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Epilepsia. 2018 Mar;59(3):679-689. doi: 10.1111/epi.14003. Epub 2018 Jan 28.

PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum.

Author information

1
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
2
Neurogenetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
3
Department of Neurology, Division of Epilepsy, University of California, San Francisco, San Francisco, CA, USA.
4
Department of Neurology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.
5
F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.

Erratum in

Abstract

OBJECTIVE:

To characterize the features associated with PCDH19-related epilepsy, also known as "female-limited epilepsy."

METHODS:

We analyzed data from participants enrolled in the PCDH19 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 PCDH19: 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 PCDH19 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 PCDH19-related epilepsy. We also note the high prevalence and severity of neurobehavioral phenotypes associated with likely pathogenic variants in PCDH19. 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 PCDH19-related neurodevelopmental syndrome in children and their genotype-positive parents.

KEYWORDS:

PCDH19 ; autism spectrum disorder; female-limited epilepsy; seizure; sleep disorder

PMID:
29377098
PMCID:
PMC6264912
[Available on 2019-03-01]
DOI:
10.1111/epi.14003
[Indexed for MEDLINE]

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