A number sign (#) is used with this entry because of evidence that rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC) is caused by compound heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.

Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC) is an autosomal recessive neurologic disorder characterized by onset of focal seizures in infancy and exercise-induced dystonia in childhood. Features usually include involuntary movements, including facial movements, and difficulties with fine motor skills of the hand. Seizures often respond to medication and remit with age; the dystonia tends to persist (summary by Luthy et al., 2019).

In 3 members from the same generation of a consanguineous Italian family, Guerrini et al. (1999) described a syndrome comprising rolandic epilepsy (RE; see 117100), paroxysmal exercise-induced dystonia (PED), and writer's cramp (WC). Onset was in infancy, with partial seizures that were often hemifacial, and paroxysmal dystonia of the neck, trunk, or limbs associated with exercise. Both the seizures and the paroxysmal dystonia had an age-related expression that peaked during childhood. Horizontal nystagmus was also present. EEG showed rolandic sharp waves or spikes.

Luthy et al. (2019) provided follow-up of the Italian patients reported by Guerrini et al. (1999), who were 31, 42, and 43 at the time of the second report. Focal motor seizures never reoccurred after ages 16, 18, and 22 under treatment with carbamazepine or oxcarbazepine; however, exercise-induced dystonia was still present in 2 of the patients, although the frequency of episodes had decreased. All 3 patients still had nystagmus and postural tremor of the hands. Brain imaging was normal.

Luthy et al. (2019) also identified 3 unrelated patients with a similar disorder. They had onset of focal motor seizures, consistent with rolandic seizures, in the first year of life, followed by onset of exercise-induced dystonia between 2 and 4 years of age. Features included clonic or myoclonic jerks of the hands and face, drooling, dysarthria, dysphagia, difficulty with fine motor movements of the hands, and involuntary movements. Symptoms were often exacerbated by fatigue, fever, or excitement. EEG in 2 patients showed frontotemporal focal discharges. Seizures remitted by age 9 years in 1 patient, but still occurred at ages 8 and 13 years in the other 2 patients. Two patients had postural hand tremor; all had normal brain imaging. Two of the patients were of Han Chinese descent.

The transmission pattern of EPRPDC in the family reported by Guerrini et al. (1999) was consistent with autosomal recessive inheritance.

In a family with RE-PED-WC, Guerrini et al. (1999) found linkage to a 6-cM region on chromosome 16p12-p11.2 between markers D16S3133 and D16S3131 (maximum lod score of 3.68). The authors noted that the disorder showed phenotypic similarities to autosomal dominant infantile convulsions and paroxysmal choreoathetosis syndrome (ICCA; 602066), which had been mapped to the same region.

In 3 members of a consanguineous Italian family with EPRPDC, Luthy et al. (2019) identified compound heterozygous missense mutations in the TBC1D24 gene (G501R, 613577.0015 and R360H, 613577.0016). The mutations, which were found by sequencing of the critical region identified by linkage analysis (Guerrini et al., 1999), segregated with the disorder in the family. Three additional patients, including 2 unrelated patients of Han Chinese origin, with sporadic occurrence of the disorder were found to carry compound heterozygous mutations (see, e.g., 613577.0017 and 613577.0018) through whole-exome sequencing. All the patients had biallelic mutations that could be described as hypomorphic mutations affecting the TBC domain, which is important for the regulation of vesicular membrane trafficking at synapses, or a mutation with a mild effect on protein function (R360H), coupled with missense mutations that severely affect the TLDc domain, which is the catalytic domain and thought to be involved in oxidative stress resistance. Studies of patient cells were not performed, but detailed structural analysis predicted that the mutations may have variable destabilizing effects on the protein. In vivo studies in Drosophila demonstrated that the G501R TLDc mutation caused activity-induced locomotion and synaptic vesicle trafficking defects, while R360H was comparatively benign. The neuronal phenotypes of the G501R mutation were consistent with exacerbated oxidative stress sensitivity, which could be rescued by treatment with antioxidants that restored synaptic vesicle trafficking levels and sustained behavioral activity. The authors suggested that the TBC1D24 TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies.