Academic literature on the topic 'X-linked clustering epilepsy'

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing ( trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.ResultsWe describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3 variant, including the patients that initially allowed reporting TFE3 as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.ConclusionThis series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3 mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.

Abstract PCDH19 gene-related epilepsy or PCDH19 clustering epilepsy (PCDH19-CE) is an infantile-onset epilepsy syndrome characterized by psychiatric (including autism-related), sensory and cognitive impairment of varying degrees. PCDH19-CE is caused by X-linked PCDH19 protein loss of function. Due to random X-chromosome inactivation, PCDH19-CE-affected females present a mosaic population of healthy and PCDH19-mutant cells. Unfortunately, to date, no current mouse model can fully recapitulate both the brain histological and behavioral deficits present in people with PCDH19-CE. Thus, the search for a proper understanding of the disease and possible future treatment is hampered. By inducing a focal mosaicism of PCDH19 expression using in utero electroporation in rats, we found here that PCDH19 signaling in specific brain areas is implicated in neuronal migration, heat-induced epileptic seizures, core/comorbid behaviors related to autism and cognitive function.

PCDH19 is a transmembrane protein and member of the protocadherin family. It is encoded by the X-chromosome and more than 200 mutations have been linked to the neurodevelopmental PCDH-clustering epilepsy (PCDH19-CE) syndrome. A disturbed cell-cell contact that arises when random X-inactivation creates mosaic absence of PCDH19 has been proposed to cause the syndrome. Several studies have shown roles for PCDH19 in neuronal proliferation, migration, and synapse function, yet most of them have focused on cortical and hippocampal neurons. As epilepsy can also be caused by impaired interneuron migration, we studied the role of PCDH19 in cortical interneurons during embryogenesis. We show that cortical interneuron migration is affected by altering PCDH19 dosage by means of overexpression in brain slices and medial ganglionic eminence (MGE) explants. We also detect subtle defects when PCDH19 expression was reduced in MGE explants, suggesting that the dosage of PCDH19 is important for proper interneuron migration. We confirm this finding in vivo by showing a mild reduction in interneuron migration in heterozygote, but not in homozygote PCDH19 knockout animals. In addition, we provide evidence that subdomains of PCDH19 have a different impact on cell survival and interneuron migration. Intriguingly, we also observed domain-dependent differences in migration of the non-targeted cell population in explants, demonstrating a non-cell-autonomous effect of PCDH19 dosage changes. Overall, our findings suggest new roles for the extracellular and cytoplasmic domains of PCDH19 and support that cortical interneuron migration is dependent on balanced PCDH19 dosage.

Girls Clustering Epilepsy is the second most common developmental and epileptic encephalopathy. GCE is due to variants in the X chromosome gene PCDH19 and is underpinned by cellular mosaicism due to X-chromosome inactivation (XCI) in females or somatic variant in males. The hallmark feature is that seizures occur in clusters and mainly affect females. At the time of thesis submission, GCE was re-named “X-linked clustering epilepsy” (XCE) to accommodate the growing number of affected male cases. Seizures typically present as generalized tonic-clonic and/or focal, which may evolve to bilateral, tonic-clonic. The clinical profile includes variable cognitive impairment and psychiatric features. The prevalence of these comorbidities and cause of the variable clinical expressivity is unknown. We performed a systematic review and meta-analysis to identify the comorbidities associated with PCDH19 variants and examine phenotype- and genotype-phenotype associations. Data from 38 peer-reviewed original articles were used and included 271 individual cases. We found that seizure onset ≤ 12 months was significantly associated (p = 4.127 x 10-7) with more severe intellectual disability compared with onset > 12 months. We identified two recurrent variants p.Asn340Ser and p.Tyr366Leufs*10, occurring in 25 (20 unrelated) and 30 (11 unrelated) cases, respectively. PCDH19 variants were associated with psychiatric comorbidities in approximately 60% females, 80% affected mosaic males, and reported in nine hemizygous males. Executive dysfunction, and hyperactive, autistic, and obsessive-compulsive features were most frequently associated with PCDH19 variants. We developed a PCDH19 survey to systematically examine the comorbidities identified in our review using standardized neuropsychiatric assessments. The survey was completed by 122/186 (66%) participants diagnosed with GCE or with a confirmed likely pathogenic PCDH19 variant. Executive functions were measured using the Behavior Rating Inventory of Executive Function. Psychiatric comorbidities were assessed via the Social Responsiveness Scale or Social Communication Questionnaire, the Strengths and Difficulties Questionnaire, and the Dimensional Obsessive-Compulsive Scale. Genetic, seizure, and developmental information were also collected. Of the 112 evaluated participants (15 males), there were 70 unique variants. Thirty-five variants were novel and included a newly identified recurrent variant Ile781Asnfs*3. There were no phenotypic differences between published and unpublished cases. Seizures occurred in clusters in 94% individuals, with seizures resolving in 28% at an average age of 17.5 years. Developmental delay prior to seizure onset occurred in 18% of our cohort. Executive dysfunction and autism spectrum disorder (ASD) occurred in approximately 60% of individuals. The ASD profile included features of attention-deficit hyperactivity disorder. Obsessive-compulsive symptomology was observed in 21% individuals. There were no phenotypic differences between heterozygous females and mosaic males. We describe a mosaic male and two hemizygous males with atypical clinical profiles. Earlier seizure onset age and increased number of seizures within a cluster were associated with more severe clinical outcomes. No clinical profile was observed for transmitting males. The penetrance of GCE is incomplete; estimated to be around 80-90%, and might be explained by cellular interference. Cellular interference postulates that the coexistence of PCDH19 wild-type and variant cells would be pathogenic, whereas a homogenous cell population would be tolerated; an idea supported by the presence of asymptomatic PCDH19-negative hemizygous and symptomatic PCDH19-mosaic males. The cellular interference hypothesis was tested through analyses of GCE penetrant and non-penetrant female fibroblast cell lines using assays to determine XCI patterns and relative PCDH19 cDNA expression. Specifically, we hypothesized that XCI and PCDH19 cDNA expression will be skewed towards complete wild-type or variant expression in non-penetrant females. We have shown that XCI patterns do not correlate with relative PCDH19 cDNA expression in fibroblasts, thus invalidating use of this assay to infer PCDH19 expression. No clear association was observed between penetrance in XCE and the degree of variant and wild-type PCDH19 mRNA expression in skin fibroblasts. Although we were able to identify three non-penetrant females with 100% wild-type PCDH19 expression, we were unable to provide support for the mechanism of cellular interference through our finding clinical phenotypes in individuals with markedly skewed XCI. Neuropsychiatric disorders can be very responsive to early intervention; therefore, a better understanding of these comorbidities may help to inform treatment and ultimately lead to better developmental outcomes for individuals affected by GCE. We show that both seizure onset age and activity are associated with clinical outcomes. Clinicians can use this information to inform prognosis and provide targeted intervention and guidance for patients and their families.
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2020