Response to Carbamazepine in KCNQ2 Related Early Infantile Epileptic Encephalopathy

Sharawat, Indar Kumar; Kasinathan, Ananthanarayanan; Sahu, Jitendra Kumar; Sankhyan, Naveen

doi:10.1007/s12098-018-2796-8

Cited by 15 publications

(9 citation statements)

References 4 publications

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“…Until recently, the only genetic KCNQ2-E mouse model that had been published was a conditional overexpression model of the DN KCNQ2-G279S variant, inserted on the mouse X chromosome (Peters et al, 2005). This variant was modeled based on a DN variant in KCNQ1, and has, in the meantime, been described in a patient with KCNQ2-E (Sharawat et al, 2019). The mice displayed spontaneous seizures, as well as cognitive and behavioral impairments when scored with the Morris water maze and open-field tests.…”

Section: Ki Mouse Models Of Human Pathogenic Kcnq2 Variantsmentioning

confidence: 99%

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

et al. 2020

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Kv7.2 subunits encoded by the KCNQ2 gene constitute a critical molecular component of the M-current, a subthreshold voltage-gated potassium current controlling neuronal excitability by dampening repetitive action potential firing. Pathogenic loss-of-function variants in KCNQ2 have been linked to epilepsy since 1998, and there is ample functional evidence showing that dysfunction of the channel indeed results in neuronal hyperexcitability. The recent description of individuals with severe developmental delay with or without seizures due to pathogenic variants in KCNQ2 (KCNQ2-encephalopathy) reveals that Kv7.2 channels also have an important role in neurodevelopment. Kv7.2 channels are expressed already very early in the developing brain when key developmental processes such as proliferation, differentiation, and synaptogenesis play a crucial role in brain morphogenesis and maturation. In this review, we will discuss the available evidence for a role of Kv7.2 channels in these neurodevelopmental processes, focusing in particular on insights derived from KCNQ2related human phenotypes, from the spatio-temporal expression of Kv7.2 and other Kv7 family member, and from cellular and rodent models, highlighting critical gaps and research strategies to be implemented in the future. Lastly, we propose a model which divides the M-current activity in three different developmental stages, correlating with the cell characteristics during these particular periods in neuronal development, and how this can be linked with KCNQ2-related disorders. Understanding these mechanisms can create opportunities for new targeted therapies for KCNQ2-encephalopathy.

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Section: Ki Mouse Models Of Human Pathogenic Kcnq2 Variantsmentioning

confidence: 99%

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

et al. 2020

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“…However, in the last two decades, other medications like levetiracetam, lacosamide, topiramate, and lamotrigine have become increasingly popular, as the older ASMs are known to have more frequent and more severe treatment‐emergent adverse effects(TEAEs). Moreover, the new generation ASMs had been shown to have similar efficacy in some recent studies, thereby making the clinicians choose them more frequently 2,3 . Lacosamide (LCM) enhances the slow inactivation of voltage‐gated sodium channels unlike phenytoin, without affecting their fast inactivation 4 .…”

Section: Introductionmentioning

confidence: 99%

Efficacy of lacosamide and phenytoin in status epilepticus: A systematic review

Panda

Sharawat

2021

Acta Neurol Scand

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Objectives To compare the evidence on efficacy, safety, tolerability, and impact on short term/long functional outcome of lacosamide (LCM) and phenytoin (PHT) in patients with status epilepticus. Materials & Methods We conducted a systematic literature search of relevant electronic databases using a suitable search strategy to identify studies directly comparing PHT and LCM, irrespective of dose and duration in patients with convulsive and/or nonconvulsive status epilepticus (SE). We used a standardized assessment form to extract information on the study design, data sources, methodologic framework, efficacy, and adverse events attributed to PHT and LCM from included studies and compared the efficacy and safety outcomes, using a fixed/random effect model. Results Five studies were found to be eligible for inclusion out of 192 search items, enrolling a total of 115 and 166 participants (predominantly with SE) in LCM and PHT arm, respectively. Baseline characteristics were comparable between both arms. The proportion with seizure control was comparable between both arms (57.3% in LCM vs. 45.7% in PHT arm, p = 0.28) and even in the subgroup analysis separately for convulsive and non‐convulsive SE. Proportion with treatment‐emergent adverse events (TEAE) were comparable in both (17.6% vs. 12.2%, p = 0.20), but serious adverse events (SAE) were higher in PHT arm (5.1% vs. 0.8%, p = 0.049). The proportion with all‐cause mortality and survival with moderate‐severe disability were comparable between both arms (p = 0.23 and 0.37, respectively). Conclusion LCM has comparable efficacy with fewer SAEs as compared to PHT for achieving seizure control in patients with SE.

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“…Hence, careful interpretation of pathogenicity analysis by bioinformatics and genotype-phenotype matching is highly essential. 26,27 Our review has several limitations. Most studies are small case series only, which used various description and quantitative measurement terminologies, which often resulted in difficulty while collating for determining pooled estimate.…”

Section: Characteristics Of Patients With Parkinson's Disease Phenotypementioning

confidence: 99%

Clinical Spectrum of TGM6-Related Movement Disorders: A New Report with a Pooled Analysis of 48 Patients

Sharawat

Panda

Bhunia

2021

JNRP

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Background Spinocerebellar ataxias (SCAs) are a diverse group of progressive neurodegenerative disorders. Until now, more than 20 genes have been implicated to be associated with this phenotype and TGM6 is one of these genes, associated with spinocerebellar ataxia-35 (SCA-35). The majority of disease-causing variants in the TGM6 gene predominantly have been reported from China and Taiwan and the association with Parkinson's disease (PD) have also been reported recently. Methods We report the first Indian case with SCA-35 in a 16-year-old-boy with atypical age of onset at 9 years, prominent extrapyramidal features, intellectual disability, and a novel missense mutation in the TGM6 gene. We also reviewed and collated all previously published cases with pathogenic TGM6 variants. Results Including the index case, 54 cases were identified from 10 relevant articles in literature and 48 cases had adequate clinical details to be included in the pooled analysis. Around two-thirds of reported cases had SCA-35 phenotype, with cerebellar atrophy. Onset in the majority of cases was the fourth decade of life onwards. A proportion of SCA-35 cases also had spasmodic torticollis, impaired proprioception, extrapyramidal features, and myoclonic jerks. The patients with PD had often early-onset milder symptoms, slower progression, and favorable response to levodopa/carbidopa. One patient each presented with episodic ataxia and dystonic tremor of the upper limb. Most of the cases had missense mutations, without any definite hotspot or genotype–phenotype correlation. Conclusions TGM6 mutation should be suspected in patients with SCA like presentation, especially when it is accompanied by extrapyramidal features, spasmodic torticollis, impaired proprioception, or myoclonus.

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Response to Carbamazepine in KCNQ2 Related Early Infantile Epileptic Encephalopathy

Cited by 15 publications

References 4 publications

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

Efficacy of lacosamide and phenytoin in status epilepticus: A systematic review

Clinical Spectrum of TGM6-Related Movement Disorders: A New Report with a Pooled Analysis of 48 Patients

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