Submission Details

PRRT2 encompasses a variety of phenotypes including benign familial infantile seizures (BFIE) and paroxysmal kinesigenic choreoathetosis (PKC). BFIE commonly present between 3 and 12 months of age, carry good response to medication, with seizures remitting by 18 months. PKC is characterized by recurrent and/or brief attacks of involuntary movement characterized by chorea, athetosis and/or other dystonic features, triggered by voluntary movement, with typical onset in childhood through adolescence and gradual reduction in severity and frequency with age. These features (BFIE and PKC) have been documented to occur in the same individuals; the presence of both of these phenotypes is identified as infantile convulsions and paroxysmal choreoathetosis (ICCA). Loss of function variants have been primarily reported in association with this gene and phenotypes, (most notably the recurrent p.Arg217Profs*8 (c.649dupC) variant) and segregate with disease in several different families in the literature (selected publications- PMID:22101681, 22243967, 22870186, 29215089). Evidence supporting this gene disease pair includes case level and experimental data. Supporting experimental evidence has been reported in mice and rat studies (selected publications- PMID:22101681, 22243967, 27172900). This association between gene and disease has been maintained over time. Of note, instances of individuals have been reported with these phenotypes together and in isolation. Given the age dependent nature of these presentations, it is possible that the manifestations of these features may be separated by many years; initial reporting of individuals with only one of the phenotypes may be a result of age at time of report. In summary, PRRT2 is definitively associated with autosomal dominant infantile convulsions and paroxysmal choreoathetosis (ICCA). This has been demonstrated in both research and clinical settings.