The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood

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.

Keywords: BFIS; PKD; PKD/IC; PRRT2; familial infantile epilepsy; hemiplegic migraine; phenotypic spectrum.

Figure 1

Distribution of clinical manifestations in a cohort with BFIS (core cohort, n = 40).

Figure 2

Pedigrees of affected families. Squares: male individuals, circles: female individuals, black circles/squares: clinically affected individuals, blank circles/squares: healthy individuals. Arrows indicating index patient. WT: wild-type; (A) family with the novel variant c.843C>G, p.(Trp281Cys) in three members displaying BFIS and/or FHM. Development of the index patient prior to seizure onset had been normal. Epilepsy gene panel diagnostic revealed a heterozygous missense variant at c.843C>G, p.(Trp281Cys). The variant was confirmed in the maternal grandmother. The mother had a history of infantile seizures and developed hemiplegic migraines later in life. The grandmother presented with hemiplegic migraine; seizures were not reported. No other movement disorders or neurologic disease were reported in the family; (B) family with five individuals with BFIS and severe hemiplegic migraines that started exceptionally early in two individuals. The index patient presented episodes of paroxysmal vertigo beginning at the age of 17 months in addition to benign infantile seizures consisting of clusters of bilateral tonic seizures beginning at four months of age. Under therapy with oxcarbazepine, the patient’s symptoms disappeared almost completely. The father and three relatives in the father’s family share a history of BFIS and hemiplegic migraine. The father has hemiplegic migraine with speech disturbance. The sister of the index patient developed BFIS without migraine. The index patient, his father and sister harbor the familial c.649dupC pathogenic variant; (C) family of two individuals presenting infantile PKD/IC. Seizures and dystonia started in the first half-year of life. The index patient and her father harbor the familial c.649dupC variant; (D) family of five affected individuals with BFIS and febrile seizures co-segregating with the familial c.649dupC pathogenic variant, one child developed continuous spikes and waves during slow sleep (CSWS).

Figure 3

Brain imaging of a girl with bi-allelic variation in PRRT2 (c.649dupC and de novo deletion of 16p11.2) displaying focal cortical dysplasia in the right parietal lobe with preserved upper cortex layers (A) on T2-fluid attenuated inversion recovery MRI. After mild head trauma the girl presented with ataxia, problems of expressive language, and myoclonia lasting one to three days. Diffusion-weighted (ADC, apparent diffusion coherent) imaging revealed hypointense areas in both cerebellar hemispheres (B) that normalized after three weeks (C).