Abstract
Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.
Highlights
Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2 (OMIM*614386), have been identified in different common familial paroxysmal neurologic disorders
We present a series of 40 patients from Germany, Switzerland, and Denmark with PRRT2-related benign infantile epilepsy and rarely reported associated comorbidities, further expanding the phenotypic spectrum
In addition to one previous report of a child with a PRRT2 variant and benign myoclonus of early infancy presenting as episodic head drops [12], we report an additional case of this rare infantile disorder
Summary
Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2 (OMIM*614386), have been identified in different common familial paroxysmal neurologic disorders. Pathogenic variants in PRRT2 were found in individuals and families with paroxysmal kinesigenic dyskinesia (PKD, OMIM#128200) [1], soon followed by reports showing that the same variants in PRRT2 cause self-limiting sporadic and familial infantile epilepsy (traditional terminology: benign sporadic and familial seizures, BFIS, OMIM#605751) [2], known as Watanabe epilepsy, and the overlapping disorder of paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC, OMIM#602066) [3,4]. While epilepsy in association with PRRT2 variants usually starts in infancy, movement disorders predominantly occur in adolescence and adulthood. In BFIS, focal and/or bilateral-tonic-clonic seizures start around six months of age in otherwise healthy infants with a self-limited course of disease, usually remitting around the age of two years Recurrent brief involuntary hyperkinesias of individuals with PKD are triggered by sudden voluntary movements and appear with a higher frequency during stress and anxiety [5,6].
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