Spectrum of PCDH19 mutations
Departments of Pediatrics and Central Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan
Mutations in the protocadeherin19-encoding gene, PCDH19, cause PCDH19-related female-limited epilepsy (PCDH19-related epilepsy), which is previously termed as epilepsy and mental retardation limited to females (EFMR). PCDH19 epilepsy is X-linked and affects only females while spares males. The mechanism underlying this unique inherited condition remains unclear, but "cellular interference" resulting from the combination of the mutant and wild-type protocadeherin19 is one of the speculated causes. We identified PCDH19 mutations in 39 Japanese female probands and analyzed their genetic and clinical characteristics along with those previously reported. The mutations vary from one point mutations to deletion or duplication of PCDH19. De novo mutations were observed in 58% of the probands, suggesting that sporadic cases are common. The onset age (9.3 ± 5.4 months) is lesser than that of Dravet syndrome. There are 2 types of onset: one involved biphasic clusters, and the other involved prolonged clusters reminiscent of acute encephalopathy. The main type of seizures is brief focal seizures, which often occur in clusters and are induced by fever. However, unlike Dravet syndrome, prolonged seizures, myoclonus, or absence are uncommon in PCDH19-related epilepsy. The seizures tend to remit spontaneously after adolescence. Psychomotor deficits vary from normal intelligence to profound mental retardation. Motor development is good, unlike that in Dravet syndrome. Autistic and hyperactive features are common. No genotype–phenotype correlation is observed. Midazolam and phenytoin are partially effective for controlling seizure clusters, but preventing seizure recurrence is challenging. Corticosteroid therapy may be a good option to control seizure clusters in PCDH19-related epilepsy.