PCDH19 Mutations Research Articles

Dravet syndrome: a genetic epileptic disorder.

Dravet syndrome (DS), or severe myoclonic epilepsy in infancy, is one of the most severe types of genetic epilepsy. It is characterized by the initial occurrence of febrile or afebrile seizures that often evolve into status epilepticus in infants with normal development, and by the subsequent appearance of myoclonic and/or atypical absence seizures as well as complex partial seizures. The key feature that characterizes DS is fever sensitivity, although photosensitivity and pattern-sensitivity are also often seen. The prognosis is unfavorable in most cases. Seizures become drug-resistant and persist, with many patients suffering from motor and cognitive impairment. Mutations of SCN1A, which encodes the voltage-gated sodium channel NaV1.1, are the most frequent genetic cause of this syndrome. SCN1A mutations and/or microchromosomal rearrangements involving SCN1A are detected in about 85ｵ of patients. Mutations of PCDH19 have also been reported in female patients with clinical findings compatible with DS. PCDH19 mutations might account for 5ｵ of overall DS cases. Thirty years after its first description, DS is considered as a model of channelopathy. This survey reviews recent developments in the research literature on DS, focusing on the clinical course, as well as its genetic causes.

PCDH19 mutation in Japanese females with epilepsy

To determine the significance of PCDH19 mutations in Japanese females with epilepsy and to delineate their phenotypes. PCDH19 sequencing analysis was performed in 116 females with various epilepsies, including 97 with Dravet syndrome (83.6%). They were referred for SCN1A analysis, and 52 carried SCN1A mutations. Seven heterozygous mutations in exon 1 were identified in 7 patients (6.0%): 2 frameshift, 2 nonsense, and 3 missense mutations. One patient was a monozygotic twin, and her sister with mild phenotype carried the same mutation. The main clinical features among these 8 patients included early seizure onset (≤25 months of age), seizure clusters (7/8), fever-associated seizures (7/8), single seizure type (6/8), and late deterioration of intellect (5/8). Seizure durations were generally up to a few minutes, and only one patient developed status epilepticus once. The main seizure types were generalized tonic-clonic (4/8), tonic (3/8) and focal seizures, with (2/8) or without secondary generalization (3/8). Myoclonic, atonic and absence seizures were extremely rare. Two patients had Dravet syndrome (25%), and this proportion was significantly smaller than that in the total subjects (p<0.01). PCDH19 mutation is a relatively frequent cause of epilepsy in Japanese females. Dravet syndrome was rare in our cohort.

Severe myoclonic epilepsy in infancy (Dravet syndrome) 30 years later

Severe myoclonic epilepsy in infancy (Dravet syndrome) 30 years later

The genetics of Dravet syndrome

Dravet syndrome (DS), otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy presenting in the first year of life. DS has a genetic etiology: between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset. The remaining SCN1A mutations comprise splice-site and missense mutations, most of which fall into the pore-forming region of the sodium channel. Mutations are randomly distributed across the SCN1A protein. Most mutations are de novo, but familial SCN1A mutations also occur. Somatic mosaic mutations have also been reported in some patients and might explain the phenotypical variability seen in some familial cases. SCN1A exons deletions or chromosomal rearrangements involving SCN1A and contiguous genes are also detectable in about 2-3% of patients. A small percentage of female patients with a DS-like phenotype might carry PCDH19 mutations. Rare mutations have been identified in the GABARG2 and SCN1B genes. The etiology of about 20% of DS patients remains unknown, and additional genes are likely to be implicated.

Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females

Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism.