PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine

Abstract

Objective: To perform a clinical and genetic study of a family with benign familial infantile seizures (BFIS) and, upon finding a PRRT2 gene mutation, to study a cohort of probands with a similar phenotype. We extended the study to all available family members to find out whether PRRT2 mutations cosegregated with additional symptoms.

Methods: We carried out a clinical and genealogic study of a 3-generation family and of 32 additional probands with BFIS (11 families), infantile convulsions and paroxysmal choreoathetosis (ICCA) (9 families), BFIS/generalized epilepsy with febrile seizures plus (5 families), and sporadic benign neonatal or infantile seizures (7 probands/families). We performed a genetic study consisting of linkage analysis and PRRT2 screening of the 33 probands/families.

Results: We obtained a positive linkage in the 16p11.3-q23.1 chromosomal region in the large BFIS family. Mutation analysis of PRRT2 gene revealed a c.649dupC (p.Arg217Profs*8) in all affected individuals. PRRT2 analysis of the 32 additional probands showed mutations in 10, 8 familial and 2 sporadic, probands. Overall we found PRRT2 mutations in 11 probands with a mutation rate of 11 out of 33 (33%). BFIS co-occurred with migraine and febrile seizures in 2 families, with childhood absence epilepsy in one family and with hemiplegic migraine in one family.

Conclusion: Our results confirm the predominant role of PRRT2 mutations in BFIS and expand the spectrum of PRRT2-associated phenotypes to include febrile seizures, childhood absence seizures, migraine, and hemiplegic migraine.

Figure 1. Pedigree of family 1

The inferred chromosome 16 haplotype is shown for affected individuals and the haplotype assumed to carry the disease allele is boxed. Patients in whom the c.649dupC PRRT2 mutation has been identified are indicated as +/m and individuals tested for mutation and found to be negative are indicated by +/+. BFIS = benign familial infantile seizures.

Figure 2. Pedigrees of the available families with benign familial infantile seizures (BFIS), infantile convulsions and choreoathetosis (ICCA), and additional features

Figure 3. Video-polygraphic recording of a focal seizure in an 8-month-old girl with PRRT2 mutation

Video-polygraphic recording of a focal seizure in an 8-month-old girl with PRRT2 mutation showing a rhythmic ictal discharge originating from the left parieto-tempo-occipital region (A), spreading to involve, 40 seconds from its onset, the whole left hemisphere and, 60 seconds later, the contralateral regions (B). The seizure ends 2 minutes after onset. The discharge is followed by small-amplitude asymmetric slow activity, corresponding to the postictal phase. Clinically the patient is unresponsive and stares for 60 seconds, then becomes stiff, manifesting some clonic, asynchronous jerking of the limbs. In the postictal phase the patient remains still for a few minutes, exhibiting intermittent oral automatisms.