Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
1.
Ann Neurol ; 88(2): 348-362, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32515017

RESUMEN

OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.


Asunto(s)
Encéfalo/diagnóstico por imagen , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Canal de Sodio Activado por Voltaje NAV1.3/genética , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/genética , Canales de Sodio/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Feto/diagnóstico por imagen , Variación Genética/genética , Células HEK293 , Humanos , Lactante , Masculino
2.
Mol Genet Metab Rep ; 39: 101078, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38571879

RESUMEN

Leigh syndrome is a severe progressive mitochondrial disorder mainly affecting children under the age of 5 years. It is caused by pathogenic variants in any one of more than 75 known genes in the nuclear or mitochondrial genomes. A 19-week-old male infant presented with lactic acidosis and encephalopathy following a 2-week history of irritability, neuroregression and poor weight gain. He was hypotonic with pathological reflexes, impaired vision, and nystagmus. Brain MRI showed extensive bilateral symmetrical T2 hyperintense lesions in basal ganglia, thalami, and brainstem. Metabolic workup showed elevated serum alanine, and heavy lactic aciduria with increased ketones, fumarate, malate, and alpha-ketoglutarate as well as reduced succinate on urine organic acid analysis. Lactic acidemia persisted, with only a marginally elevated lactate:pyruvate ratio (16.46, ref. 0-10). He demised at age 7 months due to respiratory failure. Exome sequencing followed by virtual gene panel analysis for pyruvate metabolism and mitochondrial defects could not identify any nuclear cause for Leigh syndrome. Mitochondrial DNA (mtDNA) genome sequencing revealed 88% heteroplasmy for a novel variant, NC_012920.1(MT-ND6):m.14430A>C p.(Trp82Gly), in blood DNA. This variant was absent from the unaffected mother's blood, fibroblast, and urine DNA, and detected at a level of 5% in her muscle DNA. Mitochondrial respiratory chain analysis revealed markedly reduced mitochondrial complex I activity in patient fibroblasts (34% of parent and control cells), and reduced NADH-linked respirometry (less than half of parental and control cells), while complex II driven respirometry remained intact. The combined clinical, genetic, and biochemical findings suggest that the novel MT-ND6 variant is the likely cause of Leigh syndrome in this patient. The mitochondrial ND6 protein is a subunit of complex I. An interesting finding was the absence of a significantly elevated lactate:pyruvate ratio in the presence of severe lactatemia, which directed initial diagnostic efforts towards excluding a pyruvate metabolism defect. This case highlights the value of a multidisciplinary approach and complete genetic workup to diagnosing mitochondrial disorders in South African patients.

3.
J Paediatr Child Health ; 46(1-2): 17-22, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19943867

RESUMEN

AIM: Parenteral phenobarbitone was unavailable in South Africa from 2005 to 2006. This study aimed to establish the effectiveness of enteral phenobarbitone in the management of childhood status epilepticus. METHOD: Patients in status epilepticus (December 2005-June 2006) received 20 mg/kg phenobarbitone via nasogastric tube in addition to standard status interventions (benzodiazepine boluses, phenytoin infusion). Phenobarbitone concentrations were taken post loading. Phenobarbitone population pharmacokinetics was analysed using non-linear mixed effects modelling. RESULTS: Sixteen patients (7 female, 9 male) were assessed, median age 5 months (range 9 days-168 months). Nine patients received 20 mg/kg; the maximum total dosage administered was 80 mg/kg with a concentration of 283 micromol/L. The typical population value of the volume of distribution was 1.2 (95% confidence interval (CI): 0.8-1.6) L/kg with interindividual variability (as coefficient of variation) of 53% (95% CI, 9-74%). Seizure control was documented within 1 h (n= 8), 1(1)/(2) h (n= 1), 3 h (n= 1) and 4 h (n= 5) following enteral phenobarbitone loading. No adverse effects were apparent from the enteral phenobarbitone administration. CONCLUSION: Patients tolerated enteral loading with phenobarbitone. A single enteral loading dose resulted in adequate phenobarbitone exposure. This practice was a safe intervention for centres lacking parenteral phenobarbitone. Therapeutic concentrations and seizure control after enteral loading suggested a role for enteral phenobarbitone in the management of acute status epilepticus as well as prophylaxis against seizure recurrence.


Asunto(s)
Relación Dosis-Respuesta a Droga , Nutrición Enteral , Epilepsia/tratamiento farmacológico , Fenobarbital/administración & dosificación , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Fenobarbital/farmacocinética , Fenobarbital/farmacología , Fenobarbital/uso terapéutico
4.
Seizure ; 70: 82-89, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31323565

RESUMEN

PURPOSE: This retrospective observational hospital-based study assessed the characteristics of children with epilepsy in a sub-Saharan African tertiary service over a 10-year period. METHODS: Children with a primary or secondary diagnosis of epilepsy seen during the study period were identified from the departmental database. Demographic and clinical data were collected from the database and available medical records. RESULTS: Of 4701 children managed in the neurology service, 2407 children (51%) had epilepsy. The 2017 International League Against Epilepsy Classification of the Epilepsies was used to ascribe seizure and epilepsy type, epilepsy syndrome diagnosis and aetiologic categories. Forty-three percent of children had seizure onset before age one year. Focal Epilepsy occurred in 48% of the cohort (n = 1145). Twenty-five percent had an epilepsy syndrome diagnosis. Most children (54%) had epilepsy of unknown aetiology. Among those with underlying non-genetic aetiologies (33%), sequelae of intracranial infections, perinatal insults and structural brain malformations were most prevalent. Motor disability was present in 24% of children. Seventy-four percent had at least one associated motor disability, intellectual or learning disability, developmental delay or psychiatric comorbidity. CONCLUSION: Epilepsy is common in sub-Saharan Africa. Many affected children have avoidable aetiologies. Compared to data from similar hospital-based studies in poorly resourced and resource-equipped settings, our cohort had a higher proportion of seizure onset below the age of one year and a greater number of infectious aetiologies, which is similar to population-based studies reported in sub-Saharan Africa. The presence of comorbidities is significant and demands greater advocacy for services for these children.


Asunto(s)
Epilepsia/epidemiología , Niño , Preescolar , Comorbilidad , Epilepsia/etiología , Epilepsia/terapia , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Sudáfrica/epidemiología , Centros de Atención Terciaria
5.
Front Neurol ; 10: 506, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31156538

RESUMEN

Introduction: Pediatric convulsive status epilepticus (CSE) which is refractory to first-line benzodiazepines is a significant clinical challenge, especially within resource-limited countries. Parenteral phenobarbital is widely used in Africa as second-line agent for pediatric CSE, however evidence to support its use is limited. Purpose: This study aimed to compare the use of parenteral phenobarbital against parenteral phenytoin as a second-line agent in the management of pediatric CSE. Methodology: An open-labeled single-center randomized parallel clinical trial was undertaken which included all children (between ages of 1 month and 15 years) who presented with CSE. Children were allocated to receive either parenteral phenobarbital or parenteral phenytoin if they did not respond to first-line benzodiazepines. An intention-to-treat analysis was performed with the investigators blinded to the treatment arms. The primary outcome measure was the success of terminating CSE. Secondary outcomes included the need for admission to the pediatric intensive care unit (PICU) and breakthrough seizures during the admission. In addition, local epidemiological data was collected on the burden of pediatric CSE. Results: Between 2015 and 2018, 193 episodes of CSE from 111 children were enrolled in the study of which 144 met the study requirements. Forty-two percent had a prior history of epilepsy mostly from structural brain pathology (53%). The most common presentation was generalized CSE (65%) caused by acute injuries or infections of the central nervous system (59%), with 19% of children having febrile status epilepticus. Thirty-five percent of children required second-line management. More patients who received parenteral phenobarbital were at a significantly reduced risk of failing second-line treatment compared to those who received parenteral phenytoin (RR = 0.3, p = 0.0003). Phenobarbital also terminated refractory CSE faster (p < 0.0001). Furthermore, patients who received parenteral phenobarbital were less likely to need admission to the PICU. There was no difference between the two groups in the number of breakthrough seizures that occurred during admission. Conclusion: Overall this study supports anecdotal evidence that phenobarbital is a safe and effective second-line treatment for the management of pediatric CSE. These results advocate for parenteral phenobarbital to remain available to health care providers managing pediatric CSE in resource-limited settings. Attachments: CONSORT 2010 checklist Trial registration: NCT03650270 Full trial protocol available: https://clinicaltrials.gov/ct2/show/NCT03650270?recrs=e&type=Intr&cond=Status+Epilepticus&age=0&rank=1.

6.
Neurology ; 90(1): e55-e66, 2018 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-29196579

RESUMEN

OBJECTIVE: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. METHODS: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. RESULTS: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. CONCLUSIONS: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.


Asunto(s)
Epilepsias Parciales/genética , Epilepsias Parciales/metabolismo , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Canales de Potasio/genética , Canales de Potasio/metabolismo , Edad de Inicio , Animales , Anticonvulsivantes , Preescolar , Simulación por Computador , Epilepsias Parciales/epidemiología , Epilepsias Parciales/terapia , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Modelos Genéticos , Modelos Moleculares , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Oocitos , Fenotipo , Bloqueadores de los Canales de Potasio/uso terapéutico , Canales de potasio activados por Sodio , Quinidina/uso terapéutico , Relación Estructura-Actividad , Xenopus
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA