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PCDH 19 ‐related epilepsy is associated with a broad neurodevelopmental spectrum
Author(s) -
Smith Lacey,
Singhal Nilika,
El Achkar Christelle M.,
Truglio Gessica,
Rosen Sheidley Beth,
Sullivan Joseph,
Poduri Annapurna
Publication year - 2018
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.14003
Subject(s) - epilepsy , intellectual disability , proband , autism spectrum disorder , autism , cohort , genotype , psychiatry , population , psychology , pediatrics , medicine , genetics , biology , mutation , gene , environmental health
Summary Objective To characterize the features associated with PCDH 19 ‐related epilepsy, also known as “female‐limited epilepsy.” Methods We analyzed data from participants enrolled in the PCDH 19 Registry, focusing on the seizure‐related, developmental, neurobehavioral, and sleep‐related features. We evaluated variants for pathogenicity based on previous reports, population databases, and in silico predictions, and included individuals with pathogenic or potentially pathogenic variants. We performed a retrospective analysis of medical records and administered a targeted questionnaire to characterize current or past features in probands and genotype‐positive family members. Results We included 38 individuals with pathogenic or potentially pathogenic variants in PCDH 19 : 21 de novo, 5 maternally inherited, 7 paternally inherited, and 5 unknown. All 38 had epilepsy; seizure burden varied, but typical features of clustering of seizures and association with fever were present. Thirty individuals had intellectual disability ( ID ), with a wide range of severity reported; notably, 8/38 (22%) had average intellect. Behavioral and sleep dysregulation were prominent, in 29/38 (76%) and 20/38 (53%), respectively. Autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. We had additional data from 5 genotype‐positive mothers, all with average intellect and 3 with epilepsy, and from 1 genotype‐positive father. Significance Our series represents a robust cohort with carefully curated PCDH 19 variants. We observed seizures as a core feature with a range of seizure types and severity. Whereas the majority of individuals had ID , we highlight the possibility of average intellect in the setting of PCDH 19 ‐related epilepsy. We also note the high prevalence and severity of neurobehavioral phenotypes associated with likely pathogenic variants in PCDH 19 . Sleep dysregulation was also a major area of concern. Our data emphasize the importance of appropriate referrals for formal neuropsychological evaluations as well as the need for formal prospective studies to characterize the PCDH 19 ‐related neurodevelopmental syndrome in children and their genotype‐positive parents.