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https://www.readbyqxmd.com/read/28747464/lethal-digenic-mutations-in-the-k-channels-kir4-1-kcnj10-and-slack-kcnt1-associated-with-severe-disabling-seizures-and-neurodevelopmental-delay
#1
Sonia Majed Hasan, Ameera Balobaid, Alessandro Grottesi, Omar Dabbagh, Marta Cenciarini, Rifaat Rawashdeh, Afaf Al-Sagheir, Cecilia Bove, Lara Macchioni, Mauro Pessia, Mohammed Al-Owain, Maria Cristina D'Adamo
A 2-year-old boy presented profound developmental delay, failure to thrive, ataxia, hypotonia and tonic-clonic seizures that caused the death of the patient. Targeted and whole-exome sequencing revealed two heterozygous missense variants: a novel mutation in KCNJ10 gene that encodes for the inwardly-rectifying K(+) channel Kir4.1 and another previously characterized mutation in KCNT1 that encodes for the Na(+)-activated K(+) channel known as Slo2.2 or SLACK. The objectives of this study were to perform the clinical and genetic characterization of the proband and his family and to examine the functional consequence of the Kir4...
July 26, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28608234/genomics-guided-precise-anti-epileptic-drug-development
#2
Norman Delanty, Gianpiero Cavallleri
Traditional antiepileptic drug development approaches have yielded many important clinically valuable anti-epileptic drugs. However, the screening of promising compounds has been naturally agnostic to epilepsy etiology in individual human patients. Now, genomic medicine is changing the way we view human disease. International collaborations are unraveling the many molecular genetic causes of the epilepsies, including the early onset epileptic encephalopathies, and some of the familial focal epilepsies. Further advances in precision diagnostics will be facilitated by ongoing large collaborations and the wider availability of whole exome and whole genome sequencing in clinical practice...
July 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28477354/a-de-novo-missense-mutation-in-slc12a5-found-in-a-compound-heterozygote-patient-with-epilepsy-of-infancy-with-migrating-focal-seizures
#3
T Saito, A Ishii, K Sugai, M Sasaki, S Hirose
Epilepsy of infancy with migrating focal seizures (EIMFS) is an infantile epileptic encephalopathy characterized by refractory seizures, severe psychomotor delay, and multiple moving epileptic discharges. The genetic etiology of EIMFS is relatively homogeneous with the majority of causative mutations found in KCNT1. Currently, gene panel or whole-exome sequencing is used for testing. To verify the pathogenicity of a variant, co-segregation of the variant and the disorder in a pedigree is important; hence, de novo mutations that are judged to be deleterious may be considered pathogenic because the patients are isolated...
May 6, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28366665/the-phe932ile-mutation-in-kcnt1-channels-associated-with-severe-epilepsy-delayed-myelination-and-leukoencephalopathy-produces-a-loss-of-function-channel-phenotype
#4
Katherine M Evely, Kerri D Pryce, Arin Bhattacharjee
Sodium-activated potassium (KNa) channels contribute to firing frequency adaptation and slow after hyperpolarization. The KCNT1 gene (also known as SLACK) encodes a KNa subunit that is expressed throughout the central and peripheral nervous systems. Missense mutations of the SLACK C-terminus have been reported in several patients with rare forms of early onset epilepsy and in some cases severely delayed myelination. To date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal seizures (EIMFS) and Ohtahara syndrome (OS) have been reported to be gain-of-function mutations (Villa and Combi, 2016)...
May 20, 2017: Neuroscience
https://www.readbyqxmd.com/read/28212175/advances-in-epilepsy-gene-discovery-and-implications-for-epilepsy-diagnosis-and-treatment
#5
Joseph D Symonds, Sameer M Zuberi, Michael R Johnson
PURPOSE OF REVIEW: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery. RECENT FINDINGS: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed...
April 2017: Current Opinion in Neurology
https://www.readbyqxmd.com/read/28119399/an-als-associated-mutant-sod1-rapidly-suppresses-kcnt1-slack-na-activated-k-channels-in-aplysia-neurons
#6
Yalan Zhang, Weiming Ni, Arthur L Horwich, Leonard K Kaczmarek
Mutations that alter levels of Slack (KCNT1) Na(+)-activated K(+) current produce devastating effects on neuronal development and neuronal function. We now find that Slack currents are rapidly suppressed by oligomers of mutant human Cu/Zn superoxide dismutase 1 (SOD1), which are associated with motor neuron toxicity in an inherited form of amyotrophic lateral sclerosis (ALS). We recorded from bag cell neurons of Aplysia californica, a model system to study neuronal excitability. We found that injection of fluorescent wild-type SOD1 (wt SOD1YFP) or monomeric mutant G85R SOD1YFP had no effect on net ionic currents measured under voltage clamp...
February 22, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28081520/mesial-temporal-lobe-epilepsy-associated-with-kcnt1-mutation
#7
N Hansen, G Widman, E Hattingen, C E Elger, W S Kunz
No abstract text is available yet for this article.
December 26, 2016: Seizure: the Journal of the British Epilepsy Association
https://www.readbyqxmd.com/read/27784474/-clinical-features-and-gene-mutations-in-epilepsy-of-infancy-with-migrating-focal-seizures
#8
K W Shang, Y H Zhang, X L Yang, A J Liu, Z X Yang, X Y Liu, Y W Jiang, X R Wu
Objective: To summarize the clinical features and gene mutations of epilepsy of infancy with migrating focal seizures (EIMFS). Method: Clinical features and electroencephalograms(EEG)of 9 patients with EIMFS of Peking University First Hospital from May 2015 to January 2016 were analyzed. Candidate gene mutations were screened by next generation sequencing. Result: Among the 9 patients, 3 were males and 6 were females. Two patients had family history. Seizure onset age was 2 days to 3 months after birth (median age 35 days)...
October 2, 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/27730449/integrated-transcriptome-analysis-of-human-ips-cells-derived-from-a-fragile-x-syndrome-patient-during-neuronal-differentiation
#9
Ping Lu, Xiaolong Chen, Yun Feng, Qiao Zeng, Cizhong Jiang, Xianmin Zhu, Guoping Fan, Zhigang Xue
Fragile X syndrome (FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1 (FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein (FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here, we performed in-vitro neuronal differentiation of human induced pluripotent stem (iPS) cells that were derived from fibroblasts of a FXS patient (FXS-iPSC)...
November 2016: Science China. Life Sciences
https://www.readbyqxmd.com/read/27578169/quinidine-therapy-for-west-syndrome-with-kcnti-mutation-a-case-report
#10
Masataka Fukuoka, Ichiro Kuki, Hisashi Kawawaki, Shin Okazaki, Kiyohiro Kim, Yuka Hattori, Hitomi Tsuji, Megumi Nukui, Takeshi Inoue, Yoko Yoshida, Takehiro Uda, Sadami Kimura, Yukiko Mogami, Yasuhiro Suzuki, Nobuhiko Okamoto, Hirotomo Saitsu, Naomichi Matsumoto
The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried...
January 2017: Brain & Development
https://www.readbyqxmd.com/read/27123484/paroxysmal-hypnogenic-dyskinesia-is-associated-with-mutations-in-the-prrt2-gene
#11
Xiao-Rong Liu, Dan Huang, Jie Wang, Yi-Fan Wang, Hui Sun, Bin Tang, Wen Li, Jin-Xing Lai, Na He, Mei Wu, Tao Su, Heng Meng, Yi-Wu Shi, Bing-Mei Li, Bei-Sha Tang, Wei-Ping Liao
OBJECTIVE: To explore the potential causative genes of paroxysmal hypnogenic dyskinesia (PHD), which was initially considered a subtype of paroxysmal dyskinesia and has been recently considered a form of nocturnal frontal lobe epilepsy (NFLE). METHODS: Eleven patients with PHD were recruited. Mutations in proline-rich region transmembrane protein-2 (PRRT2), myofibrillogenesis regulator 1 (MR-1), solute carrier family 2, member 1 (SLC2A1), calcium-activated potassium channel alpha subunit (KCNMA1), cholinergic receptor, nicotinic, alpha 4 (CHRNA4), cholinergic receptor, nicotinic, beta 2 (CHRNB2), cholinergic receptor, nicotinic, alpha 2 (CHRNA2), and potassium channel subfamily T member 1 (KCNT1) were screened by direct sequencing...
April 2016: Neurology. Genetics
https://www.readbyqxmd.com/read/27029629/a-targeted-resequencing-gene-panel-for-focal-epilepsy
#12
Michael S Hildebrand, Candace T Myers, Gemma L Carvill, Brigid M Regan, John A Damiano, Saul A Mullen, Mark R Newton, Umesh Nair, Elena V Gazina, Carol J Milligan, Christopher A Reid, Steven Petrou, Ingrid E Scheffer, Samuel F Berkovic, Heather C Mefford
OBJECTIVES: We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group of the epilepsies. METHODS: The targeted resequencing gene panel was designed using molecular inversion probe (MIP) capture technology and sequenced using massively parallel Illumina sequencing. RESULTS: We demonstrated proof of principle that mutations can be detected in 4 previously genotyped focal epilepsy cases...
April 26, 2016: Neurology
https://www.readbyqxmd.com/read/26993267/improving-diagnosis-and-broadening-the-phenotypes-in-early-onset-seizure-and-severe-developmental-delay-disorders-through-gene-panel-analysis
#13
Natalie Trump, Amy McTague, Helen Brittain, Apostolos Papandreou, Esther Meyer, Adeline Ngoh, Rodger Palmer, Deborah Morrogh, Christopher Boustred, Jane A Hurst, Lucy Jenkins, Manju A Kurian, Richard H Scott
BACKGROUND: We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. METHODS: In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. RESULTS: We identified causative mutations in 71/400 patients (18%)...
May 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/26802095/multiplex-families-with-epilepsy-success-of-clinical-and-molecular-genetic-characterization
#14
Zaid Afawi, Karen L Oliver, Sara Kivity, Aziz Mazarib, Ilan Blatt, Miriam Y Neufeld, Katherine L Helbig, Hadassa Goldberg-Stern, Adel J Misk, Rachel Straussberg, Simri Walid, Muhammad Mahajnah, Tally Lerman-Sagie, Bruria Ben-Zeev, Esther Kahana, Rafik Masalha, Uri Kramer, Dana Ekstein, Zamir Shorer, Robyn H Wallace, Marie Mangelsdorf, James N MacPherson, Gemma L Carvill, Heather C Mefford, Graeme D Jackson, Ingrid E Scheffer, Melanie Bahlo, Jozef Gecz, Sarah E Heron, Mark Corbett, John C Mulley, Leanne M Dibbens, Amos D Korczyn, Samuel F Berkovic
OBJECTIVE: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. METHODS: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate...
February 23, 2016: Neurology
https://www.readbyqxmd.com/read/26785903/usefulness-of-ketogenic-diet-in-a-girl-with-migrating-partial-seizures-in-infancy
#15
Tatsuo Mori, Katsumi Imai, Taikan Oboshi, Yuh Fujiwara, Saoko Takeshita, Hirotomo Saitsu, Naomichi Matsumoto, Yukitoshi Takahashi, Yushi Inoue
Migrating partial seizures in infancy (MPSI) are an age-specific epilepsy syndrome characterized by migrating focal seizures, which are intractable to various antiepileptic drugs and cause severe developmental delay. We report a case of MPSI with heterozygous missense mutation in KCNT1, which was successfully managed by ketogenic diet. At age 2months, the patient developed epilepsy initially manifesting focal seizures with eye deviation and apnea, then evolving to secondarily generalized clonic convulsion. Various antiepileptic drugs including phenytoin, valproic acid, zonisamide, clobazam, levetiracetam, vitamin B6, and carbamazepine were not effective, but high-dose phenobarbital allowed discontinuation of midazolam infusion...
June 2016: Brain & Development
https://www.readbyqxmd.com/read/26784557/characterization-of-two-de-novokcnt1-mutations-in-children-with-malignant-migrating-partial-seizures-in-infancy
#16
Francesca Rizzo, Paolo Ambrosino, Anna Guacci, Massimiliano Chetta, Giovanna Marchese, Teresa Rocco, Maria Virginia Soldovieri, Laura Manocchio, Ilaria Mosca, Gianluca Casara, Marilena Vecchi, Maurizio Taglialatela, Giangennaro Coppola, Alessandro Weisz
The KCNT1 gene encodes for subunits contributing to the Na(+)-activated K(+) current (KNa), expressed in many cell types. Mutations in KCNT1 have been found in patients affected with a wide spectrum of early-onset epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI), a severe early-onset epileptic encephalopathy characterized by pharmacoresistant focal seizures migrating from one brain region or hemisphere to another and neurodevelopment arrest or regression, resulting in profound disability...
April 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/26740507/kcnt1-mutations-in-seizure-disorders-the-phenotypic-spectrum-and-functional-effects
#17
REVIEW
Chiao Xin Lim, Michael G Ricos, Leanne M Dibbens, Sarah E Heron
Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date...
April 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/26725113/epilepsy-related-slack-channel-mutants-lead-to-channel-over-activity-by-two-different-mechanisms
#18
Qiong-Yao Tang, Fei-Fei Zhang, Jie Xu, Ran Wang, Jian Chen, Diomedes E Logothetis, Zhe Zhang
Twelve sodium-activated potassium channel (KCNT1, Slack) genetic mutants have been identified from severe early-onset epilepsy patients. The changes in biophysical properties of these mutants and the underlying mechanisms causing disease remain elusive. Here, we report that seven of the 12 mutations increase, whereas one mutation decreases, the channel's sodium sensitivity. Two of the mutants exhibit channel over-activity only when the intracellular Na(+) ([Na(+)]i) concentration is ∼80 mM. In contrast, single-channel data reveal that all 12 mutants increase the maximal open probability (Po)...
January 5, 2016: Cell Reports
https://www.readbyqxmd.com/read/26648591/unexplained-early-onset-epileptic-encephalopathy-exome-screening-and-phenotype-expansion
#19
Nicholas M Allen, Judith Conroy, Amre Shahwan, Bryan Lynch, Raony G Correa, Sergio D J Pena, Dara McCreary, Tiago R Magalhães, Sean Ennis, Sally A Lynch, Mary D King
Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes as well as emerging diagnostic strategies. In this single-center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole-exome sequencing (WES), targeting a list of 137 epilepsy-associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible...
January 2016: Epilepsia
https://www.readbyqxmd.com/read/26597493/genetic-heterogeneity-in-26-infants-with-a-hypomyelinating-leukodystrophy
#20
Natsuko Arai-Ichinoi, Mitsugu Uematsu, Ryo Sato, Tasuku Suzuki, Hiroki Kudo, Atsuo Kikuchi, Naomi Hino-Fukuyo, Mitsuyo Matsumoto, Kazuhiko Igarashi, Kazuhiro Haginoya, Shigeo Kure
T2 hyperintensity of brain white matter lesions detected by magnetic resonance imaging (MRI) are characteristic of a heterogeneous group of diseases. Persistent T2 high intensity in combination with T1 iso- or high intensity of white matter in infants indicates a lack of normal myelination, that is, hypomyelination. However, the precise diagnosis of hypomyelinating leukodystrophy based solely on MRI findings can be difficult, especially in the early stage of the disease. We studied 26 patients who were diagnosed with hypomyelinating leukodystrophy according to MRI findings and clinical features to uncover their genetic etiology through chromosomal analyses, targeted gene analyses, and an array comparative genomic hybridization (aCGH) assay...
January 2016: Human Genetics
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