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INTRODUCTION: Video EEG monitoring (VEM) is an important tool for characterizing clinical events suspected as seizures. It is also used for pre-surgical workups in patients with drug-resistant epilepsy (DRE). In-hospital VEM high cost, long admission waiting periods and some other inconveniences led to an interest in home VEM (HVEM). However, because antiseizure medications cannot be reduced at home, HVEM may require longer monitoring. While the economic aspect is one of the main motivations for HVEM, the cost of HVEM lasting several weeks has not been assessed. METHODS: We modeled the cost of HVEM for 8 weeks and compared it to the cost of 1-week in-hospital VEM. Additionally, we modeled the per-patient cost for a combination of HVEM and in-hospital VEM, considering that if in a proportion of patients HVEM fails to achieve its goal, they should undergo in-hospital VEM with drug reduction. RESULTS: The average cost of HVEM up to 4-6 weeks of monitoring was lower than that for the 1-week in-hospital VEM. Combining the 3-week HVEM with 1-week in-hospital VEM (if needed) reduced the per-patient cost by 6.6-28.6% as compared to the situation when all the patients with DRE were referred to the in-hospital VEM. CONCLUSIONS: A prolonged intermittent HVEM can be cost-effective, especially if the minimal seizure frequency is about one seizure per week. The study findings support directing efforts into clinical trials and technology development.
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OBJECTIVE: Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy. METHODS: This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified. RESULTS: A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity. SIGNIFICANCE: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.
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Epilepsias Parciales , Epilepsia , Niño , Humanos , Epilepsias Parciales/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Epilepsia/inducido químicamente , Convulsiones/tratamiento farmacológico , Piridonas/efectos adversos , Ácido Glutámico , Protocadherinas , Subunidades alfa de la Proteína de Unión al GTP Gi-GoRESUMEN
We describe the underlying genetic cause of a novel Rett-like phenotype accompanied by areflexia in three methyl-CpG-binding protein 2-negative individuals from two unrelated families. Discovery analysis was performed using whole-exome sequencing followed by Sanger sequencing for validation and segregation. Functional studies using short-hairpin RNA for targeted gene knockdown were implemented by the transfection of mouse cultured primary hippocampal neurons and in vivo by in utero electroporation. All patients shared a common homozygous frameshift mutation (chr9:135073515, c.376dupT, p.(Ser126PhefsTer241)) in netrin-G2 (NTNG2, NM_032536.3) with predicted nonsense-mediated decay. The mutation fully segregated with the disease in both families. The knockdown of either NTNG2 or the related netrin-G family member NTNG1 resulted in severe neurodevelopmental defects of neuronal morphology and migration. While NTNG1 has previously been linked to a Rett syndrome (RTT)-like phenotype, this is the first description of a RTT-like phenotype caused by NTNG2 mutation. Netrin-G proteins have been shown to be required for proper axonal guidance during early brain development and involved in N-methyl- d-aspartate-mediated synaptic transmission. Our results demonstrating that knockdown of murine NTNG2 causes severe impairments of neuronal morphology and cortical migration are consistent with those of RTT animal models and the shared neurodevelopmental phenotypes between the individuals described here and typical RTT patients.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Proteínas Ligadas a GPI/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Netrinas/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Animales , Niño , Preescolar , Consanguinidad , Modelos Animales de Enfermedad , Facies , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Ratones , Neuronas/metabolismo , Fenotipo , Análisis de Secuencia de ADN , Secuenciación del ExomaRESUMEN
Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.
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Calcineurina/genética , Epilepsia/genética , Mutación , Trastornos del Neurodesarrollo/genética , Transmisión Sináptica/fisiología , Adolescente , Adulto , Calcineurina/metabolismo , Niño , Preescolar , Estudios de Cohortes , Epilepsia/patología , Exoma/genética , Femenino , Humanos , Lactante , Recién Nacido , Síndrome de Lennox-Gastaut/patología , Masculino , Trastornos del Neurodesarrollo/patología , Análisis de Secuencia de ADN , Índice de Severidad de la Enfermedad , Espasmos Infantiles/genética , Espasmos Infantiles/patología , Adulto JovenRESUMEN
The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.
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Anomalías Múltiples/diagnóstico , Distonía/diagnóstico , Trastornos Distónicos/diagnóstico , Discapacidad Intelectual/diagnóstico , Malformaciones del Desarrollo Cortical/diagnóstico , Polimicrogiria/diagnóstico , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Niño , Preescolar , Distonía/complicaciones , Distonía/diagnóstico por imagen , Distonía/fisiopatología , Trastornos Distónicos/diagnóstico por imagen , Trastornos Distónicos/fisiopatología , Electroencefalografía , Epilepsia/complicaciones , Epilepsia/diagnóstico , Epilepsia/diagnóstico por imagen , Epilepsia/fisiopatología , Femenino , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/fisiopatología , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/fisiopatología , Neuroimagen/métodos , Polimicrogiria/complicaciones , Polimicrogiria/diagnóstico por imagen , Polimicrogiria/fisiopatología , Adulto JovenRESUMEN
AIM: To collect preliminary functional data on ataxia telangiectasia and create a disease specific scale: the Ataxia Telangiectasia Functional Scale (ATFS). METHOD: Retrospective information on patients with ataxia telangiectasia referred to the Assistive Technology Unit was included. Functional mobility scales (the Gross Motor Function Classification System [GMFCS] and the Functional Mobility Scale [FMS]-5, FMS-50, FMS-500) and activities of daily living [ADL] parameters were recorded. We created a 51-point ATFS, that consisted of three ambulation items adapted for ataxia telangiectasia in the frame of FMS (home, school, outdoors), five ADL items, and one schooling item. RESULTS: Twenty-seven participants (17 males, 10 females; mean age 10y 8mo [SD 5y 1mo], range 1y 9mo-25y 6mo), were enrolled; 168 measurements were recorded. Patients walked at a mean age of 1 year 4 months (SD 5y 4mo) and lost ambulatory capacity at 8 years 8 months (SD 2y 1mo). GMFCS level and FMS-5, FMS-50, FMS-500 assessments correlated with age (Spearman's correlations r=0.555, -0.617, -0.639, -0.662 respectively, p<0.01 for all), but plateaued after 12 years of age. ATFS mean score was 37.46 (SD 7.88) and increased with age (Spearman's correlation r=0.585, p<0.01). The scale showed three stages of disease progression. INTERPRETATION: In this pilot study we show longitudinal functional data of ambulation and ADL skills in ataxia telangiectasia, and created a framework for a functional scale. This functional scale closely approximated disease course, but further validation is required. WHAT THIS PAPER ADDS: The Gross Motor Function Classification System and the Functional Mobility Scale are ill-suited for ataxia telangiectasia assessments. Three functional mobility scales (home, school, outdoors) suited to ataxia telangiectasia were created. The Ataxia Telangiectasia Functional Scale (ATFS) combines mobility and items of activities of daily living. The ATFS closely approximates the three-stage progression of the disorder.
MEDICIONES DE PARÁMETROS FUNCIONALES EN NIÑOS CON ATAXIA TELANGIECTASIA: OBJETIVO: Recopilar datos funcionales preliminares sobre la ataxia telangiectasia y crear una escala específica de la enfermedad: la escala funcional de la ataxia telangiectasia (ATFS). MÉTODO: Se incluyó información retrospectiva sobre pacientes con ataxia telangiectasia remitidos a la Unidad de Tecnología Asistiva. Se registraron las escalas de movilidad funcional (el sistema de clasificación de la función motora gruesa [GMFCS] y la escala de movilidad funcional [FMS-5, FMS-50, FMS-500]) y los parámetros de las actividades de la vida diaria [ADL]. Creamos un ATFS de 51 puntos, que constaba de tres elementos de asistencia a la deambulación adaptados para la ataxia telangiectasia según los requerimientos de FMS (hogar, escuela, exteriores), cinco elementos de ADL y un elemento de escolarización. RESULTADOS: Se reclutaron 27 participantes (17 varones, 10 mujeres; edad media 10a 8m[DE 5a 1m], rango 1a 9m- 25a 6m); se registraron 168 mediciones. Los pacientes caminaron a una edad promedio de 1 año y 4 meses (DE 5 y 4 meses) y perdieron la capacidad ambulatoria a los 8 años y 8 meses (DE 2 y 1 meses). Las evaluaciones GMFCS y FMS-5, FMS-50, FMS-500 se correlacionaron con la edad (correlaciones de Spearman r = 0,555, -0,617, -0,639, -0,662 respectivamente, p <0,01 para todos), pero se estancaron después de los 12 años de edad. La puntuación media de ATFS fue 37,46 (SD 7,88) y aumentó con la edad (correlación de Spearman r = 0,585, p <0,01). La escala mostró tres etapas de progresión de la enfermedad. INTERPRETACIÓN: En este estudio piloto, mostramos datos funcionales longitudinales de ambulación y habilidades de ADL en la ataxia telangiectasia, y creamos un marco para una escala funcional. Esta escala funcional se aproximó mucho al curso de la enfermedad, pero se requiere validación adicional.
MEDIDAS DE PARÂMETROS FUNCIONAIS EM CRIANÇAS COM ATAXIA TELANGIECTASIA: OBJETIVO: Coletar dados funcionais prelimiares sobre ataxia telangiectasia e criar uma escala específica para a doença: a Escala Funcional de Ataxia Telangiectasia (EFAT). MÉTODO: Informações retrospectivas sobre pacientes com ataxia telangiectasia encaminhados para a Unidade de Tecnologia Assistiva foram incluídas. Escalas de mobilidade funcional (o Sistema de Classificação da Função Motora grossa [GMFCS] e a Escala de Mobilidade Funcional [FMS]-5, FMS-50, FMS-500) e parâmetros de atividades da vida diária [AVD] foram registrados. Uma EFAT de 51 pontos foi criada, consistindo de três itens de deambulação adaptados para ataxia telangiectasia na estrutura da FMF (casa, escola, comunidade), cinco itens de AVDs, e um item sobre escolaridade. RESULTADOS: Vinte e sete participantes (17 do sexo masculino, 10 nomes do sexo feminino; média de idade 10a 8m [DP 5a 1m], variação 1a 9m-25a 6m), foram recrutados; 168 medidas foram registradas. Os pacientes deambularam com uma média de (DP 5a 4m) e perderam a capacidade deambulatória com 8a 8m (DP 2a 1m). As avaliações de GMFCS e FMS-5, FMS-50, FMS-500 se correlacionara mcom a idade (correlações de r=0,555, -0,617, -0,639, -0,662 respectivamen, p<0,01 para todos), mas atingiram platô após a idade de 12 anos. O escore médio da EFAT foi 37,46 (DP 7,88) e houve aumento com a idade (correlação de Spearman r=0,585, p<0,01). A escala mostrou três estágios de progressão da doença. INTERPRETAÇÃO: Neste estudo piloto, mostramos dados funcionais longitudinais sobre a deambulação e AVDs em ataxia telangiectasia, e criamos uma estrutura para uma escala fncional. Esta escala funcional se assemelhou com o curso da doença, porém maiores estudos para validação são necessaries.
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Ataxia Telangiectasia/diagnóstico , Gravedad del Paciente , Actividades Cotidianas , Adolescente , Adulto , Ataxia Telangiectasia/fisiopatología , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Proyectos Piloto , Datos Preliminares , Estudios Retrospectivos , Instituciones Académicas , Caminata , Adulto JovenRESUMEN
Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285∗), c.247_250del (p.Asn83Hisfs∗4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.
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Trastornos Distónicos/genética , Ácidos Grasos/biosíntesis , Mitocondrias/metabolismo , Mutación , Atrofia Óptica/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Ganglios Basales/metabolismo , Células Cultivadas , Niño , Preescolar , Femenino , Fibroblastos , Prueba de Complementación Genética , Humanos , Lactante , Masculino , Enfermedades Mitocondriales/genética , Modelos Moleculares , Mutación Missense/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Linaje , Sitios de Empalme de ARN/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismoRESUMEN
INTRODUCTION: The new anticonvulsant brivaracetam is a levetiracetam analog which binds to the synaptic vesicle protein 2A, and inhibits excitatory neurotransmitters' release. Brivaracetam was Food and Drug Administration (FDA) and European Medicine Agency (EMA) approved in 2016 as adjunctive treatment for focal onset seizures in patients over 16â¯years of age, and in 2018 for children over four years of age. Our aim was to describe effectiveness and tolerability in real-life pediatric epilepsy clinic. METHODS: Cross-sectional retrospective chart review of patients under 20â¯years of age, treated with brivaracetam. Positive response to treatment was considered when 50% decrease in seizure frequency was noted. In responders to levetiracetam, positive effect was regarded if switching to brivaracetam maintained at least the same seizure control. RESULTS: Thirty-one patients (67.7% males), aged 13.8⯱â¯4.07 (6.9-20â¯years), were treated with brivaracetam 3.8â¯mg/kg⯱â¯1.8. Age of onset of epilepsy was 5.7⯱â¯3.7â¯years; 20 patients had focal epilepsies; and 11 had epileptic syndromes (5 - Lennox-Gastaut, 3 - myoclonic absence, 3 - myoclonic-atonic). Responder rate was 45.2%, with no statistical difference under and over 16â¯years of age (40% vs. 54.5%, Fisher's exact test). Eight patients had better response to seizures compared to levetiracetam. Gender, duration of epilepsy, and dosage did not affect epilepsy control. Six patients had seizure aggravation. Adverse effects were rare: mild somnolence (6.4%), psychosis (3.2%), and nausea (3.2%). CONCLUSION: Brivaracetam is an effective add-on treatment in focal, as well as generalized seizures in children, with negligible side effects, including children who failed previously on levetiracetam. Seizure exacerbation may occur, but it's reason is unclear.
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Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Síndromes Epilépticos/tratamiento farmacológico , Pirrolidinonas/uso terapéutico , Adolescente , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.
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Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Encefalopatías/genética , Encefalopatías/patología , Mitocondrias/metabolismo , Dinámicas Mitocondriales/genética , Encefalopatías/diagnóstico por imagen , Encefalopatías/mortalidad , Células Cultivadas , Preescolar , Consanguinidad , Salud de la Familia , Femenino , Fibroblastos/patología , Fibroblastos/ultraestructura , Estudios de Asociación Genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Consumo de Oxígeno/genética , Transporte de Proteínas/genética , TransfecciónRESUMEN
BACKGROUND: Ataxia telangiectasia (AT) is a genetic multisystem disorder, presenting with progressive ataxia, immune deficiency, and propensity toward malignancy. Endocrine abnormalities (growth retardation, reproductive dysfunction, and diabetes) have been described, however detailed information regarding this aspect is lacking. We aimed to characterize endocrine anomalies and growth patterns in a large cohort of AT patients. METHODS: Retrospective study comprising all 52 patients (aged 2-26.2 y) followed at a national AT Clinic. Anthropometric and laboratory measurements were extracted from the charts. RESULTS: Median height-SDS was already subnormal during infancy, remaining negative throughout follow up to adulthood. Height-SDS was more impaired than weight-SDS up to age 4 y, thereafter weight-SDS steadily decreased, resulting in progressively lower BMI-SDS. IGF-I-SDS was low (-1.53 ± 1.54), but did not correlate with height-SDS. Gonadal failure was present in all 13 females older than 10 y but only in one male. Two patients had diabetes and 10 had dyslipidemia. Vitamin D deficiency was observed in 52.2% of the evaluated patients. CONCLUSION: Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.
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Ataxia Telangiectasia/fisiopatología , Estatura , Peso Corporal , Sistema Endocrino/fisiopatología , Adolescente , Adulto , Antropometría , Ataxia Telangiectasia/complicaciones , Glucemia/metabolismo , Niño , Preescolar , Estudios Transversales , Dislipidemias/complicaciones , Femenino , Trastornos del Crecimiento , Humanos , Sistema Inmunológico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Estudios Retrospectivos , Deficiencia de Vitamina D/complicaciones , Adulto JovenRESUMEN
OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. METHODS: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. RESULTS: Fifty-three patients, 27 (49%) boys, age 14.6â±â5.2 years (range 5.9-26.1 years), were included. Twenty-three patients (43.4%), age 9.9â±â5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8â±â73.8âIU/L, aspartate aminotransferase 70â±â50âIU/L, alkaline phosphatase 331â±â134âIU/L, and gamma glutamyl transferase 114.7â±â8âIU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (Pâ<â0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. CONCLUSIONS: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.
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Ataxia Telangiectasia/fisiopatología , Hepatopatías/etiología , Hígado/fisiopatología , Adolescente , Adulto , Ataxia Telangiectasia/sangre , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Biopsia , Niño , Preescolar , Estudios de Cohortes , Progresión de la Enfermedad , Dislipidemias/etiología , Femenino , Estudios de Seguimiento , Humanos , Israel/epidemiología , Hígado/diagnóstico por imagen , Hígado/patología , Hepatopatías/diagnóstico por imagen , Hepatopatías/epidemiología , Hepatopatías/fisiopatología , Masculino , Mutación , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/etiología , Prevalencia , Estudios Retrospectivos , Ultrasonografía , Adulto JovenRESUMEN
PURPOSE: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene-disease associations. METHODS: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients. RESULTS: We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10(-8)). This enrichment is only partially explained by mutations found in known disease-causing genes. CONCLUSION: This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.
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Exoma , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Biología Computacional/métodos , Femenino , Estudios de Asociación Genética , Genómica/métodos , Genotipo , Humanos , Masculino , Mutación , FenotipoRESUMEN
OBJECTIVE: Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene, and characterized by cognitive and communicative regression, loss of hand use, and midline hand stereotypies. Epilepsy is a core symptom, but literature is controversial regarding genotype-phenotype correlation. Analysis of data from a large cohort should overcome this shortcoming. METHODS: Data from the Rett Syndrome Networked Database on 1,248 female patients were included. Data on phenotypic and genotypic parameters, age of onset, severity of epilepsy, and type of seizures were collected. Statistical analysis was done using the IBM SPSS Version 21 software, logistic regression, and Kaplan-Meier survival curves. RESULTS: Epilepsy was present in 68.1% of the patients, with uncontrolled seizures in 32.6% of the patients with epilepsy. Mean age of onset of epilepsy was 4.68 ± (standard deviation) 3.5 years. Younger age of onset was correlated to severity of epilepsy (Spearman correlation r = 0.668, p < 0.01). Patients with late truncating deletions had lower prevalence of epilepsy. Compared to them, the p.R133C mutation, associated with a milder Rett phenotype, increased the risk for epilepsy (odds ratio [OR] 2.46, confidence interval [CI] 95% 1.3-4.66), but not for severe epilepsy. The p.R255X mutation conferred an increased risk for epilepsy (OR 2.07, CI 95% 1.2-3.59) as well as for severe epilepsy (OR 3.4, CI 95% 1.6-7.3). The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy (OR 3.09 and 2.69, CI 95% 1.48-6.4 and 1.19-6.05, respectively), but not for epilepsy occurrence. SIGNIFICANCE: Various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. This might suggest a site-specific effect of MeCp2 on epileptic pathways. Further investigation of these mechanisms should promote better understanding of epileptogenesis in Rett syndrome.
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Bases de Datos Factuales , Epilepsia/diagnóstico , Epilepsia/genética , Proteína 2 de Unión a Metil-CpG/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Adolescente , Niño , Preescolar , Femenino , Estudios de Asociación Genética/métodos , Humanos , Lactante , Masculino , Adulto JovenRESUMEN
BACKGROUND: Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population. METHODS: A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel. RESULTS: The most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%). CONCLUSION: Purified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.
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Cannabidiol , Epilepsia Refractaria , Síndrome de Lennox-Gastaut , Niño , Adulto Joven , Humanos , Femenino , Masculino , Cannabidiol/efectos adversos , Epilepsia Refractaria/tratamiento farmacológico , Epilepsia Refractaria/diagnóstico , Anticonvulsivantes/uso terapéutico , Estudios Retrospectivos , Calidad de Vida , Convulsiones/tratamiento farmacológico , Síndrome de Lennox-Gastaut/tratamiento farmacológicoRESUMEN
BACKGROUND: Ataxia telangiectasia is a multisystem disorder with progressive neurodegeneration. Corticosteroids can improve neurological functioning in patients with the disorder but adrenal suppression and symptom recurrence on treatment discontinuation has limited their use, prompting the development of novel steroid delivery systems. The aim of the ATTeST study was to evaluate the efficacy and safety of intra-erythrocyte delivery of dexamethasone sodium phosphate compared with placebo in children with ataxia telangiectasia. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 22 centres in 12 countries (Australia, Belgium, Germany, India, Israel, Italy, Norway, Poland, Spain, Tunisia, the UK, and the USA). Eligible participants were children aged 6 years or older weighing more than 15 kg who met clinical criteria for ataxia telangiectasia but who had preserved autonomous gait. Participants were randomly assigned (1:1:1) to low-dose (approximately 5-10 mg), or high-dose (approximately 14-22 mg) intra-erythrocyte dexamethasone sodium phosphate, or placebo, using an independent interactive web response system, with minimisation for sex and age (6-9 years vs ≥10 years). Intravenous intra-erythrocyte dexamethasone sodium phosphate was administered once a month for 6 months. Participants, employees of the sponsor, investigators, all raters of efficacy endpoints, and central reviewers were masked to treatment assignment and dose allocations. The primary efficacy endpoint was change in the modified International Cooperative Ataxia Rating Scale (mICARS) from baseline to month 6, assessed in the modified intention-to-treat (mITT) population, which included all randomly assigned participants who received at least one dose of study drug and had at least one post-baseline efficacy assessment. This trial is registered with Clinicaltrials.gov (NCT02770807) and is complete. FINDINGS: Between March 2, 2017, and May 13, 2021, 239 children were assessed for eligibility, of whom 176 were randomly assigned. One patient assigned to high-dose intra-erythrocyte dexamethasone sodium phosphate did not initiate treatment. 175 patients received at least one dose of treatment (59 patients received the low dose and 57 received the high dose of intra-erythrocyte dexamethasone sodium phosphate, and 59 received placebo). The mITT population comprised 164 participants (56 children in the low-dose group, 54 children in the high-dose group, and 54 in the placebo group). Compared with the placebo group, no differences were identified with regard to change in mICARS score from baseline to 6 months in the low-dose group (least squares mean difference -1·37 [95% CI -2·932 to 0·190]) or the high-dose group (-1·40 [-2·957 to 0·152]; p=0·0765). Adverse events were reported in 43 (73%) of 59 participants in the low-dose group, 47 (82%) of 57 participants in the high-dose group, and 43 (73%) of 59 participants in the placebo group. Serious adverse events were observed in six (10%) of 59 participants in the low-dose group, seven (12%) of 57 participants in the high-dose group, and seven (12%) of 59 participants in the placebo group. There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths. INTERPRETATION: Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age. Studies of intra-erythrocyte delivery of dexamethasone sodium phosphate will continue in participants aged 6-9 years, on the basis of findings from subgroup analyses from this trial. FUNDING: EryDel and Quince Therapeutics.
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Ataxia Telangiectasia , Dexametasona , Humanos , Dexametasona/administración & dosificación , Dexametasona/análogos & derivados , Método Doble Ciego , Niño , Femenino , Masculino , Adolescente , Ataxia Telangiectasia/tratamiento farmacológico , Resultado del Tratamiento , Eritrocitos/efectos de los fármacosRESUMEN
BACKGROUND: Previous reports on the cutaneous manifestations of ataxia-telangiectasia (A-T) have relied on data from small series, in patients not genetically tested for A-T. OBJECTIVE: The aim of our study was to characterize the dermatologic manifestations in patients with A-T followed up at the national A-T clinic in Israel. METHODS: This retrospective cross-sectional study included 32 patients followed up at a multidisciplinary A-T clinic from 2010 to 2012. Complete skin examination was done by a single dermatologist. Information about mutations and neurologic status was extracted from the patients' charts. Relevant demographic, clinical, and laboratory characteristics of all patients were collected and summarized. RESULTS: Of the 32 patients, 97% had ocular telangiectasia, the hallmark of the disease. Telangiectasia on other body parts was less frequent. Pigmentary anomalies included café-au-lait macules (84%), hypopigmented macules (44%), and melanocytic nevi (37%). A facial papulosquamous rash was found in 41% of cases. Other manifestations included hypertrichosis and birdlike facies. We did not observe premature hair graying or poliosis. No genotype-phenotype correlation was found in terms of skin manifestations. LIMITATIONS: There was a modest sample size, because of the rarity of the disease. CONCLUSION: Recognition of the ocular and dermatologic manifestations of A-T can facilitate early diagnosis in a child with neurologic deterioration.
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Ataxia Telangiectasia/complicaciones , Enfermedades de la Piel/etiología , Adolescente , Adulto , Ataxia Telangiectasia/genética , Manchas Café con Leche/diagnóstico , Manchas Café con Leche/etiología , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Masculino , Trastornos de la Pigmentación/diagnóstico , Trastornos de la Pigmentación/etiología , Estudios Retrospectivos , Enfermedades de la Piel/genética , Adulto JovenRESUMEN
Ataxia-telangiectasia (A-T), an autosomal recessive disorder is characterized by progressive neurodegeneration, immunodeficiency, sensitivity to ionizing radiation, and predisposition to cancer, especially to lymphoid malignancies. A-T variant is characterized by a milder clinical phenotype and is caused by missense or leaky splice site mutations that produce residual ataxia telangiectasia mutated (ATM) kinase activity. Lymphoid malignancy can precede the diagnosis of A-T, particularly in young children with mild neurological symptoms. We studied a consanguineous family with four A-T variant patients, three of them developed T-ALL at a young age before the diagnosis of A-T was established. ATM mutation analysis detected two new missense mutations both within exon 12: c.1514T>C and c.1547T>C. All four patients are homozygous for the two mutations, while their parents are heterozygous for the mutations. ATM protein level was low in all patients and the response to the radiomimetic agent, neocarzinostatin, was reduced. Leukemic presentation in a young age in three members of consanguineous family led to the identification of a new missense mutation in the ATM gene. The diagnosis of A-T or A-T variant should be considered in children with neurological abnormalities who develop T-ALL at a young age.
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Antibióticos Antineoplásicos/administración & dosificación , Proteínas de la Ataxia Telangiectasia Mutada/genética , Ataxia Telangiectasia , Mutación Missense , Leucemia-Linfoma Linfoblástico de Células Precursoras , Cinostatina/administración & dosificación , Adulto , Factores de Edad , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/tratamiento farmacológico , Ataxia Telangiectasia/genética , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
Introduction: Concerns regarding felbamate adverse effects restrict its widespread use in children with drug-resistant epilepsy. We aimed to examine the efficacy and safety of felbamate in those children and identify the ones who may benefit most from its use. Methods: We retrospectively reviewed the medical files of all patients who were treated with felbamate in a tertiary pediatric epilepsy clinic between 2009-2021. Drug efficacy was determined at the first 3 months of treatment and thereafter. Therapeutic response and adverse reactions were monitored throughout the course of treatment. Results: Our study included 75 children (age 8.9 ± 3.7 years), of whom 53 were treated with felbamate for seizures, 16 for electrical status epilepticus during sleep and 6 for both. The median follow-up time was 16 months (range 1-129 months). The most common cause for epilepsy was genetic (29%). The median number of previous anti-seizure medications was six [4-8]. A therapeutic response ≥50% was documented in 37 (51%) patients, and a complete response in 9 (12%). Nineteen patients (25%) sustained adverse reactions, including three cases of elevated liver enzymes and one case of neutropenia with normal bone marrow aspiration. In all cases, treatment could be continued. All children with intractable epilepsy following herpes encephalitis showed a response to felbamate. Conclusion: Felbamate is an efficacious and safe anti-seizure medication in the pediatric population.
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BACKGROUND: Limping and/or refusal to walk is a common complaint in the setting of the pediatric department, with a widely diverse differential diagnosis. An unusual etiology, is that of a hereditary neuropathy. Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy, most commonly caused by a 17p11.2 chromosomal deletion encompassing the PMP22 gene. METHODS: We pursued chromosomal microarray analysis (CMA) in multiple affected individuals of a single extended family, manifesting a range of phenotypic features consistent with HNPP. RESULTS: A 4.5 years-old boy presented for in-patient evaluation due to refusal to walk. Initial investigations including spine MRI and bone scan failed to yield a conclusive diagnosis. Following family history, which implied an autosomal dominant mode of inheritance, CMA was pursued and confirmed a 17p11.2 deletion in the proband consistent with HNPP. Importantly, following this diagnosis, four additional affected family members were demonstrated to harbor the deletion. Their variable phenotypic features, ranging from a prenatal diagnosis of a 6 months-old sibling, to recurrent paresthesias manifesting in the fourth decade of life, are discussed. CONCLUSIONS: Our experience with the family reported herein demonstrates how a thorough anamnesis can lead to a rare genetic etiology with a favorable prognosis and prevent unnecessary investigations, and underscores HNPP as an uncommon diagnostic possibility in the limping child.
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Artrogriposis , Neuropatía Hereditaria Motora y Sensorial , Artrogriposis/diagnóstico , Artrogriposis/genética , Variación Biológica Poblacional , Niño , Preescolar , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Neuropatía Hereditaria Motora y Sensorial/genética , Humanos , Lactante , Masculino , Proteínas de la Mielina/genéticaRESUMEN
OBJECTIVE: To define the neurologic characteristics and course of ataxia-telangiectasia (A-T). STUDY DESIGN: Retrospective cross-sectional chart study of 57 children (ages 2 to 19 years) followed at an A-T clinic. Cerebellar and extracerebellar symptoms were graded according to degree of functional impairment. Head circumferences were plotted from the charts and z-scores were calculated and compared with that of family members. RESULTS: Ataxia was present in 87.7%, followed by dysarthria (82.1%), dysmetria (75.4%), bradykinesia (69.2%), hyperkinetic movements (58.9%), and dystonia (15.8%). All features aggravated with age. The most striking clinical observation in our patients was low head circumference (z-score below 1), which was present in 60.9%; 17% had true microcephaly (z-score below 2). Microcephaly appeared postnatally, was proportionate to height and weight, and did not correlate with severity of ataxia or genotype. CONCLUSIONS: In addition to cerebellar ataxia, extrapyramidal symptoms, especially bradykinesia, were frequent and disabling. Microcephaly is an integral part of A-T; understanding its pathogenesis may shed light on the mechanism by which ATM mutation causes dysfunction in the nervous system.