title: PCDH19-related female-limited epilepsy: further details regarding early clinical features and therapeutic efficacy.
abstract: Abnormalities in the protocadherin 19 (PCDH19) gene cause early-onset epilepsy exclusively in females. We aimed to explore the genetic and clinical characteristics of PCDH19-related epilepsy by focusing on its early features and treatment efficacy. PCDH19 was analyzed in 159 Japanese female patients with early-onset epilepsy via direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis. We identified 17 patients with PCDH19 abnormalities: point mutations were observed in 14 patients and whole PCDH19 deletions were detected in 3 patients. One affected sister of a proband with a mild phenotype was also analyzed. The frequency of PCDH19 deletion among all probands identified in Japan was 12.5% (3/24, including 7 probands reported previously by us). Clinical features included early onset (mean age at onset, 8.6 months), recurrent clusters of brief seizures (17/18), fever sensitivity (18/18), tonic seizures (13/18, probably including focal tonic seizures), tonic-clonic seizures (8/18), focal seizures often with subsequent generalization (17/18), intellectual disabilities (15/18), and autistic traits (13/18). Three patients exhibited delay in motor milestones before seizure onset. In 16 patients, seizures appeared in clusters from the onset of the disease. Among 6 patients for whom detailed information at onset was available, 2 onset patterns were identified: a biphasic course of short seizure clusters (each within days) in 2 patients and a prolonged course of clusters (from weeks to a month) in 4 patients. In both cases, initial seizures started during fever and transiently disappeared with the decline of fever; however, afebrile clusters recurred. In the former patients, motor development was delayed before onset, and seizures appeared in strong clusters from the onset of the disease. In the latter patients, initial development was normal and initial seizures were mild, but were followed by strong clusters lasting several weeks, even without fever. Treatment using phenytoin, potassium bromide, and clobazam showed high efficacy. Although focal seizures were the main feature in PCDH19-epilepsy, the efficacy of carbamazepine was poor. This study highlighted the significance of PCDH19 deletion, a unique pattern of initial seizure clusters, and the efficacy of antiepileptic drugs. Our data will facilitate early diagnosis and development of a treatment strategy for better clinical management of patients with PCDH19-related epilepsy.
authors.affiliation: Department of Pediatrics, School of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Higurashi
authors.forename: Mai
authors.initials: M
authors.lastname: Nakamura
authors.forename: Misaki
authors.initials: M
authors.lastname: Sugai
authors.forename: Masaharu
authors.initials: M
authors.lastname: Ohfu
authors.forename: Masako
authors.initials: M
authors.lastname: Sakauchi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sugawara
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.forename: Daisuke
authors.initials: D
authors.lastname: Usui
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Mogami
authors.forename: Yumi
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Tomoshiro
authors.initials: T
authors.lastname: Ito
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imai
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Megumi
authors.initials: M
authors.lastname: Nukui
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Shin
authors.initials: S
authors.lastname: Okazaki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kirino
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tomonoh
authors.forename: Takahito
authors.initials: T
authors.lastname: Inoue
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takano
authors.forename: Shuichi
authors.initials: S
authors.lastname: Shimakawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000927:Anticonvulsants / Q000627:therapeutic use*; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D004247:DNA / Q000235:genetics; D004827:Epilepsy / Q000145:classification / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008279:Magnetic Resonance Imaging; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D000091363:Protocadherins; D012640:Seizures / Q000145:classification / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D015820:Cadherins; D062550:NAV1.1 Voltage-Gated Sodium Channel; C438605:PCDH19 protein, human; D000091363:Protocadherins; C568242:SCN1A protein, human; D004247:DNA
keywords: Antiepileptic drugs; Early diagnosis; Genetic analysis; Multiplex ligation-dependent probe amplification; Seizure clusters; Treatment