (c.897_912del; 620108.0005) that was present in 5 of the families, although it showed incomplete penetrance in 4. Functional studies of the variants were not performed. The patients were ascertained from a cohort of 86 PRRT2-negative probands with PKD; TMEM151A mutations accounted for 11.6% of the cases.

In a French male with EKD3, Wirth et al. (2022) identified a de novo heterozygous missense mutation in the TMEM151A gene (G56R; 620108.0006). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was classified as likely pathogenic. The authors noted that TMEM151A mutations can occur in populations other than Chinese. The French patient was from a cohort of 23 French patients with sporadic PRRT2-negative PKD who underwent genetic studies and was the only patient found to carry a TMEM151A mutation.

Ma et al. (2022) identified 2 novel heterozygous frameshift mutations in the TMEM151A gene (c.627_643dup and c.627delG) in 2 unrelated Chinese patients with EKD3. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were each inherited from the respective mothers; there was incomplete penetrance. Functional studies of the variants were not performed. The patients were ascertained from a cohort of 181 Chinese patients with various movement disorders who were sequenced. TMEM151A mutations were not identified in other types of movement disorders.

In 4 affected members of a 3-generation Chinese family with EKD3, Wang et al. (2022) identified a heterozygous missense mutation in the TMEM151A gene (E362G; 620108.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional studies of the variant and studies of patient cells were not performed, but it was classified as likely pathogenic.

In 3 unrelated Chinese patients with EKD3, Huang et al. (2023) identified heterozygous mutations in the TMEM151A gene (620108.0006, 620108.0008-620108.0009). The mutations, which were identified by whole-exome sequencing, were not present in the gnomAD and 1000 Genomes Project databases.

Li et al. (2021) found that Tmem151a -/- mice exhibited frequent spontaneous dyskinesia attacks that were absent in Tmem151a +/- and wildtype mice. Dyskinesia attacks lasted 10 to 37 seconds, after which the mutant mice recovered normal locomotion.