RESUMO
OBJECTIVE: KCNQ2 gene mutation usually manifests as neonatal seizures in the first week of life. Nonsense mutations cause a unique self-limited familial neonatal epilepsy (SLFNE), which is radically different from developmental epileptic encephalopathy (DEE). However, the exact underlying mechanisms remain unclear. METHODS: The proband, along with their mother and grandmother, carried the c.1342C > T (p.Arg448Ter) mutation in the KCNQ2 gene. The clinical phenotypes, electroencephalography (EEG) findings, and neurodevelopmental outcomes were comprehensively surveyed. The mutant variants were transfected into HEK293 cells to investigate functional changes. RESULTS: The proband exhibited behavior arrests, autonomic and non-motor neonatal seizures with changes in heart rate and respiration. EEG exhibited focal sharp waves. Seizures were remitted after three months of age. The neurodevelopmental outcomes at three years of age were unremarkable. A functional study demonstrated that the currents of p.Arg448Ter were non-functional in homomeric p.Arg448Ter compared with that of the KCNQ2 wild type. However, the current density and V1/2 exhibited significant improvement and close to that of the wild-type after transfection with heteromeric KCNQ2 + p.Arg448Ter and KCNQ2 + KCNQ3 + p.Arg448Ter respectively. Channel expression on the cell membrane was not visible after homomeric transfection, but not after heteromeric transfection. Retigabine did not affect homomeric p.Arg448Ter but improved heteromeric p. Arg448Ter + KCNQ2 and heteromeric KCNQ2 + Arg448Ter + KCNQ3. CONCLUSIONS: The newborn carrying the p. Arg448Ter mutation presented frequent behavioral arrests, autonomic, and non-motor neonatal seizures. This unique pattern differs from KCNQ2 seizures, which typically manifest as motor seizures. Although p.Arg448Ter is a non-sense decay, the functional study demonstrated an almost-full compensation mechanism after transfection of heteromeric KCNQ2 and KCNQ3.
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Eletroencefalografia , Canal de Potássio KCNQ2 , Mutação , Humanos , Canal de Potássio KCNQ2/genética , Células HEK293 , Feminino , Masculino , Convulsões/genética , Convulsões/fisiopatologia , Recém-Nascido , Fenilenodiaminas/farmacologia , Carbamatos/farmacologia , Epilepsia Neonatal Benigna/genética , Epilepsia Neonatal Benigna/fisiopatologia , LactenteRESUMO
Despite the increasing availability of genomic data and enhanced data analysis procedures, predicting the severity of associated diseases remains elusive in the absence of clinical descriptors. To address this challenge, we have focused on the KV7.2 voltage-gated potassium channel gene (KCNQ2), known for its link to developmental delays and various epilepsies, including self-limited benign familial neonatal epilepsy and epileptic encephalopathy. Genome-wide tools often exhibit a tendency to overestimate deleterious mutations, frequently overlooking tolerated variants, and lack the capacity to discriminate variant severity. This study introduces a novel approach by evaluating multiple machine learning (ML) protocols and descriptors. The combination of genomic information with a novel Variant Frequency Index (VFI) builds a robust foundation for constructing reliable gene-specific ML models. The ensemble model, MLe-KCNQ2, formed through logistic regression, support vector machine, random forest and gradient boosting algorithms, achieves specificity and sensitivity values surpassing 0.95 (AUC-ROC > 0.98). The ensemble MLe-KCNQ2 model also categorizes pathogenic mutations as benign or severe, with an area under the receiver operating characteristic curve (AUC-ROC) above 0.67. This study not only presents a transferable methodology for accurately classifying KCNQ2 missense variants, but also provides valuable insights for clinical counseling and aids in the determination of variant severity. The research context emphasizes the necessity of precise variant classification, especially for genes like KCNQ2, contributing to the broader understanding of gene-specific challenges in the field of genomic research. The MLe-KCNQ2 model stands as a promising tool for enhancing clinical decision making and prognosis in the realm of KCNQ2-related pathologies.
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Epilepsia Neonatal Benigna , Epilepsia Generalizada , Recém-Nascido , Humanos , Inteligência Artificial , Mutação de Sentido Incorreto , Mutação , Epilepsia Neonatal Benigna/genética , Canal de Potássio KCNQ2/genéticaRESUMO
OBJECTIVES: To determine: i) seizure recurrence; ii) developmental disability; iii) co-morbidities and risk factors in self-limited familial neonatal and/or infantile epilepsy (SeLFE) in a multigenerational study. METHODS: Families were retrospectively recruited from epilepsy databases (2021-2022) in 2 paediatric hospitals, Sydney, Australia. Eligible families had 2 first degree relatives with seizures and underwent genetic testing. Demographics/clinical data were collected from interviews and medical records. Vineland Adaptive Behaviour Scales-Third Edition measured adaptive function. RESULTS: Fifteen families participated. Fourteen had a genetic diagnosis (93%): 11 pathogenic; PRRT2 (n=4), KCNQ2 (n=3), SCN2A (n=4), 3 likely pathogenic; KCNQ2 (n=1), SCN8A (n=2). Seizures affected 73 individuals (ages 1-76 years); 30 children and 20 adults had in-depth phenotyping. Ten of 50 individuals (20%) had seizure recurrence, aged 8-65 years. Median time from last neonatal/infantile seizure was 11.8/12.8 years. Predictors of recurrence were high seizure number (p=0.05) and longer treatment duration (p=0.03). Seven children had global developmental delay (GDD): mild (n=4), moderate (n=1) and severe (n=2). Vineland-3 identified 3 had low-average and 3 had mild-moderately impaired functioning. The majority (82%) were average. GDD was associated with older age at last seizure (p=0.03), longer epilepsy duration (p=0.02), and higher number of anti-seizure medications (p=0.05). Four children had speech delay, 5 (10%) had Autism Spectrum Disorder. Paroxysmal kinesiogenic dyskinesia (n=5) occurred in 4 families and hemiplegic migraine (n=8) in 3 families. CONCLUSIONS: Individuals with SeLFE have a small risk of recurrent seizures (20%) and neurodevelopmental disability. Significant predictors are higher seizure number and longer epilepsy duration. Developmental surveillance is imperative.
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Transtorno do Espectro Autista , Epilepsia Neonatal Benigna , Epilepsia , Síndromes Epilépticas , Criança , Recém-Nascido , Adulto , Humanos , Epilepsia Neonatal Benigna/genética , Estudos Retrospectivos , Mutação , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Austrália/epidemiologia , Epilepsia/epidemiologia , Epilepsia/genética , Convulsões/epidemiologia , Convulsões/genéticaRESUMO
Introducción Las convulsiones neonatales son un reto diagnóstico, dada la inmadurez del recién nacido. La mayoría son secundarias a un evento agudo. Un pequeño porcentaje constituye el inicio de una epilepsia. Objetivos Analizar a los neonatos ingresados en un hospital de tercer nivel con diagnóstico de crisis entre noviembre de 2009 y mayo de 2021, y su evolución posterior a epilepsia. Material y métodos. Se ha realizado un estudio observacional retrospectivo utilizando la base de datos del hospital. Se ha recogido la información de los neonatos con diagnóstico en el alta de convulsiones o encefalopatía hipóxico-isquémica moderada o grave. Se analizaron distintas variables: etiología de las crisis, tipo, persistencia temporal, tratamiento y correlato electroclínico. Resultados De 165 pacientes, 55 presentaron crisis neonatales. En cuanto a la etiología, 43 pacientes (78%) tuvieron crisis secundarias a un evento agudo, de las cuales 19 (34%) fueron encefalopatías hipóxico-isquémicas, y 22 (40%), otras alteraciones agudas. En seis (11%) se encontró alteración genética. Trece pacientes (24%) evolucionaron a una epilepsia posterior, de los cuales siete presentaron una epilepsia sintomática, con un período de latencia tras el evento agudo en dos pacientes. Seis pacientes tuvieron epilepsia neonatal con crisis no provocadas. Veintidós (62%) mostraron correlato electroclínico. El 100% de las crisis confirmadas fueron focales. Todas las crisis se trataron. El fármaco de elección fue el fenobarbital. Conclusiones El diagnóstico de convulsiones neonatales requiere una alta sospecha clínica y una confirmación electroclínica. La mayoría tiene evolución favorable, pero un porcentaje constituye el inicio de una epilepsia, cuya identificación determinará su manejo terapéutico. (AU)
INTRODUCTION Given the immaturity of the newborn, neonatal seizures are a diagnostic challenge. Most of them are secondary to an acute event. A small percentage constitute the onset of epilepsy. AIMS. The aim was to analyse neonates with a diagnosis of seizures admitted to a tertiary hospital between November 2009 and May 2021, and their subsequent progression to epilepsy. Material and methods. A retrospective observational study was carried out using the hospital database. Information was collected on neonates with a discharge diagnosis of seizures or moderate or severe hypoxic-ischaemic encephalopathy. Different variables were analysed: aetiology of the seizures, type, persistence over time, treatment and electroclinical correlates. RESULTS Of 165 patients, 55 presented neonatal seizures. As regards aetiology, 43 patients (78%) had seizures secondary to an acute event, of which 19 (34%) were hypoxic-ischaemic encephalopathies, and 22 (40%) had other acute disorders. Genetic alteration was found in six of them (11%). Thirteen patients (24%) progressed to subsequent epilepsy, of whom seven had symptomatic epilepsy, with a period of latency after the acute event in two patients. Six patients had neonatal epilepsy with unprovoked seizures. Twenty-two (62%) showed electroclinical correlates. All of the confirmed crises (100%) were focal. All the seizures were treated. The drug of choice was phenobarbital. CONCLUSIONS Diagnosis of neonatal seizures requires high clinical suspicion and electroclinical confirmation. Most of them progress favourably, but a percentage constitute the onset of epilepsy, the identification of which will determine their therapeutic management. (AU)
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Humanos , Recém-Nascido , Epilepsia Neonatal Benigna/diagnóstico , Epilepsia/diagnóstico , Estudos Retrospectivos , Epilepsia/tratamento farmacológico , Epilepsia/terapia , FenobarbitalRESUMO
OBJECTIVE: Pathogenic PRRT2 variants cause self-limited (familial) infantile epilepsy (SeLIE), which is responsive to sodium channel blocking antiseizure medications. The interictal EEG is typically normal. We describe a cohort of infants with PRRT2-related SeLIE with striking peri-ictal EEG abnormalities. METHODS: We included all infants diagnosed with PRRT2-related SeLIE during July 2020 to November 2021 at the Royal Children's Hospital, Melbourne. Clinical features and results of aetiologic investigations were collected from electronic medical records. All EEGs were reviewed independently by two epileptologists. RESULTS: Ten infants presented with focal seizures at a median age of 5 months (range: 3-6 months). Eight had a family history of epilepsy, paroxysmal kinesigenic dyskinesia (PKD) or hemiplegic migraine. Seven of the eight infants with an EEG performed within 24 h of the most recent seizure had epileptiform discharges. Their EEGs showed focal sharp waves, spikes, polyspikes or fast activity independently over the left and right temporo-occipital regions. Conversely, the two infants with last known seizure greater than 24 h prior to their EEG had no epileptiform discharges. Oxcarbazepine was commenced in two infants and was effective. Eight infants were initially treated with levetiracetam, and all were subsequently switched to oxcarbazepine due to ongoing seizures or side effects. SIGNIFICANCE: Posterior polymorphic focal epileptiform discharges on a peri-ictal EEG recording are a feature of PRRT2-related SeLIE. This finding, particularly in the presence of a family history of infantile epilepsy, PKD or hemiplegic migraine, suggests a diagnosis of PRRT2-related SeLIE and has important treatment implications.
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Epilepsia Neonatal Benigna , Epilepsia , Transtornos de Enxaqueca , Criança , Humanos , Lactente , Epilepsia Neonatal Benigna/diagnóstico , Epilepsia Neonatal Benigna/genética , Oxcarbazepina , Hemiplegia , Mutação , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Linhagem , Convulsões/tratamento farmacológico , EletroencefalografiaRESUMO
PURPOSE: Heterozygous variants in PRRT2 are mostly associated with benign phenotypes, being the major genetic cause of benign familial infantile seizures (BFIS), as well as in paroxysmal disorders. We report two children from unrelated families with BFIS that evolved to encephalopathy related to status epilepticus during sleep (ESES). METHODS AND RESULTS: Two probands presented with focal motor seizures at 3 months of age, with a limited course. Both children presented, at around 5 years of age, with centro-temporal interictal epileptiform discharges with a source in the frontal operculum, markedly activated by sleep, and associated with stagnation on neuropsychological development. Whole-exome sequencing and co-segregation analysis revealed a frameshift mutation c.649dupC in the proline-rich transmembrane protein 2 (PRRT2) in both probands and all affected family members. CONCLUSION: The mechanism leading to epilepsy and the phenotypic variability of PRRT2 variants remain poorly understood. However, its wide cortical and subcortical expression, in particular in the thalamus, could partially explain both the focal EEG pattern and the evolution to ESES. No variants in the PRRT2 gene have been previously reported in patients with ESES. Due to the rarity of this phenotype, other possible causative cofactors are likely contributing to the more severe course of BFIS in our probands.
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Epilepsia Neonatal Benigna , Estado Epiléptico , Humanos , Epilepsia Neonatal Benigna/complicações , Epilepsia Neonatal Benigna/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Convulsões/genética , Convulsões/complicações , Estado Epiléptico/genéticaRESUMO
The self-limited (familial) epilepsies with onset in neonates or infants, formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders characterized by neonatal- or infantile-onset focal motor seizures and the absence of neurodevelopmental complications. Seizures tend to remit during infancy or early childhood and are therefore called "self-limited". A positive family history for epilepsy usually suggests the genetic etiology, but incomplete penetrance and de novo inheritance occur. Here, we review the phenotypic spectrum and the genetic architecture of self-limited (familial) epilepsies with onset in neonates or infants. Using an illustrative case study, we describe important clues in recognition of these syndromes, diagnostic steps including genetic testing, management, and genetic counseling.
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Epilepsia Neonatal Benigna , Epilepsia , Síndromes Epilépticas , Recém-Nascido , Lactente , Humanos , Pré-Escolar , Alfabetização , Epilepsia/diagnóstico , Epilepsia/genética , Convulsões/genética , Testes Genéticos , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Epilepsia Neonatal Benigna/genética , MutaçãoRESUMO
BACKGROUND: Autosomal dominant mutations of the KCNQ2 gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE). This systematic review aims to identify the best reported therapy for these patients, relating to phenotype, neurodevelopmental outcome, and an eventual correlation between phenotype and genotype. METHODS: We searched on PubMed using the search terms "KCNQ2" AND "therapy" and "KCNQ2" AND "treatment"; we found 304 articles. Of these, 29 met our criteria. We collected the data from 194 patients. All 29 articles were retrospective studies. RESULTS: In all, 104 patients were classified as DEE and 90 as BFNS. After treatment began, 95% of BFNS patients became seizure free, whereas the seizures stopped only in 73% of those with DEE. Phenobarbital and sodium channel blockers were the most used treatment in BFNS. Most of the DEE patients (95%) needed polytherapy for seizure control and even that did not prevent subsequent developmental impairment (77%).Missense mutations were discovered in 96% of DEE patients; these were less common in BFNS (50%), followed by large deletion (16%), truncation (16%), splice donor site (10%), and frameshift (7%). CONCLUSION: Phenobarbital or carbamazepine appears to be the most effective antiseizure medication for children with a "benign" variant. On the contrary, polytherapy is often needed for DEE patients, even if it does not seem to improve neurological outcomes. In DEE patients, most mutations were located in S4 and S6 helix, which could serve as a potential target for the development of more specific treatment in the future.
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Epilepsia Neonatal Benigna , Canal de Potássio KCNQ2 , Criança , Recém-Nascido , Humanos , Estudos Retrospectivos , Canal de Potássio KCNQ2/genética , Epilepsia Neonatal Benigna/genética , Mutação , Convulsões , Fenótipo , Genótipo , FenobarbitalRESUMO
OBJECTIVE: Self-limited infantile epilepsy (SeLIE) has distinctive clinical features, and the PRRT2 gene is known to be a considerable genetic cause. There have been a few studies on PRRT2-positive SeLIE only, and anti-seizure medications are often required due to frequent seizures at initial seizure onset. This study aimed to provide clinical information for the early recognition of patients with PRRT2-positive SeLIE and to propose effective anti-seizure medications for seizure control. METHODS: We retrospectively reviewed 36 patients diagnosed with SeLIE with genetically confirmed pathogenic variants of PRRT2. In addition, six atypical cases with neonatal-onset seizures and unremitting after 3 years of age were included to understand the expanded clinical spectrum of PRRT2-related epilepsy. We analyzed the initial presentation, clinical course, and seizure control response to anti-seizure medications. RESULTS: Patients with PRRT2-related epilepsy had characteristic seizure semiology at the initial presentation, including all afebrile, clustered (n = 23, 63.9%), short-duration (n = 33, 91.7%), and bilateral tonic-clonic seizures (n = 26, 72.2%). Genetic analysis revealed that c. 649dupC was the most common variant, and six patients had a 16p11.2 microdeletion containing the PRRT2 gene. One-third of the patients were sporadic cases without a family history of epilepsy or paroxysmal movement disorders. In the 33 patients treated with anti-seizure medications, sodium channel blockers, such as carbamazepine, were the most effective in seizure control. SIGNIFICANCE: Our results delineated the clinical characteristics of PRRT2-positive SeLIE, differentiating it from other genetic infantile epilepsies and discovered the effective anti-seizure medications for initial clustered seizure control. If afebrile bilateral tonic-clonic seizures develop in a normally developed infant as a clustered pattern, PRRT2-positive SeLIE should be considered as a possible diagnosis, and sodium channel blockers should be administered as the first medication for seizure control.
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Epilepsia Neonatal Benigna , Epilepsia , Lactente , Recém-Nascido , Humanos , Epilepsia Neonatal Benigna/tratamento farmacológico , Epilepsia Neonatal Benigna/genética , Epilepsia Neonatal Benigna/diagnóstico , Mutação , Estudos Retrospectivos , Bloqueadores dos Canais de Sódio , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Convulsões/tratamento farmacológico , Convulsões/genéticaRESUMO
A number of mutations to members of several CNS potassium (K) channel families have been identified which result in rare forms of neonatal onset epilepsy, or syndromes of which one prominent characteristic is a form of epilepsy. Benign Familial Neonatal Convulsions or Seizures (BFNC or BFNS), also referred to as Self-Limited Familial Neonatal Epilepsy (SeLNE), results from mutations in 2 members of the KV7 family (KCNQ) of K channels; while generally self-resolving by about 15 weeks of age, these mutations significantly increase the probability of generalized seizure disorders in the adult, in some cases they result in more severe developmental syndromes. Epilepsy of Infancy with Migrating Focal Seizures (EIMSF), or Migrating Partial Seizures of Infancy (MMPSI), is a rare severe form of epilepsy linked primarily to gain of function mutations in a member of the sodium-dependent K channel family, KCNT1 or SLACK. Finally, KCNMA1 channelopathies, including Liang-Wang syndrome (LIWAS), are rare combinations of neurological symptoms including seizure, movement abnormalities, delayed development and intellectual disabilities, with Liang-Wang syndrome an extremely serious polymalformative syndrome with a number of neurological sequelae including epilepsy. These are caused by mutations in the pore-forming subunit of the large-conductance calcium-activated K channel (BK channel) KCNMA1. The identification of these rare but significant channelopathies has resulted in a resurgence of interest in their treatment by direct pharmacological or genetic modulation. We will briefly review the genetics, biophysics and pharmacology of these K channels, their linkage with the 3 syndromes described above, and efforts to more effectively target these syndromes.
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Canalopatias , Epilepsia Neonatal Benigna , Epilepsia , Recém-Nascido , Adulto , Humanos , Canalopatias/genética , Canalopatias/terapia , Síndrome , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia Neonatal Benigna/genética , Mutação , Canais de Cálcio/genética , Canais de Potássio Ativados por Sódio/genética , Proteínas do Tecido Nervoso/metabolismoRESUMO
Introducción: Los estudios para terapia cetógena (TC) se han concentrado en niños mayores de 2 años y adultos. Su eficacia en lactantes se ha descrito, pero hay pocos estudios en este grupo de edad. Pacientes y métodos: Se describe una serie de casos de nueve neonatos y lactantes menores de 4 meses de edad con epilepsia refractaria que recibieron tratamiento con TC. Se evaluaron, retrospectivamente, los registros clínicos de niños tratados entre 2015 y 2021. Resultados: Se recolectaron datos de siete pacientes. Seis pacientes iniciaron con crisis epilépticas el primer día de vida, y uno, el día 45. La etiología de la epilepsia fue variada (metabólica, genética y estructural). La TC se inició tan temprano como a los 9 días de vida. La edad promedio de inicio fue los 24 días de vida. Se inició con una tasa cetógena de 1:1 o 1:2, y se progresó posteriormente a 4:1. Después de un mes de TC, 5/7 pacientes presentaron una reducción significativa en la frecuencia de las crisis (>50%) y 2/7 experimentaron un control completo. A los seis meses, 4/7 pacientes lograron un control completo y 1/7 un control >50%. Dos pacientes se perdieron en el seguimiento. No se notificaron efectos gastrointestinales que obligaran al ajuste o la suspensión de la dieta. Se notificaron hipoglucemia e hipertrigliceridemia. Conclusión: A pesar de que la evidencia en la TC en lactantes y neonatos apenas está empezando a aparecer, nuestra experiencia muestra que puede ser una buena opción terapéutica para el control de las crisis epilépticas, sin efectos adversos importantes. Existe un gran potencial de investigación en el área de la TC en lactantes y neonatos.(AU)
Introduction: Ketogenic therapy (KT) studies have focused in children older than 2 years and adults. Recently its efficacy in infants has been reported, but there are few studies in this age group. Patients and methods: We report a case series of nine newborn and children younger than 4 months of age with refractory epilepsy treated with KT. We retrospectively reviewed charts of children treated at our center between 2015-2021. Results: Data was collected on seven patients. Six patients began having seizures on day one of life, one had seizures starting on day 45. Different epilepsy etiologies were found. KT was started as soon as 9 days of life. The average age at which ketogenic therapy was started was 24 days of life. Initially, the diet was started at 1:1 or 2:1 ratio, and was progressed to a 4:1 ratio. After one month of KT 5/7 patients experienced a significant reduction in seizure frequency (>50%) and 2/7 had complete seizure control. At six months, 4/7 patients achieve complete seizure freedom and 1/7 had >50% seizure reduction. Two patients were lost to follow-up. None of our patients reported gastrointestinal side effects that required diet adjustments. One patient had mild and one mild hypertriglyceridemia. CONCLUSION. Even though evidence about KT in young children are starting to emerge, our experience shows it can be successful in controlling seizure burden without considerable adverse effects. There is great research potential regarding KT in young children.(AU)
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Humanos , Recém-Nascido , Saúde da Criança , Dieta Cetogênica , Epilepsia Resistente a Medicamentos , Epilepsia Neonatal Benigna , Pacientes Internados , Exame Físico , Colômbia , Neurologia , Doenças do Sistema NervosoRESUMO
BACKGROUND: Previous studies report increasing cholangiocarcinoma (CCA) incidence up to 2015. This contemporary retrospective analysis of CCA incidence and mortality in the US from 2001-2017 assessed whether CCA incidence continued to increase beyond 2015. PATIENTS AND METHODS: Patients (≥18 years) with CCA were identified in the National Cancer Institute Surveillance, Epidemiology, and End Results 18 cancer registry (International Classification of Disease for Oncology [ICD-O]-3 codes: intrahepatic [iCCA], C221; extrahepatic [eCCA], C240, C241, C249). Cancer of unknown primary (CUP) cases were identified (ICD-O-3: C809; 8140/2, 8140/3, 8141/3, 8143/3, 8147/3) because of potential misclassification as iCCA. RESULTS: Forty-thousand-and-thirty CCA cases (iCCA, n=13,174; eCCA, n=26,821; iCCA and eCCA, n=35) and 32,980 CUP cases were analyzed. From 2001-2017, CCA, iCCA, and eCCA incidence (per 100 000 person-years) increased 43.8% (3.08 to 4.43), 148.8% (0.80 to 1.99), and 7.5% (2.28 to 2.45), respectively. In contrast, CUP incidence decreased 54.4% (4.65 to 2.12). CCA incidence increased with age, with greatest increase among younger patients (18-44 years, 81.0%). Median overall survival from diagnosis was 8, 6, 9, and 2 months for CCA, iCCA, eCCA, and CUP. From 2001-2016, annual mortality rate declined for iCCA (57.1% to 41.2%) and generally remained stable for eCCA (40.9% to 37.0%) and for CUP (64.3% to 68.6%). CONCLUSIONS: CCA incidence continued to increase from 2001-2017, with greater increase in iCCA versus eCCA, whereas CUP incidence decreased. The divergent CUP versus iCCA incidence trends, with overall greater absolute change in iCCA incidence, provide evidence for a true increase in iCCA incidence that may not be wholly attributable to CUP reclassification.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias Primárias Desconhecidas , Adolescente , Adulto , Neoplasias dos Ductos Biliares/epidemiologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/epidemiologia , Discinesias , Epilepsia Neonatal Benigna , Humanos , Incidência , Estudos Retrospectivos , Convulsões , Estados Unidos/epidemiologia , Adulto JovemRESUMO
In a three-generation family, five individuals exhibited the typical phenotype of paroxysmal kinesigenic dyskinesia (PKD). Intriguingly, one of the individuals also showed benign familial infantile convulsions (BFIC) at age 4 months and spontaneously resolved at age 18 months. At age 12, she developed a typical PKD, and was gradually relieved at age 21. Therefore, the clinical phenotype was consistent with PKD with infantile convulsions (PKD/IC). Whole exome sequence and co-segregation analysis revealed a novel heterozygous variant c.1085A > G in the TMEM151A gene. Our study suggests that the TMEM151A gene may be associated with the disease spectrum of PKD-PKD/IC-BFIC.
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Epilepsia Neonatal Benigna , Proteínas do Tecido Nervoso , Distonia , Epilepsia Neonatal Benigna/diagnóstico , Epilepsia Neonatal Benigna/genética , Feminino , Humanos , Proteínas de Membrana/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Linhagem , Fenótipo , Convulsões/genéticaRESUMO
A clinical case of a patient with neonatal epilepsy at the age of 5 months, with impaired bone formation, early osteoporosis and frequent limb fractures is described. Panel sequencing confirmed by Sanger sequencing revealed two independent hereditary diseases - osteogenesis imperfect type 1, associated with a mutation in the COL1A1 gene (c.2010delT) and benign non-familial infantile seizures associated with a mutation in the PRRT2 gene (c.649dupC). A unique clinical case of a combination of these diseases is presented.
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Epilepsia Neonatal Benigna , Osteogênese Imperfeita , Epilepsia Neonatal Benigna/genética , Humanos , Lactente , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Linhagem , ConvulsõesRESUMO
BACKGROUND: The PRRT2 gene located at 16p11.2 encodes proline-rich transmembrane protein 2. In recent reviews, clinical spectrum caused by pathogenic PRRT2 variants is designated as PRRT2-associated paroxysmal movement disorders, which include paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions with choreoathetosis, and hemiplegic migraine. The recurrent 16p11.2 microdeletion encompassing PRRT2 has also been reported to cause neurodevelopmental syndrome, associated with autism spectrum disorder. Although PRRT2 variants and 16p11.2 microdeletion cause each disease with the autosomal dominant manner, rare cases with bi-allelic PRRT2 variants or concurrent existence of PRRT2 variants and 16p11.2 microdeletion have been reported to show more severe phenotypes. CASE REPORT: A 22-year-old man presents with episodic ataxia, paroxysmal kinesigenic dyskinesia, seizure, intellectual disability and autism spectrum disorder. He also has obesity, hypertension, hyperuricemia, and mild liver dysfunction. Exome sequencing revealed a c.649dup variant in PRRT2 in one allele and a de novo 16p11.2 microdeletion in another allele. CONCLUSIONS: Our case showed combined clinical features of PRRT2-associated paroxysmal movement disorders and 16p11.2 microdeletion syndrome. We reviewed previous literatures and discussed phenotypic features of patients who completely lack the PRRT2 protein.
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Transtorno do Espectro Autista , Distonia , Epilepsia Neonatal Benigna , Transtornos dos Movimentos , Distonia/genética , Epilepsia Neonatal Benigna/genética , Humanos , Masculino , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , LinhagemRESUMO
BACKGROUND AND PURPOSE: Mutations in KCNQ3 have classically been associated with benign familial neonatal and infantile seizures and more recently identified in patients with neurodevelopmental disorders and abnormal electroencephalogram (EEG) findings. We present 4 affected patients from a family with a pathogenic mutation in KCNQ3 with a unique constellation of clinical findings. METHODS: A family of 3 affected siblings and mother sharing a KCNQ3 pathogenic variant are described, including clinical history, genetic results, and EEG and magnetic resonance imaging (MRI) findings. RESULTS: This family shows a variety of clinical manifestations, including neonatal seizures, developmental delays, autism spectrum disorder, and anxiety. One child developed absence epilepsy, 2 children have infrequent convulsive seizures that have persisted into childhood, and their parent developed adult-onset epilepsy. An underlying c.1091G>A (R364H) variant in KCNQ3 was found in all affected individuals. CONCLUSIONS: The phenotypic variability of KCNQ3 channelopathies continues to expand as more individuals and families are described, and the variant identified in this family adds to the understanding of the manifestations of KCNQ3-related disorders.
Assuntos
Epilepsia Neonatal Benigna , Epilepsia , Canal de Potássio KCNQ3 , Adulto , Transtorno do Espectro Autista/genética , Criança , Epilepsia/genética , Epilepsia Neonatal Benigna/genética , Humanos , Recém-Nascido , Canal de Potássio KCNQ3/genética , Convulsões/genéticaRESUMO
OBJECTIVE: To analyze the clinical phenotype and genetic variant in a Chinese pedigree affected with benign familial neonatal convulsion (BFNC). METHODS: Clinical data and peripheral blood samples of the pedigree were obtained with informed consent. Whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing. RESULTS: The pedigree comprised 9 individuals, among whom 4 were affected, including 3 males and 1 female. All patients had developed seizures during the neonatal period, which had ceased in 4 to 6 months. One patient had recurrence in between 1 and 2 years old. Genetic testing has identified a novel nonsense c.810G>A (p.W270X) variant in exon 5 of the KCNQ2 gene, which has co-separated with the BFNC phenotype in the pedigree. CONCLUSION: The patients from this pedigree have conformed to the diagnosis of BFNC with good prognosis, which was in keeping with previously reported cases. The heterozygous c.810G>A (p.W270X) nonsense variant of the KCNQ2 gene probably underlay the pathogenesis of BFNC in this pedigree, which has expanded the mutational spectrum of the disease.
Assuntos
Epilepsia Neonatal Benigna , Povo Asiático/genética , Pré-Escolar , China , Epilepsia Neonatal Benigna/genética , Feminino , Testes Genéticos , Humanos , Lactente , Masculino , Mutação , LinhagemAssuntos
Epilepsia Neonatal Benigna , Criança , Humanos , Mutação , Linhagem , Convulsões/diagnóstico , Convulsões/etiologiaRESUMO
OBJECTIVE@#To analyze the clinical phenotype and genetic variant in a Chinese pedigree affected with benign familial neonatal convulsion (BFNC).@*METHODS@#Clinical data and peripheral blood samples of the pedigree were obtained with informed consent. Whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing.@*RESULTS@#The pedigree comprised 9 individuals, among whom 4 were affected, including 3 males and 1 female. All patients had developed seizures during the neonatal period, which had ceased in 4 to 6 months. One patient had recurrence in between 1 and 2 years old. Genetic testing has identified a novel nonsense c.810G>A (p.W270X) variant in exon 5 of the KCNQ2 gene, which has co-separated with the BFNC phenotype in the pedigree.@*CONCLUSION@#The patients from this pedigree have conformed to the diagnosis of BFNC with good prognosis, which was in keeping with previously reported cases. The heterozygous c.810G>A (p.W270X) nonsense variant of the KCNQ2 gene probably underlay the pathogenesis of BFNC in this pedigree, which has expanded the mutational spectrum of the disease.