Quinidine therapy for West syndrome with KCNTI mutation: A case report

Fukuoka, Masataka; Kuki, Ichiro; Kawawaki, Hisashi; Okazaki, Shin; Kim, Kiyohiro; Hattori, Yukio; Tsuji, Hitomi; Nukui, Megumi; Inoue, Takeshi; Yoshida, Yoko; Uda, Takehiro; Kimura, Shigeharu; Mogami, Yukiko; Suzuki, Yasuhiro; Okamoto, Nobuhiko; Saitsu, Hirotomo; Matsumoto, Naomichi

doi:10.1016/j.braindev.2016.08.002

Cited by 51 publications

(63 citation statements)

References 7 publications

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“…KCNT1 is associated with epilepsy of infancy with migrating focal seizures, autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies [87–89]. Ohba et al [88] found 11 KCNT1 mutations in a total of 362 epilepsy patients: 9/18 epilepsy of infancy with migrating focal seizures cases (50%), 1/180 West syndrome cases (0.56%), and 1/66 unclassified early onset epileptic encephalopathy cases (1.52%), suggesting that KCNT1 may be a causal gene for West syndrome.…”

Section: Discussionmentioning

confidence: 99%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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Pediatric refractory epilepsy is a broad phenotypic spectrum with great genetic heterogeneity. Next-generation sequencing (NGS) combined with Sanger sequencing could help to understand the genetic diversity and underlying disease mechanisms in pediatric epilepsy. Here, we report sequencing results from a cohort of 172 refractory epilepsy patients aged 0–14 years. The pathogenicity of identified variants was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria. We identified 43 pathogenic or likely pathogenic variants in 40 patients (23.3%). Among these variants, 74.4% mutations (32/43) were de novo and 60.5% mutations (26/43) were novel. Patients with onset age of seizures ≤12 months had higher yields of deleterious variants compared to those with onset age of seizures > 12 months (P = 0.006). Variants in ion channel genes accounted for the greatest functional gene category (55.8%), with SCN1A coming first (16/43). 81.25% (13/16) of SCN1A mutations were de novo and 68.8% (11/16) were novel in Dravet syndrome. Pathogenic or likely pathogenic variants were found in the KCNQ2, STXBP1, SCN2A genes in Ohtahara syndrome. Novel deleterious variants were also found in West syndrome, Doose syndrome and glucose transporter type 1 deficiency syndrome patients. One de novo MECP2 mutation were found in a Rett syndrome patient. TSC1/TSC2 variants were found in 60% patients with tuberous sclerosis complex patients. Other novel mutations detected in unclassified epilepsy patients involve the SCN8A, CACNA1A, GABRB3, GABRA1, IQSEC2, TSC1, VRK2, ATP1A2, PCDH19, SLC9A6 and CHD2 genes. Our study provides novel insights into the genetic origins of pediatric epilepsy and represents a starting-point for further investigations into the molecular pathophysiology of pediatric epilepsy that could eventually lead to better treatments.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0392-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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“…Prior case series have described patients with seizure onset in the neonatal period in KCNT1 ‐associated EIMFS, although only one case has been diagnosed so early on in the disease course . All patients in this series initiated quinidine therapy at an early age, with 2 patients initiating therapy within the first 2 months of life . Despite early targeting of the pathologic channel, no disease‐modifying effects were noted in the clinical phenotype.…”

Section: Discussionmentioning

confidence: 89%

“…18 All patients in this series initiated quinidine therapy at an early age, with 2 patients initiating therapy within the first 2 months of life. [15][16][17][18]33 Despite early targeting of the pathologic channel, no disease-modifying effects were noted in the clinical phenotype. In contrast to previous hypotheses, our data do not support "age at quinidine initiation" as a variable that can modify overall outcome.…”

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confidence: 99%

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

et al. 2018

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Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.

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“…PIGA deficiency patients may be responsive to ketogenic diet treatment, as a recent study showed (Joshi et al., ). As many genes are associated with epileptic encephalopathy and hypotonia besides PIGA and related GPI biosynthesis gene, and there have been a wide range of medicine in clinical use with many of which being directed to a particular genotype (e.g., quinidine is a specific medicine for KCNT1 epileptic encephalopathy genotype) (Fukuoka et al., ), a solid genotype determination is needed to guide the treatment. Genetic analysis can also help guide the prenatal diagnosis, and help prevent the birth of PIGA deficient offspring in the future as an important precautious measure in family plan for the patient family and other members in the pedigree.…”

Section: Discussionmentioning

confidence: 99%

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

Yang

Wang

Zhuo

et al. 2018

Molec Gen & Gen Med

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BackgroundGlycosylphosphatidylinositol (GPI) anchoring is a special type of protein posttranslational modification, by which proteins with diverse function are attached to cell membrane through a covalent linkage between the protein and the glycolipid. Phosphatidylinositol glycan anchor biosynthesis class A (PIGA) is a key enzyme in GPI anchor biosynthesis, somatic mutations or genetic variants of which have been associated with paroxysmal nocturnal hemoglobinuria (PNH), or PIGA deficiency, respectively. More than 10 PIGA pathogenic or likely pathogenic variants have been reported in a wide spectrum of clinical syndromes of PIGA deficiency, including multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2).MethodsWhole‐exome sequencing (WES) was performed on two trios, that is., the proband's family and his affected maternal cousin's family, from a nonconsanguineous Chinese family pedigree with hypotonia‐encephalopathy‐seizures disease history and putative X‐linked recessive inheritance. Sanger sequencing for PIGA variant was performed on affected members as well as unaffected members in the family pedigree to verify its familial segregation.ResultsA novel likely pathogenic variant in PIGA was identified through comparative WES analysis of the two affected families. The single‐nucleotide substitution (NC_000023.9:g.15343279T>C) is located in intron 3 of the PIGA gene and within the splice acceptor consensus sequence (NM_002641.3:c.849‐5A>G). Even though we have not performed RNA studies, in silico tools predict that this intronic variant may alter normal splicing, causing a four base pair insertion which creates a frameshift and a premature stop codon at position 297 (NP_002632.1:p.(Arg283Serfs*15)). Sanger sequencing analysis of the extended family members confirmed the presence of the variant and its X‐linked inheritance.Conclusion WES data analysis along with familial segregation of a rare intronic variant are suggestive of a diagnosis of X‐liked PIGA deficiency with clinical features of MCAHS2.

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Quinidine therapy for West syndrome with KCNTI mutation: A case report

Cited by 51 publications

References 7 publications

Novel and de novo mutations in pediatric refractory epilepsy

Novel and de novo mutations in pediatric refractory epilepsy

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

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