PO-20 | Phenotypic description of a multigenerational family with PRRT2 gene mutation: a case series of six members affected by hemiplegic migraine and paroxysmal events

Fabiana Cerulli,¹ Costanza Sottani,¹ Giulia Di Lazzaro,^1,2 Paolo Calabresi,^1,2 Anna Rita Bentivoglio,^1,2 Catello Vollono^1,3 | ¹Dipartimento Universitario di Neuroscienze, Università Cattolica del Sacro Cuore, Rome; ²UOC Neurologia, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy; 3Neurofisiopatologia, Dipartimento di Scienze dell'invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy

Background: Mutations in the PRRT2 gene have been identified as the cause of a spectrum of disorders, including paroxysmal kinesigenic dyskinesia (PKD) and benign familial infantile epilepsy. Recent evidence suggests its potential role in migraine phenotypes, particularly in cases presenting with complex aura. We present a case series from a single multigenerational family in which six heterozygous carriers of the PRRT2 c.649dup mutation, exhibit migraine and/or paroxysmal neurological events.

Methods: Clinical data were retrospectively collected from six family members through outpatient neurological evaluations, headache diaries, neuroimaging, and genetic testing. The analysis focused on age of migraine onset, aura characteristics, attacks frequency and neurological comorbidities, including movement disorders and early-life paroxysmal events.

Results: All six individuals reported a history of migraine with or without aura. The mean age of onset was 13.5 ± 7.3 years (range 6–28). Four subjects experienced recurrent episodes fulfilling criteria for hemiplegic migraine, one currently reported only a single motor aura episode and one had migraine without aura. Aura episodes included visual, sensory, language, and brainstem symptoms The frequency of migraine attacks ranged from less than 1 to 15 episodes/month, with a mean of 6.2 ± 4.8 monthly migraine days. One subject presented with PKD; two individuals reported childhood paroxysmal events (febrile seizures, absence episodes). Brain MRIs were unremarkable in all except for one subject, who showed a nonspecific cerebellar T2 hyperintensity.

Conclusion: This case series highlights the phenotypic variability and incomplete penetrance of the PRRT2 c.649dup variant within a single multigenerational family. The presence of motor aura in five out of six individuals suggests that PRRT2 mutations may contribute to a broader spectrum of migraine phenotypes than previously recognized. The coexistence of migraine with aura and other paroxysmal neurological manifestations highlights the need for a comprehensive clinical-genetic approach. Our findings support the inclusion of PRRT2 in gene panels for hemiplegic and complex aura migraine.