[Genotype and phenotype of female Dravet syndrome with PCDH19 mutations]

To explore the genotype and phenotype of female Dravet syndrome (DS) patients with PCDH19 mutations.

Clinical data of all DS patients seen at Pediatric Department of Peking University First Hospital from February 2005 to May 2015 were prospectively collected. Genomic DNAs were extracted from the patients and their family members. Female DS patients without SCN1A mutation were enrolled. PCR and Sanger sequencing were performed to identify PCDH19 mutations. Clinical data of DS patients with PCDH19 mutations were summarized.

Five different heterozygous PCDH19 mutations were identified in six unrelated patients of 75 SCN1A-negative female DS patients (8%), among whom five patients had de novo mutations and one patient's mutation was inherited from her affected mother. Three missense mutations and two insertion mutations were all located in exon 1. Mean age of onset of the six patients with PCDH19 mutations was 6.8 months (range 5-9 months). Onset of seizures were triggered by fever in four patients, after vaccination in one and without fever in one. Generalized tonic clonic seizure (GTCS) was the first seizure type in four patients and focal seizure with secondary generalized tonic clonic seizures in the remaining two. During the course, all patients presented multiple seizure types including generalized tonic clonic seizures and focal seizures in all six patients, myoclonic seizures in three, absence seizures and atonic seizures in one respectively. In all patients, seizures manifested fever-sensitive and in clusters. Seizures were always in brief duration, in most less than 5 minutes, except one experienced twice status epilepticus triggered by fever. Six patients had development delay after the seizure onset, two with autism spectrum disorder, three with ataxia.

PCDH19 is another important gene of DS after SCN1A, mutations mainly occurred de novo. PCDH19 gene mutation should be routinely screened in female DS patients without SCN1A mutation. The clinical features of female DS patients with PCDH19 mutations include that the main seizures types are generalized tonic clonic seizures and focal seizures, seizures occurr in clusters and fever-sensitive, short seizure duration, rare status epilepticus, common development delay and some may manifest autism spectrum disorders.