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1.
Nat Commun ; 11(1): 5168, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057011

RESUMO

The potassium ion (K+) channel plays a fundamental role in controlling K+ permeation across the cell membrane and regulating cellular excitabilities. Mutations in the transmembrane pore reportedly affect the gating transitions of K+ channels, and are associated with the onset of neural disorders. However, due to the lack of structural and dynamic insights into the functions of K+ channels, the structural mechanism by which these mutations cause K+ channel dysfunctions remains elusive. Here, we used nuclear magnetic resonance spectroscopy to investigate the structural mechanism underlying the decreased K+-permeation caused by disease-related mutations, using the prokaryotic K+ channel KcsA. We demonstrated that the conformational equilibrium in the transmembrane region is shifted toward the non-conductive state with the closed intracellular K+-gate in the disease-related mutant. We also demonstrated that this equilibrium shift is attributable to the additional steric contacts in the open-conductive structure, which are evoked by the increased side-chain bulkiness of the residues lining the transmembrane helix. Our results suggest that the alteration in the conformational equilibrium of the intracellular K+-gate is one of the fundamental mechanisms underlying the dysfunctions of K+ channels caused by disease-related mutations.


Assuntos
Proteínas de Bactérias/metabolismo , Ativação do Canal Iônico/genética , Canais de Potássio/metabolismo , Potássio/metabolismo , Alanina/genética , Ataxia/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Epilepsia/genética , Humanos , Síndrome do QT Longo/genética , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto , Canais de Potássio/genética , Canais de Potássio/isolamento & purificação , Conformação Proteica em alfa-Hélice/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Streptomyces lividans , Valina/genética
2.
Artigo em Russo | MEDLINE | ID: mdl-33081460

RESUMO

The authors present a detailed review of current advances in the field of genetics of epilepsy. Separately, new views on the etiology and pathogenesis of genetic epileptic encephalopathies, focal epilepsy and idiopathic generalized epilepsies are examined. The authors emphasize the importance of genetic discoveries for the clinical practice, including the prospects in the development of patients' personalized treatment. A comparative analysis of the value of various methods of genetic research in the diagnosis of epilepsy, methods of integrating molecular genetic analyses into everyday practical medicine is presented.


Assuntos
Epilepsias Parciais , Epilepsia Generalizada , Epilepsia , Epilepsia/genética , Humanos
3.
Adv Exp Med Biol ; 1298: 177-187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32852734

RESUMO

Protocadherin-19 (PCDH19) pathogenic variants cause an infantile onset epilepsy syndrome called Girls Clustering Epilepsy due to the vast majority of affected individuals being female. This syndromic name was developed to foster early recognition and diagnosis in infancy. It has, however, sparked debate, as, there are rare males with postzygotic somatic, and therefore, mosaic, PCDH19 pathogenic variants with similar clinical features to females. Conversely, "transmitting" males with germline inherited PCDH19 variants are considered asymptomatic. To date, there has been no standardized neuropsychiatric assessment of males with PCDH19 pathogenic variants. Here, we studied 15 males with PCDH19 pathogenic variants (nine mosaic and six transmitting) aged 2 to 70 years. Our families completed a survey including standardized clinical assessments: Social Responsiveness Scale, Strengths and Difficulties Questionnaire, Behavior Rating Inventory of Executive Function, and Dimensional Obsessive-Compulsive Scale. We identified neuropsychiatric abnormalities in two males with germline PCDH19 possibly pathogenic variants. One had a prior history of a severe encephalopathic illness, which may have been unrelated. We also describe a non-penetrant somatic mosaic male with mosaicism confirmed in blood, but not identified in skin fibroblasts. Our data suggest that transmitting hemizygous males are generally unaffected, in contrast to males with postzygotic somatic mosaic variants who show a similar neuropsychiatric profile to females who are naturally mosaic, due to X-chromosome inactivation. The penetrance of PCDH19 pathogenic variants has been estimated to be 80%. Like females, not all mosaic males are affected. From our small sample, we estimate that males with mosaic PCHD19 pathogenic variants have a penetrance of 85%. With these insights into the male phenotypic spectrum of PCDH19 epilepsy, we propose the new term Clustering Epilepsy (CE). Both affected females and males typically present with infantile onset of clusters of seizures.


Assuntos
Caderinas/genética , Epilepsia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Epilepsia/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Mutação , Penetrância , Adulto Jovem
4.
Adv Clin Exp Med ; 29(7): 793-801, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32745381

RESUMO

BACKGROUND: Epilepsy is a common chronic neurological disorder worldwide. OBJECTIVES: To investigate the effects of miR-21-5p and signal transducer and activator of transcription-3 (STAT3) expressions on the apoptosis of hippocampal neurons in epileptic rats. MATERIAL AND METHODS: We created a rat model of epilepsy and examined the relationship between miR-21-5p and STAT3 using a bioinformatics website and dual the luciferase reporter (DLR) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were used to detect the expression levels of miR-21-5p and STAT3 in hippocampal neurons as well as the protein expression levels of cleaved caspase-3, Bax and Bcl-2, which were related to apoptosis of hippocampal neuron. The apoptosis and survival of hippocampal neurons were detected using TUNEL and Nissl staining. Expressions of inflammatory factors interleukin (IL)-6 and tumor necrosis factor α (TNF-α) in serum were examined with enzyme-linked immunosorbent assay (ELISA). RESULTS: miR-21-5p can bind to STAT3. Compared with the miR-21-5p inhibitor negative control (NC) group, the expression levels of caspase-3 and Bax were higher and the expression level of Bcl-2 was lower in the miR-21-5p inhibitor group, whereas the caspase-3 and Bax levels were lower and Bcl-2 level was higher in the si-STAT3 (interfering STAT3 gene expression by transfecting small interfering RNA) group (all p < 0.05). Treatment with miR-21-5p inhibitor can lead to significant loss and apoptosis of hippocampal neurons, while interfering with STAT3 expression can reduce the loss and apoptosis of the neurons (all p < 0.05). Compared with the miR-21-5p inhibitor NC group, the level of IL-6 was lower in the si-STAT3 group and higher in the miR-21-5p inhibitor group (both p < 0.05). CONCLUSIONS: miR-21-5p can inhibit STAT3 expression and reduce apoptosis and loss of hippocampal neurons and IL-6 level, thereby achieving protective effects on hippocampal neurons of epileptic rats.


Assuntos
Epilepsia , Animais , Apoptose , Epilepsia/genética , Hipocampo , MicroRNAs , Neurônios , Ratos , Fator de Transcrição STAT3
5.
PLoS One ; 15(8): e0238121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845893

RESUMO

Variants implicated in childhood epilepsy have been identified in all four voltage-gated sodium channels that initiate action potentials in the central nervous system. Previous research has focused on the functional effects of particular variants within the most studied of these channels (NaV1.1, NaV1.2 and NaV1.6); however, there have been few comparative studies across channels to infer the impact of mutations in patients with epilepsy. Here we compare patterns of variation in patient and public databases to test the hypothesis that regions of known functional significance within voltage-gated sodium (NaV) channels have an increased burden of deleterious variants. We assessed mutational burden in different regions of the Nav channels by (1) performing Fisher exact tests on odds ratios to infer excess variants in domains, segments, and loops of each channel in patient databases versus public "control" databases, and (2) comparing the cumulative distribution of variant sites along DNA sequences of each gene in patient and public databases (i.e., independent of protein structure). Patient variant density was concordant among channels in regions known to play a role in channel function, with statistically significant higher patient variant density in S4-S6 and DIII-DIV and an excess of public variants in SI-S3, DI-DII, DII-DIII. On the other hand, channel-specific patterns of patient burden were found in the NaV1.6 inactivation gate and NaV1.1 S5-S6 linkers, while NaV1.2 and NaV1.6 S4-S5 linkers and S5 segments shared patient variant patterns that contrasted with those in NaV1.1. These different patterns may reflect different roles played by the NaV1.6 inactivation gate in action potential propagation, and by NaV1.1 S5-S6 linkers in loss of function and haploinsufficiency. Interestingly, NaV1.2 and NaV1.6 both lack amino acid substitutions over significantly long stretches in both the patient and public databases suggesting that new mutations in these regions may cause embryonic lethality or a non-epileptic disease phenotype.


Assuntos
Epilepsia/patologia , Ativação do Canal Iônico/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Substituição de Aminoácidos/genética , Sequência de Bases , Encéfalo/fisiologia , Epilepsia/genética , Variação Genética/genética , Humanos , Potenciais da Membrana/genética , Mutação/genética , Técnicas de Patch-Clamp , Análise de Sequência de DNA
6.
Am J Hum Genet ; 107(3): 564-574, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32822602

RESUMO

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.


Assuntos
Atrofia/genética , Doenças Cerebelares/genética , Deficiência Intelectual/genética , Lisina Acetiltransferase 5/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Atrofia/diagnóstico por imagem , Atrofia/fisiopatologia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/fisiopatologia , Pré-Escolar , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Histonas/genética , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto/genética , Processamento de Proteína Pós-Traducional/genética
8.
Clin Chem ; 66(1): 199-206, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609854

RESUMO

BACKGROUND: Exome sequencing has become a commonly used clinical diagnostic test. Multiple studies have examined the diagnostic utility and individual laboratory performance of exome testing; however, no previous study has surveyed and compared the data quality from multiple clinical laboratories. METHODS: We examined sequencing data from 36 clinical exome tests from 3 clinical laboratories. Exome data were compared in terms of overall characteristics and coverage of specific genes and nucleotide positions. The sets of genes examined included genes in Consensus Coding Sequence (CCDS) (n = 17723), a subset of genes clinically relevant to epilepsy (n = 108), and genes that are recommended for reporting of secondary findings (n = 57; excludes X-linked genes). RESULTS: The average exome nucleotide coverage (≥20×) of each laboratory varied at 96.49% (CV = 3%), 96.54% (CV = 1%), and 91.68% (CV = 4%), for laboratories A, B, and C, respectively. For CCDS genes, the average number of completely covered genes varied at 12184 (CV = 29%), 11687 (CV = 13%), and 5989 (CV = 37%), for laboratories A, B, and C, respectively. With smaller subsets of genes related to epilepsy and secondary findings, the CV revealed low consistency, with a maximum CV seen in laboratory C for both epilepsy genes (CV = 60%) and secondary findings genes (CV = 71%). CONCLUSIONS: Poor consistency in complete gene coverage was seen in the clinical exome laboratories surveyed. The degree of consistency varied widely between the laboratories.


Assuntos
Exoma/genética , Proteína BRCA1/genética , Epilepsia/genética , Epilepsia/patologia , Éxons , Guias como Assunto , Humanos , Laboratórios Hospitalares/normas , Proteína 1 Homóloga a MutL/genética , Sequenciamento Completo do Exoma
9.
Cell Prolif ; 53(8): e12856, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32648622

RESUMO

OBJECTIVES: Glial cell activation contributes to the inflammatory response and occurrence of epilepsy. Our preliminary study demonstrated that the long non-coding RNA, H19, promotes hippocampal glial cell activation during epileptogenesis. However, the precise mechanisms underlying this effect remain unclear. MATERIALS AND METHODS: H19 and let-7b were overexpressed or silenced using an adeno-associated viral vector in vivo. Their expression in a kainic acid-induced epilepsy model was evaluated by real-time quantitative PCR, fluorescence in situ hybridization, and cytoplasmic and nuclear RNA isolation. A dual-luciferase reporter assay was used to evaluate the direct binding of let-7b to its target genes and H19. Western blot, video camera monitoring and Morris water maze were performed to confirm the role of H19 and let7b on epileptogenesis. RESULTS: H19 was increased in rat hippocampus neurons after status epilepticus, which might be due to epileptic seizure-induced hypoxia. Increased H19 aggravated the epileptic seizures, memory impairment and mossy fibre sprouting of the epileptic rats. H19 could competitively bind to let-7b to suppress its expression. Overexpression of let-7b inhibited hippocampal glial cell activation, inflammatory response and epileptic seizures by targeting Stat3. Moreover, overexpressed H19 reversed the inhibitory effect of let-7b on glial cell activation. CONCLUSIONS: LncRNA H19 could competitively bind to let-7b to promote hippocampal glial cell activation and epileptic seizures by targeting Stat3 in a rat model of temporal lobe epilepsy.


Assuntos
Epilepsia do Lobo Temporal/genética , Hipocampo/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/metabolismo , Animais , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Genes Supressores de Tumor/fisiologia , Masculino , Ratos Sprague-Dawley , Convulsões/genética , Convulsões/metabolismo
10.
Gene ; 753: 144815, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32479982

RESUMO

Lymphedema are characterized by interstitial edema leading to swelling of extremities. They can be divided into primary and secondary lymphedema. Developmental abnormalities of the lymphatic system are responsible for the primary form of lymphedema. The secondary form of lymphedema is caused by damage of the lymphatic system due to external factors. Lymphedema can rarely be observed in patients with tuberous sclerosis complex (TSC), which is a neurocutaneous syndrome caused by pathogenic variants in the genes TSC1 or TSC2. Patients with TSC usually present with neurological manifestations and the development of multiple benign tumors of ectodermal origin. Typical onset for several symptoms is during the first year of life and in some cases lesions can be detected prenatally. Epilepsy is one of the most common manifestations, affecting up to 90% of TSC patients, and is associated with developmental delay. Early pharmacotherapy improves long term patient outcome. Trio exome sequencing was performed in a 3 weeks old girl with congenital lymphedema of the right lower extremity. Using a filter for de novo variants, the heterozygous missense variant c.2524C>T, p.(Gln842Ter) in TSC1 (NM_000368.4) could be identified. After the first onset of infantile spams at age 7 months treatment with vigabatrin was started immediately. We propose to include TSC1 and TSC2 analysis in the diagnostic work-up of patients with (isolated) congenital lymphedema as early diagnosis facilitates consequent treatment strategies potentially improving the prognosis of TSC patients.


Assuntos
Linfedema/genética , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Deficiências do Desenvolvimento/complicações , Epilepsia/genética , Feminino , Humanos , Lactente , Linfedema/complicações , Linfedema/patologia , Mutação de Sentido Incorreto/genética , Prognóstico , Esclerose Tuberosa/complicações , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Sequenciamento Completo do Exoma
11.
Gene ; 754: 144847, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32531456

RESUMO

BACKGROUND: A 30-year-old man presented with intellectual disability associated with epilepsy. The epilepsy was initially treated with sodium valproate and since he was 28 years-old with lamotrigine. With the addition of lamotrigine, a pattern of Brugada syndrome appeared on the electrocardiogram. The family history was positive for epilepsy from the mothers side, who had never been treated with lamotrigine. OBJECTIVE: Determine the genetic cause of the intellectual disability, epilepsy and Brugada syndrome of the patient and try to establish a possible correlation between the genetic background and the Brugada syndrome pattern under lamotrigine treatment. METHODS: A standard karyotype, array comparative genomic hybridization and two different NGS panels have done to the index case to identify the genetic causes of the intellectual disability, epilepsy and Brugada syndrome pattern. RESULTS: Genetic analyses in the family identified a de novo duplication of 1.3 Mb in 8p21.3 as well as two novel heterozygous rare variants in SCN9A and AKAP9 genes, both inherited from the mother. CONCLUSION: We hypothesize that in this family the SCN9A variant was responsible for the epileptic syndrome. In addition, given that SCN9A is lightly expressed in the heart tissue, we postulate that this SCN9A variant, alone or in combination with AKAP9 variant, might be responsible for the Brugada pattern when challenged by lamotrigine.


Assuntos
Anticonvulsivantes/efeitos adversos , Síndrome de Brugada/patologia , Epilepsia/tratamento farmacológico , Duplicação Gênica , Lamotrigina/efeitos adversos , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Adulto , Síndrome de Brugada/induzido quimicamente , Síndrome de Brugada/genética , Epilepsia/genética , Epilepsia/patologia , Humanos , Masculino
12.
Medicine (Baltimore) ; 99(22): e20507, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481472

RESUMO

RATIONALE: Asparagine synthetase deficiency (ASNSD) refers to a congenital metabolic abnormality caused by mutation in the asparagine synthetase (ASNS) gene encoded by chromosome 7q21. Herein, we report the first case of ASNSD in China, in which novel ASNS mutations were identified. PATIENT CONCERNS: A 6-month-old boy presented with a 4-month history of microcephaly and psychomotor developmental retardation and a 2-month history of epilepsy. Four months after birth, magnetic resonance imaging demonstrated a giant cyst in the right lateral ventricle, and a ventriculoperitoneal shunt was placed. Video electroencephalography showed a hypsarrhythmia pattern with a string of tonic-clonic and myoclonic seizures. On admission, physical examination showed microcephaly. Neurologic examination showed a decreased tension in the trunk muscles and an increased tension in the extremity muscles; tendon hyperreflexia was noted, and bilateral pathologic reflexes were positive. DIAGNOSIS: A diagnosed of congenital microcephaly was made. Whole-exome sequencing revealed a heterozygous deletion mutation c.666_667delCT (p.L2221Lfs*5) in exon 6 of the ASNS gene and a heterozygous missense mutation c.1424C>T (p.T457I) in exon 13 of the ASNS gene. INTERVENTIONS: After admission, intravenous adrenocorticotropic hormone and oral topiramate was administrated for 4 weeks, while the seizures persisted. Then, levetiracetam and clonazepam were added. OUTCOMES: After the follow-up period of 18 months, video electroencephalography showed that complex episodes disappeared with changes in multiple focal spike and sharp waves; 1 focal attack arising from the left occipital region and 2 focal attacks arising from the right middle temporal and the right occipital region were recorded. LESSONS: This is the first case of ASNSD in China. We identified 2 novel mutations (c.666_667delCT and c.1424C>T) in the ASNS gene, which expands the ASNS gene mutation profile and will be beneficial for genetic diagnosis.


Assuntos
Aspartato-Amônia Ligase/genética , Epilepsia/genética , Microcefalia/genética , Anticonvulsivantes/uso terapêutico , Aspartato-Amônia Ligase/deficiência , China , Clonazepam/uso terapêutico , Eletroencefalografia , Epilepsia/tratamento farmacológico , Humanos , Lactente , Levetiracetam/uso terapêutico , Masculino , Mutação de Sentido Incorreto
13.
Zhonghua Er Ke Za Zhi ; 58(6): 493-498, 2020 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-32521962

RESUMO

Objective: To investigate the clinical and genetic characteristics of developmental and epileptic encephalopathy (DEE) caused by syntaxin-binding protein 1 (STXBP1) gene mutation. Methods: The clinical data, gene variation and treatment outcome of 15 children with STXBP1 encephalopathy admitted to Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2014 to June 2019 were analyzed retrospectively. Results: Among 15 patients, 11 were male and 4 were female, age ranged from 2 months to 69 months. The clinical manifestations of 14 children were epilepsy and developmental delay (DD) and the remaining one showed developmental delay without seizure. The onset age of epilepsy ranged from two days to 19 months and 11 of them experienced the first attack before 1 year of age. The common seizure types were epileptic spasms and tonic seizures. Seven patients were diagnosed with Ohtahara syndrome or West syndrome. Epileptic form discharges were observed in the interictal electroencephalograms (EEG) of 11 patients, including multifocal discharges, suppression-burst and hypsarrhythmia. The brain magnetic resonance imaging of 7 children were abnormal, including myelin dysplasia, less white matter, lack of corpus callosum or hypoplasia. The follow-up time ranged from 2 months to 57 months, after the last follow-up, 3 cases were seizure free, 6 children showed partial response and the other 5 patients had no response on multitherapy. Six of 8 patients showed good responses to levetiracetam (LEV) monotherapy or in combination with other antiepileptic drugs (AEDs). Vigabatrin (VGB) was applied to 5 patients with epileptic spasms and 4 of them showed response. All patients showed different degrees of developmental delay while four of them showed autistic features. STXBP1 gene mutations were identified in all cases and there were 15 types of gene variations, including 8 missense mutations, 1 nonsense mutation, 5 frame shift mutations and 1 complex mutation. Five novel mutations were unreported before, including c.1193A>G, c.172delG, c.1769C>T, c.1038_1039delCC, c.348_351dupTGAA. Conclusions: Development delay and epilepsy are the major and independent clinical phenotypes in children with STXBP1 encephalopathy. The variation of STXBP1 gene is mainly de novo. Levetiracetam and vigabatrin may be more effective in epilepsy control than other AEDs.


Assuntos
Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Eletroencefalografia , Epilepsia/genética , Proteínas Munc18/genética , Espasmos Infantis/genética , Encefalopatias/diagnóstico , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Epilepsia/etiologia , Feminino , Humanos , Lactente , Masculino , Mutação , Mutação Puntual , Estudos Retrospectivos , Espasmos Infantis/etiologia
15.
Pharmacol Rev ; 72(3): 606-638, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32540959

RESUMO

Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs ("precision medicine") for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Resistência a Medicamentos , Epilepsia/genética , Epilepsia/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Nat Commun ; 11(1): 2510, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427860

RESUMO

In mammals, a subset of arginine tRNA isoacceptors are methylated in the anticodon loop by the METTL2 methyltransferase to form the 3-methylcytosine (m3C) modification. However, the mechanism by which METTL2 identifies specific tRNA arginine species for m3C formation as well as the biological role of m3C in mammals is unknown. Here, we show that human METTL2 forms a complex with DALR anticodon binding domain containing 3 (DALRD3) protein to recognize particular arginine tRNAs destined for m3C modification. DALRD3-deficient human cells exhibit nearly complete loss of the m3C modification in tRNA-Arg species. Notably, we identify a homozygous nonsense mutation in the DALRD3 gene that impairs m3C formation in human patients exhibiting developmental delay and early-onset epileptic encephalopathy. These findings uncover an unexpected function for the DALRD3 protein in the targeting of distinct arginine tRNAs for m3C modification and suggest a crucial biological role for DALRD3-dependent tRNA modification in proper neurological development.


Assuntos
Citosina/análogos & derivados , Epilepsia/metabolismo , RNA de Transferência de Arginina/metabolismo , tRNA Metiltransferases/metabolismo , Idade de Início , Linhagem Celular , Citosina/metabolismo , Epilepsia/genética , Humanos , Conformação de Ácido Nucleico , Ligação Proteica , RNA de Transferência de Arginina/química , RNA de Transferência de Arginina/genética , tRNA Metiltransferases/genética
17.
Neurobiol Aging ; 92: 153.e1-153.e5, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32409253

RESUMO

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins.


Assuntos
Esclerose Amiotrófica Lateral/genética , Epilepsia/genética , Variação Genética , Estudo de Associação Genômica Ampla , Resultados Negativos , Frequência do Gene , Humanos , Risco
18.
BMC Med Genet ; 21(1): 96, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381069

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
19.
Am J Hum Genet ; 106(5): 659-678, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386536

RESUMO

Access to large-scale genomics datasets has increased the utility of hypothesis-free genome-wide analyses. However, gene signals are often insufficiently powered to reach experiment-wide significance, triggering a process of laborious triaging of genomic-association-study results. We introduce mantis-ml, a multi-dimensional, multi-step machine-learning framework that allows objective assessment of the biological relevance of genes to disease studies. Mantis-ml is an automated machine-learning framework that follows a multi-model approach of stochastic semi-supervised learning to rank disease-associated genes through iterative learning sessions on random balanced datasets across the protein-coding exome. When applied to a range of human diseases, including chronic kidney disease (CKD), epilepsy, and amyotrophic lateral sclerosis (ALS), mantis-ml achieved an average area under curve (AUC) prediction performance of 0.81-0.89. Critically, to prove its value as a tool that can be used to interpret exome-wide association studies, we overlapped mantis-ml predictions with data from published cohort-level association studies. We found a statistically significant enrichment of high mantis-ml predictions among the highest-ranked genes from hypothesis-free cohort-level statistics, indicating a substantial improvement over the performance of current state-of-the-art methods and pointing to the capture of true prioritization signals for disease-associated genes. Finally, we introduce a generic mantis-ml score (GMS) trained with over 1,200 features as a generic-disease-likelihood estimator, outperforming published gene-level scores. In addition to our tool, we provide a gene prioritization atlas that includes mantis-ml's predictions across ten disease areas and empowers researchers to interactively navigate through the gene-triaging framework. Mantis-ml is an intuitive tool that supports the objective triaging of large-scale genomic discovery studies and enhances our understanding of complex genotype-phenotype associations.


Assuntos
Esclerose Amiotrófica Lateral/genética , Epilepsia/genética , Genômica/métodos , Insuficiência Renal Crônica/genética , Aprendizado de Máquina Supervisionado , Animais , Área Sob a Curva , Aprendizado Profundo , Modelos Animais de Doenças , Exoma/genética , Estudos de Associação Genética , Humanos , Camundongos , Redes Neurais de Computação , Curva ROC , Reprodutibilidade dos Testes , Processos Estocásticos
20.
Dev Med Child Neurol ; 62(7): 784-792, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32227486

RESUMO

Genetic variants in brain-expressed voltage-gated sodium channels (SCNs) have emerged as one of the most frequent causes of Mendelian forms of epilepsy and neurodevelopmental disorders (NDDs). This review explores the biological concepts that underlie sodium channel NDDs, explains their phenotypic heterogeneity, and appraises how this knowledge may inform clinical practice. We observe that excitatory/inhibitory neuronal expression ratios of sodium channels are important regulatory mechanisms underlying brain development, homeostasis, and neurological diseases. We hypothesize that a detailed understanding of gene expression, variant tolerance, location, and function, as well as timing of seizure onset can aid the understanding of how variants in SCN1A, SCN2A, SCN3A, and SCN8A contribute to seizure aetiology and inform treatment choice. We propose a model in which variant type, development-specific gene expression, and functions of SCNs explain the heterogeneity of sodium channel associated NDDs. Understanding of basic disease mechanisms and detailed knowledge of variant characteristics have increasing influence on clinical decision making, enabling us to stratify treatment and move closer towards precision medicine in sodium channel epilepsy and NDDs. WHAT THIS PAPER ADDS: Sodium-channel disorder heterogeneity is explained by variant-specific gene expression timing and function. Gene tolerance and location analyses aid sodium channel variant interpretation. Sodium-channel variant characteristics can contribute to clinical decision making.


Assuntos
Fenômenos Eletrofisiológicos/fisiologia , Epilepsia/fisiopatologia , Expressão Gênica/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.1/fisiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenômenos Eletrofisiológicos/genética , Epilepsia/genética , Expressão Gênica/genética , Humanos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Transtornos do Neurodesenvolvimento/genética
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