Epilepsy and genetic in Rett syndrome: A review

Operto, Francesca Felicia; Mazza, Roberta; Pastorino, Grazia Maria Giovanna; Verrotti, Alberto; Coppola, Giangennaro

doi:10.1002/brb3.1250

Cited by 62 publications

(74 citation statements)

References 72 publications

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“…In RTT patients, the differential expression of multiple genes related to intracellular signaling, modulation of cytoskeleton plasticity and cell metabolism [9] support the involvement of MeCP2 in neural development and synaptic function. Interestingly, perturbations in the genes acting in GABAergic circuits [10] could result in neuron hyperexcitability, which in turn is potentially responsible for epilepsy reported in 60–80% of RTT patients [11].…”

Section: Introductionmentioning

confidence: 99%

“…Next generation sequencing (NGS) and particularly Whole Exome Sequencing (WES) have emerged as a powerful tool to identify new genes involved in rare genetic diseases [18] and to give a diagnosis to patients without a known genetic cause. Thanks to these technological advances, in the last few years, several uncommon causative genes for classic or variant Rett syndrome or similar phenotypes (RTT-like) have been discovered [11,14,19,20,21,22,23,24]. Among the novel genes, several have been previously associated with developmental delay, often in comorbidity with epilepsy.…”

Section: Introductionmentioning

confidence: 99%

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Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes

Cogliati

Giorgini

Masciadri

et al. 2019

IJMS

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Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40–73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants—one in GABRB2 and, for first time, one in GABRG2—were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes

Cogliati

Giorgini

Masciadri

et al. 2019

IJMS

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“…The variant on which we applied gene editing represents only about 10% of RTT cases but this could be however relevant for those patients, considering that there is currently no cure for this syndrome. Moreover, since eight recurrent variants underlie ~70% MECP2 -mutated RTT cases [ 1 , 4 , 9 ], a relevant portion of patients might be targeted with appropriate validation of a limited number of constructs. Moreover, the results from Le et al in iPSCs suggest that it might be possible to use a single sgRNA to mediate the insertion of specific sequences into MECP2 gene by Homologous Recombination [ 30 ]; a similar approach could be employed to correct MeCP2 C-terminal deletions, further extending the spectrum of treatable variants.…”

Section: Discussionmentioning

confidence: 99%

“…Rett syndrome (RTT; OMIM# 312750) is one of the most common genetic causes of intellectual disability in girls with an estimated prevalence of about 1:10.000 [ 1 ]. Classic RTT patients present a normal development for the first 6–18 months of life.…”

Section: Introductionmentioning

confidence: 99%

“…Over 100 different pathogenic variations have been identified, including point variants, insertions, duplications and small or large deletions. However, eight single nucleotide recurrent changes, namely c.316 C > T (p.(Arg106Trp)), c.397 C > T (p.(Arg133Cys)), c.473 C > T (p.(Thr158Met)), c.502 C > T (p.(Arg168*)), c.763 C > T (p.(Arg255*)), c.810 A > G (p.(Arg270*)), c.880 C > T (p.(Arg294*)) and c.916 C > T (p.(Arg306Cys)), account for ~70% of all identified variations [ 1 , 4 , 5 ]. The most frequent one is the missense change c.473 C > T (p.(Thr158Met)) that accounts for ~10% of classic RTT ( https://www.rettdatabasenetwork.org ) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

et al. 2020

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Rett syndrome is a progressive neurodevelopmental disorder which affects almost exclusively girls, caused by variants in MECP2 gene. Effective therapies for this devastating disorder are not yet available and the need for tight regulation of MECP2 expression for brain to properly function makes gene replacement therapy risky. For this reason, gene editing with CRISPR/Cas9 technology appears as a preferable option for the development of new therapies. To study the disease, we developed and characterized a human neuronal model obtained by genetic reprogramming of patient-derived primary fibroblasts into induced Pluripotent Stem Cells. This cellular model represents an important source for our studies, aiming to correct MECP2 variants in neurons which represent the primarily affected cell type. We engineered a gene editing toolkit composed by a two-plasmid system to correct a hotspot missense variant in MECP2 , c.473 C > T (p.(Thr158Met)). The first construct expresses the variant-specific sgRNA and the Donor DNA along with a fluorescent reporter system. The second construct brings Cas9 and targets for auto-cleaving, to avoid long-term Cas9 expression. NGS analysis on sorted cells from four independent patients demonstrated an exceptionally high editing efficiency, with up to 80% of HDR and less than 1% of indels in all patients, outlining the relevant potentiality of the approach for Rett syndrome therapy.

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Assessment of Adaptive Functioning and the Impact of Seizures in KBG Syndrome

Sarino,

Guo,

et al. 2024

American J of Med Genetics Pt A

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This study aimed to examine the adaptive functioning status and the impact of epileptic seizures on neurocognitive outcomes in KBG syndrome, a rare genetic neurodevelopmental disorder characterized by pathogenic variants in ANKRD11. A single clinician interviewed individuals and families with genetically confirmed cases of KBG syndrome. Trained professionals also conducted assessments using the Vineland–3 Adaptive Behavior Scales. The assessment covered the domains of communication, daily living skills, socialization, and maladaptive behaviors, and then compared individuals with and without epilepsy. Further comparisons were made with data from interviews and participants' medical records. Thirty‐nine individuals (22 males, 17 females) with KBG syndrome, confirmed through genetic analysis, were interviewed via videoconferencing, followed by Vineland–3 assessment by trained raters. Individuals with KBG syndrome came from 36 unique families spanning 11 countries. While the KBG cohort displayed lower overall adaptive behavior composite scores compared with the average population, several members displayed standard scores at or higher than average, as well as higher scores compared with those with the neurodevelopmental disorder Ogden syndrome. Within the KBG cohort, males consistently scored lower than females across all domains, but none of these categories reached statistical significance. While the group with epilepsy exhibited overall lower scores than the nonseizure group in every category, statistical significance was only reached in the written communication subdomain. Our research provides insights that can aid in epilepsy screening and inform assessment strategies for neurocognitive functioning in those with this condition. The cohort performed overall higher than expected, with outliers existing in both directions. Although our results suggest that seizures might influence the trajectory of KBG syndrome, the approaching but overall absence of statistical significance between study groups underscores the need for a more extensive cohort to discern subtle variations in functioning.

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Epilepsy and genetic in Rett syndrome: A review

Cited by 62 publications

References 72 publications

Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes

Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes

High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

Assessment of Adaptive Functioning and the Impact of Seizures in KBG Syndrome

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