SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet

Wong, Virginia; Fung, Cheuk‐Wing; Kwong, Anna Ka-Yee

doi:10.1016/j.braindev.2014.10.008

Cited by 18 publications

(15 citation statements)

References 18 publications

(23 reference statements)

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“…Previous studies have shown that patients with Dravet syndrome with SCN1A mutations respond well to KD ( 21 , 24 ), as did a patient with an SCN2A mutation who was treated with a modified Atkins diet ( 19 ). Here, as well as in several other studies ( 25 , 26 ), patients with CDKL5 mutations showed poor responses to or only short-term efficacy of KD.…”

Section: Discussionmentioning

confidence: 99%

“…To date, few reports on the efficacy of KD in patients with DEE with specific genotypes have been published ( 17 – 19 ), and of these, most are anecdotal reports or include short-term evaluations of the efficacy in only one specific genotype. In the present study, we assessed the long-term response to KD (over 12 months) in patients with each genotype of DEE.…”

Section: Discussionmentioning

confidence: 99%

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The Efficacy of Ketogenic Diet for Specific Genetic Mutation in Developmental and Epileptic Encephalopathy

Jung

Kim

et al. 2018

Front. Neurol.

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Objectives: Pathogenic mutations in developmental and epileptic encephalopathy (DEE) are increasingly being discovered. However, little has been known about effective targeted treatments for this rare disorder. Here, we assessed the efficacy of ketogenic diet (KD) according to the genes responsible for DEE.Methods: We retrospectively evaluated the data from 333 patients who underwent a targeted next-generation sequencing panel for DEE, 155 of whom had tried KD. Patients showing ≥90% seizure reduction from baseline were considered responders. The KD efficacy was examined at 3, 6, and 12 months after initiation. Patients were divided into those with an identified pathogenic mutation (n = 73) and those without (n = 82). The KD efficacy in patients with each identified pathogenic mutation was compared with that in patients without identified genetic mutations.Results: The responder rate to KD in the patients with identified pathogenic mutations (n = 73) was 52.1, 49.3, and 43.8% at 3, 6, and 12 months after initiation, respectively. Patients with mutations in SCN1A (n = 18, responder rate = 77.8%, p = 0.001), KCNQ2 (n = 6, responder rate = 83.3%, p = 0.022), STXBP1 (n = 4, responder rate = 100.0%, p = 0.015), and SCN2A (n = 3, responder rate = 100.0%, p = 0.041) showed significantly better responses to KD than patients without identified genetic mutations. Patients with CDKL5 encephalopathy (n = 10, responder rate = 0.0%, p = 0.031) showed significantly less-favorable responses to KD.Conclusions: The responder rate to KD remained consistent after KD in DEE patients with specific pathogenic mutations. KD is effective in patients with DEE with genetic etiology, especially in patients with SCN1A, KCNQ2, STXBP1, and SCN2A mutations, but is less effective in patients with CDKL5 mutations. Therefore, identifying the causative gene can help predict the efficacy of KD in patients with DEE.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Efficacy of Ketogenic Diet for Specific Genetic Mutation in Developmental and Epileptic Encephalopathy

Jung

Kim

et al. 2018

Front. Neurol.

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“…Epilepsies with onset beyond the early infantile period account for approximately 30% of the SCN2A DEE spectrum, with >60 published patients so far …”

Section: The Spectrum Of Scn2a‐related Disordersmentioning

confidence: 99%

Phenotypic spectrum and genetics of SCN2A‐related disorders, treatment options, and outcomes in epilepsy and beyond

Wolff¹,

Brunklaus

Zuberi

2019

Epilepsia

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Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration.Phenotypes include benign (self-limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later-onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.

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“…In recent studies, we proposed using Sanger sequencing of our selected panel of seven genes ( ARX, CDKL5, KCNQ2, PCDH19, SCN1A, SCN2A and STXBP1 ) as an option for genetic diagnosis in small‐scale mutational studies . We have identified 13 variants (46%) within this panel in 28 non‐syndromic neonatal/infantile EE (NIEE) patients without clinical signs suggestive of a clear genetic syndrome, such as dysmorphic features or positive findings after extensive metabolic and neuroimaging studies . Despite this, the underlying etiology of the remaining patients with negative findings remained unexplained.…”

mentioning

confidence: 99%

“…6 We have identified 13 variants (46%) within this panel in 28 non-syndromic neonatal/infantile EE (NIEE) patients without clinical signs suggestive of a clear genetic syndrome, such as dysmorphic features or positive findings after extensive metabolic and neuroimaging studies. [6][7][8] Despite this, the underlying etiology of the remaining patients with negative findings remained unexplained. In the present study, we have applied gene panel analysis of 430 epilepsy-associated genes in 31 non-syndromic cryptogenic NIEE patients for genetic-based diagnosis and subsequent potential treatment strategy.…”

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confidence: 99%

Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy

2017

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SummaryObjectiveEpileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic‐based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high‐throughput next‐generation sequencing (NGS) was used to investigate the genetic causes of non‐syndromic cryptogenic neonatal/infantile EE (NIEE).MethodsWe have selected a cohort of 31 patients with seizure cryptogenic NIEE and seizure onset before 24 months. All investigations including metabolic work‐up, were negative. Using NGS, we distinguished a panel of 430 epilepsy‐associated genes by NGS was utilized to identify possible pathogenic variants in the patients. Segregation analysis and multiple silico analysis prediction tools were used for pathogenicity assessment. The identified variants were classified as “pathogenic,” “likely pathogenic” and “uncertain significance,” according to the American College of Medical Genetics (ACMG) guidelines.ResultsPathogenic or likely pathogenic variants were identified in six genes (ALG13 [1], CDKL5 [2], KCNQ2 [2], PNPO [1], SCN8A [1], SLC9A6 [2]) in 9 NIEE patients (9/31; 29%). Variants of uncertain significance (VUS) were found in DNM1 and TUBA8 in 2 NIEE patients (2/31; 6%). Most phenotypes in our cohort matched with those reported cases.SignificanceThe diagnostic rate (29%) of pathogenic and likely pathogenic variants was comparable to the recent studies of early‐onset epileptic encephalopathy, indicating that gene panel analysis through NGS is a powerful tool to investigate cryptogenic NIEE in patients. Six percent of patients had neurometabolic disorders. Some of our diagnosed cases illustrated that successful molecular investigation may allow a better treatment strategy and avoid unnecessary and even invasive investigations. Functional analysis could be performed to further study the pathogenicity of the VUS identified in DNM1 and TUBA8.

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SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet

Cited by 18 publications

References 18 publications

The Efficacy of Ketogenic Diet for Specific Genetic Mutation in Developmental and Epileptic Encephalopathy

The Efficacy of Ketogenic Diet for Specific Genetic Mutation in Developmental and Epileptic Encephalopathy

Phenotypic spectrum and genetics of SCN2A‐related disorders, treatment options, and outcomes in epilepsy and beyond

Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy

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