X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Department of Genetic Medicine, Level 9 Rieger Building, Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia.
Nature Genetics (Impact Factor: 29.35). 05/2008; 40(6):776-781. DOI: 10.1038/ng.149


Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

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    • "A heterozygous defect in the gene encoding protocadherin 19 (PCDH19) causes early-onset intractable epilepsy in females (i.e., PCDH19-related female epilepsy, PCDH19-FE, or previously, epilepsy and mental retardation limited to females, EFMR) [1]. PCHD19, an adhesion molecule of the d2-protocadherin subclass of the cadherin superfamily, is highly expressed in the vertebrate brain. "
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    ABSTRACT: The pathomechanism and treatment of PCDH19 female epilepsy (PCDH19-FE) remain unclear. Here, we report that corticosteroids are effective for control of the seizure clusters or other acute symptoms of PCDH19-FE and argue for the possible involvement of a compromised blood-brain barrier (BBB) in its pathogenesis. The efficacy of corticosteroids was retrospectively reviewed in five Japanese patients with PCDH19-FE. The results of antibody assays against the N-methyl-d-aspartate-type glutamate receptor (abs-NR) in serum/cerebrospinal fluid were also compiled. Corticosteroid treatments significantly improved the acute symptoms, including seizure clusters, in all cases, most often immediately after the initial administration. However, the effect was transient, and some seizures recurred within a few weeks, especially in association with fever. Serum and/or cerebrospinal fluid abs-NR were detected in all patients. Target sequences of the detected antibodies were multiple, and the titers tended to decrease over time. In one patient, immunohistochemical analysis using rat hippocampal slices also revealed serum antibodies targeting an unknown epitope in neuronal cytoplasm. Our findings imply an involvement of inflammatory processes in the pathogenesis of PCDH19-FE and therapeutic utility for corticosteroids as an adjunctive option in acute treatment. PCDH19 is well expressed in brain microvascular endothelial cells and thus its impairment may cause BBB vulnerability, which may be ameliorated by corticosteroids. The abs-NR detected in our patients may not indicate an autoimmune pathomechanism, but may rather represent non-specific sensitization to degraded neuronal components entering the general circulation, the latter process facilitated by the BBB vulnerability. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
    Full-text · Article · Feb 2015 · Seizure
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    • "rt to this , because the association with epilepsy was particularly high among ASD females with comorbid ID . In addition , this ID - epilepsy - female gender association has become a more significant research area after discovery of the causative gene for the condition known as ' ' epilepsy and mental retardation limited to females ' ' ( EFMR ) ( Dibbens et al . 2008 ) . This gender - specific disorder is characterized by seizure onset during early childhood and usually cognitive impairment , and interestingly , is associated with several psychiatric disorders including ASD ( Scheffer et al . 2008 ) . Understanding of this condition and its comorbidity with other psychiatric disorders is , however ,"
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    ABSTRACT: The present population-based study examines associations between epilepsy and autism spectrum disorders (ASD). The cohort includes register data of 4,705 children born between 1987 and 2005 and diagnosed as cases of childhood autism, Asperger's syndrome or pervasive developmental disorders-not otherwise specified. Each case was matched to four controls by gender, date of birth, place of birth, and residence in Finland. Epilepsy was associated with ASD regardless of the subgroup after adjusting for covariates. The associations were stronger among cases with intellectual disability, especially among females. Epilepsy's age at onset was similar between the cases and controls regardless of the ASD subgroup. These findings emphasize the importance to examine the neurodevelopmental pathways in ASD, epilepsy and intellectual disability.
    Full-text · Article · May 2014 · Journal of Autism and Developmental Disorders
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    • "Mutations to PCDH19, a member of the cadherin superfamily , cause epilepsy and mental retardation that are limited to females (EFMR) (Dibbens and others 2008). EFMR is characterized by an inheritance pattern unusual for an X-linked disorder: heterozygous females are affected, but transmitting males are spared (Dibbens and others 2008). Although males with these mutations are seizure-free, they exhibit behavioral disturbances reminiscent of autism (van Harssel and others 2013). "
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    ABSTRACT: X-linked intellectual disability (XLID) affects 1% to 3% of the population. XLID subsumes several heterogeneous conditions, all of which are marked by cognitive impairment and reduced adaptive skills. XLID arises from mutations on the X chromosome; to date, 102 XLID genes have been identified. The proteins encoded by XLID genes are involved in higher brain functions, such as cognition, learning and memory, and their molecular role is the subject of intense investigation. Here, we review recent findings concerning a representative group of XLID proteins: the fragile X mental retardation protein; methyl-CpG-binding protein 2 and cyclin-dependent kinase-like 5 proteins, which are involved in Rett syndrome; the intracellular signaling molecules of the Rho guanosine triphosphatases family; and the class of cell adhesion molecules. We discuss how XLID gene mutations affect the structure and function of synapses.
    Full-text · Article · Jul 2013 · The Neuroscientist
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