Common genes and recurrent causative variants in 957 Asian patients with pediatric epilepsy

Kim, Se Hee; Seo, Jieun; Kwon, Soon Sung; Teng, Lip‐Yuen; Won, DongJu; Shin, Saeam; Lee, Joon Soo; Lee, Seung‐Tae; Choi, Jong Rak; Kang, Hoon‐Chul

doi:10.1111/epi.17857

Cited by 4 publications

(1 citation statement)

References 48 publications

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“…We have previously described the methodology used to detect variants. 4 5 6 Additionally, the online SpliceAI server ( https://spliceailookup.broadinstitute.org/ ) was used to predict the splicing effects of variants. SpliceAI scores range from 0 to 1, with higher scores indicating a higher probability of splicing being affected.…”

Section: Methodsmentioning

confidence: 99%

Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy

Shin,

Ko,

Kim

et al. 2024

J Clin Neurol

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Background and Purpose There is extensive literature on monogenic epilepsies caused by mutations in familiar channelopathy genes such as SCN1A . However, information on other less-common channelopathy genes is scarce. This study aimed to explore the genetic and clinical characteristics of patients diagnosed with unusual voltage-gated sodium and potassium channelopathies related to epilepsy. Methods This observational, retrospective study analyzed pediatric patients with epilepsy who carried pathogenic variants of unusual voltage-gated sodium and potassium channelopathy genes responsible for seizure-associated phenotypes. Targeted next-generation sequencing (NGS) panel tests were performed between November 2016 and June 2022 at Severance Children’s Hospital, Seoul, South Korea. Clinical characteristics and the treatment responses to different types of antiseizure medications were further analyzed according to different types of gene mutation. Results This study included 15 patients with the following unusual voltage-gated sodium and potassium channelopathy genes: SCN3A ( n =1), SCN4A ( n =1), KCNA1 ( n =1), KCNA2 ( n =4), KCNB1 ( n =6), KCNC1 ( n =1), and KCNMA1 ( n =1). NGS-based genetic testing identified 13 missense mutations (87%), 1 splice-site variant (7%), and 1 copy-number variant (7%). Developmental and epileptic encephalopathy was diagnosed in nine (60%) patients. Seizure freedom was eventually achieved in eight (53%) patients, whereas seizures persisted in seven (47%) patients. Conclusions Our findings broaden the genotypic and phenotypic spectra of less-common voltage-gated sodium and potassium channelopathies associated with epilepsy.

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Section: Methodsmentioning

confidence: 99%

Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy

Shin,

Ko,

Kim

et al. 2024

J Clin Neurol

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A retrospective study of the yield of next‐generation sequencing in the diagnosis of developmental and epileptic encephalopathies and epileptic encephalopathies in 0–12 years aged children at a single tertiary care hospital in South India

Murthy,

Banerjee,

Shetty

et al. 2024

Epileptic Disorders

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ObjectiveStudies on the genetic yield of developmental and epileptic encephalopathy and Epileptic encephalopathies using next‐generation sequencing techniques are sparse from the Indian subcontinent. Hence, the study was conducted to assess the yield of genetic testing and the proportion of children where a positive genetic yield influenced treatment decisions.MethodsIn this retrospective observational study, electronic medical records of children (0–12 years) with suspected genetic epilepsy who underwent genetic testing using whole exome sequencing, focused exome sequencing and epilepsy gene panels were retrieved. Genetic yield was ascertained based on the detection of pathogenic and likely pathogenic variants.ResultsA total of 100 patients with epilepsy underwent genetic testing. A yield of 53.8% (42/78) was obtained. Pathogenic variants were identified in 18 (42.8%) cases and likely pathogenic variants in 24 (57.1%) cases. Yield was 66.6% each through whole exome sequencing, focused exome sequencing and 40% through Epilepsy gene panels (p = .07). Yield was not statistically significant across different age groups (p = .2). It was however found to significantly vary across different epilepsy syndromes with maximum yield in Epilepsy in infancy with migrating focal seizures in 2 (100%), followed by developmental and epileptic encephalopathy unspecified in 14 (77.7%), Dravet syndrome in 14 (60.8%), early infantile developmental and epileptic encephalopathy in 3 (60%), infantile epileptic spasm syndrome in 5 (35.7%), and other epileptic encephalopathies in 4 (30.7%) cases (p = .04). After genetic diagnosis and drug optimization, drug‐refractory proportion reduced from 73.8% to 45.3%. About half of the cases achieved seizure control.SignificanceA reasonably high yield of 53.8% was obtained irrespective of the choice of panel or exome or age group using next‐generation sequencing‐based techniques. Yield was however higher in certain epilepsy syndromes and low in Infantile epileptic spasms syndrome. A specific genetic diagnosis facilitated tailored treatment leading to seizure freedom in 28.6% and marked seizure reduction in 54.7% cases.

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Effectiveness of add‐on acetazolamide in children with drug‐resistant CHD2‐related epilepsy and in a zebrafish CHD2 model

Melikishvili,

Striano,

Shojeinia

et al. 2024

Epilepsia Open

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CHD2‐related epilepsy is characterized by early‐onset photosensitive myoclonic epilepsy with developmental delay and a high rate of pharmacoresistance. We sought to evaluate the efficacy of acetazolamide (ACZ) in CHD2‐related epilepsy, due to ACZ's unexpected efficacy in our first patient harboring a pathogenic CHD2 variant. We collected patients from different Eastern European countries with drug‐resistant CHD2‐related epilepsy who were then treated with ACZ. Patients underwent video EEG before and during ACZ treatment. In a zebrafish model of CHD2‐related epilepsy, ictal‐like events were recorded 5 days post‐fertilization after overnight ACZ exposure. Developmental delay preceded the onset of seizures in 10 of the 12 patients. Four had ataxia, and 6 exhibited autistic features. Seizures, primarily myoclonic, began at an average age of 3.4 years and were photosensitive in all 12 patients. Add‐on ACZ treatment controlled photosensitive seizures in all patients: 6 became seizure‐free, and in the remaining 6, seizure frequency decreased by over 75%. Four patients transitioned to ACZ monotherapy. The median follow‐up was 13 months. In the zebrafish model, ACZ exposure reduced ictal‐like events by 72%. ACZ, a well‐tolerated and cost‐effective medication, could be a good option for CHD2‐related epilepsy, predominantly manifesting with myoclonic seizures and photosensitivity.Plain Language SummaryEpilepsy associated with CHD2 mutations is often pharmacoresistant and associated with developmental delay and eventually ataxia. There are several generalized seizure types, including generalized tonic–clonic seizures, but the most characteristic are jerks triggered by light stimulation. We collected 12 patients who received acetazolamide, a drug usually given as a diuretic and registered as a mild antiseizure medication. All jerks triggered by light disappeared while the frequency of spontaneous seizures decreased by over 75%. Further studies are needed to confirm this promising finding and identify the mechanism by which an old compound seems to have such a specific antiseizure effect.

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Common genes and recurrent causative variants in 957 Asian patients with pediatric epilepsy

Cited by 4 publications

References 48 publications

Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy

Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy

A retrospective study of the yield of next‐generation sequencing in the diagnosis of developmental and epileptic encephalopathies and epileptic encephalopathies in 0–12 years aged children at a single tertiary care hospital in South India

Effectiveness of add‐on acetazolamide in children with drug‐resistant CHD2‐related epilepsy and in a zebrafish CHD2 model

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