Abstract
Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation. © 2010 Wiley-Liss, Inc.
Highlights
Mutations in the PCDH19 gene, located on chromosome X and encoding the protocadherin 19, were originally identified in Epilepsy and mental retardation limited to females (Dibbens, et al, 2008)
This unusual mode of inheritance is likely to be due to cellular interference, a mechanism assuming that only the co-existence of PCDH19-positive and -negative cells, as a result of random X inactivation in females, is pathogenic (Depienne, et al, 2009; Johnson, 1980; Wieland, et al, 2004)
Intellectual outcome was reported to range from normal intellect to mental retardation within families; all patients reported to date either had intellectual disability or belonged to families where cognitive delay was present in other family members (Scheffer, et al, 2008)
Summary
Mutations in the PCDH19 gene, located on chromosome X and encoding the protocadherin 19, were originally identified in Epilepsy and mental retardation limited to females (or Epilepsy, Female-restricted, with Mental Retardation, EFMR; MIM# 300088) (Dibbens, et al, 2008). EFMR is a disorder with a remarkable X-linked inheritance: only females with heterozygous mutations are affected whereas males with hemizygous mutations are unaffected (Fabisiak and Erickson, 1990; Juberg and Hellman, 1971; Ryan, et al, 1997). This unusual mode of inheritance is likely to be due to cellular interference, a mechanism assuming that only the co-existence of PCDH19-positive and -negative cells, as a result of random X inactivation in females, is pathogenic (Depienne, et al, 2009; Johnson, 1980; Wieland, et al, 2004). Intellectual outcome was reported to range from normal intellect to mental retardation within families; all patients reported to date either had intellectual disability or belonged to families where cognitive delay was present in other family members (Scheffer, et al, 2008)
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