RESUMEN
Spinal muscular atrophy (SMA) is characterized by progressive weakness of skeletal and respiratory muscles. This study aimed to evaluate the prevalence of pre-existing anti adeno-associated virus serotype 9 antibody (AAV9-Ab) titers among infantile-onset SMA diagnosed infants pre-screened for treatment with AAV9-based onasemnogene abeparvovec, and to explore whether clinical and/or demographic characteristics are correlated with AAV9 Ab test results. This is a retrospective multicenter study of children diagnosed with 5q SMA younger than two years of age. The obtained data included demographic data, SMA type, SMN2 gene copy number, onset date, and results of AAV9-Ab test and of SMA prior treatments. Thirty-four patients were enrolled; six patients had positive results of AAV9-Ab (titer > 1:50) in the initial screening, 15 patients were re-tested for AAV9-Abs, of whom, three patients had seroreverted [1.5-4.5 months] between the two AAV9-Abs tests. One patient had seroconverted (5.5 months after the first AAV9-Abs test). The remaining 11 patients presented matching titer results in the two tests. No demographic/clinical factors were correlated to high AAV9-Abs titers (P > 0.05).We recommend AAV9-Ab re-tests to be performed until the age of 8 months, or, if 1.5 months or more have passed after the initial AAV9-Abs test.
Asunto(s)
Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Niño , Humanos , Lactante , Serogrupo , Dependovirus/genética , Atrofia Muscular Espinal/terapia , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Atrofias Musculares Espinales de la Infancia/genética , Terapia Genética/métodosRESUMEN
Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.
Asunto(s)
Anticonvulsivantes , Epilepsia , Recién Nacido , Humanos , Anticonvulsivantes/uso terapéutico , Levetiracetam/uso terapéutico , Fenitoína/uso terapéutico , Consenso , Epilepsia/tratamiento farmacológico , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológicoRESUMEN
Therapeutic monoclonal antibodies (mAbs) have emerged as the fastest growing drug class. As such, mAbs are increasingly being co-prescribed with other drugs, including antiseizure medications (ASMs). Although mAbs do not share direct targets or mechanisms of disposition with small-molecule drugs (SMDs), combining therapeutics of both types can increase the risk of adverse effects and treatment failure. The primary goal of this literature review was identifying mAb-ASM combinations requiring the attention of professionals who are treating patients with epilepsy. Systematic PubMed and Embase searches (1980-2021) were performed for terms relating to mAbs, ASMs, drug interactions, and their combinations. Additional information was obtained from documents from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Evidence was critically appraised - key issues calling for clinicians' consideration and important knowledge gaps were identified, and practice recommendations were developed by a group of pharmacists and epileptologists. The majority of interactions were attributed to the indirect effects of cytokine-modulating antibodies on drug metabolism. Conversely, strong inhibitors or inducers of drug-metabolizing enzymes or drug transporters could potentially interact with the cytotoxic payload of antibody-drug conjugates, and ASMs could alter mAb biodistribution. In addition, mAbs could potentiate adverse ASM effects. Unfortunately, few studies involved ASMs, requiring the formulation of class-based recommendations. Based on the current literature, most mAb-ASM interactions do not warrant special precautions. However, specific combinations should preferably be avoided, whereas others require monitoring and potentially adjustment of the ASM doses. Reduced drug efficacy or adverse effects could manifest days to weeks after mAb treatment onset or discontinuation, complicating the implication of drug interactions in potentially deleterious outcomes. Prescribers who treat patients with epilepsy should be familiar with mAb pharmacology to better anticipate potential mAb-ASM interactions and avoid toxicity, loss of seizure control, or impaired efficacy of mAb treatment.
Asunto(s)
Anticuerpos Monoclonales , Epilepsia , Anticuerpos Monoclonales/efectos adversos , Anticonvulsivantes/efectos adversos , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Humanos , Convulsiones/tratamiento farmacológico , Distribución TisularRESUMEN
Presented herein are recommendations for use of nirmatrelvir/ritonavir in patients with epilepsy, as issued by the Steering Committee of the Israeli chapter of the International League Against Epilepsy. The recommendations suggest that patients on moderate-to-strong enzyme-inducing antiseizure medications (ASMs) and everolimus should not be treated with nirmatrelvir/ritonavir; rectal diazepam may be used as an alternative to buccal midazolam; doses of ASMs that are cytochrome P450 (CYP3A4) substrates might be adjusted; and patients treated with combinations of nirmatrelvir/ritonavir and ASMs that are CYP3A4 substrates or lamotrigine should be monitored for drug efficacy and adverse drug reactions.
Asunto(s)
Epilepsia , Ritonavir , Anticonvulsivantes/efectos adversos , Citocromo P-450 CYP3A , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Humanos , Israel , Ritonavir/uso terapéuticoRESUMEN
A congenital disorder of glycosylation due to biallelic mutations in B4GALT1 has been previously reported in only three patients with two different mutations. Through homozygosity mapping followed by segregation analysis in an extended pedigree, we identified three additional patients homozygous for a novel mutation in B4GALT1, expanding the phenotypic spectrum of the disease. The patients showed a uniform clinical presentation with intellectual disability, marked pancytopenia requiring chronic management, and novel features including pulmonary hypertension and nephrotic syndrome. Notably, affected individuals exhibited a moderate elevation of Man3GlcNAc4Fuc1 on serum N-glycan analysis, yet two of the patients had a normal pattern of transferrin glycosylation in repeated analysis. The novel mutation is the third disease-causing variant described in B4GALT1, and the first one within its transmembrane domain.
Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Galactosiltransferasas/genética , Discapacidad Intelectual/genética , Síndrome Nefrótico/genética , Colestasis/genética , Colestasis/patología , Trastornos Congénitos de Glicosilación/patología , Glicosilación , Homocigoto , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/patología , Lactante , Recién Nacido , Discapacidad Intelectual/patología , Masculino , Mutación/genética , Síndrome Nefrótico/patología , Linaje , Convulsiones/genética , Convulsiones/patología , Trombocitopenia/genética , Trombocitopenia/patologíaRESUMEN
BACKGROUND: The coronavirus disease-2019 (COVID-19) and its management in patients with epilepsy can be complex. Prescribers should consider potential effects of investigational anti-COVID-19 drugs on seizures, immunomodulation by anti-seizure medications (ASMs), changes in ASM pharmacokinetics, and the potential for drug-drug interactions (DDIs). The goal of the Board of the Israeli League Against Epilepsy (the Israeli Chapter of the International League Against Epilepsy, ILAE) was to summarize the main principles of the pharmacological treatment of COVID-19 in patients with epilepsy. This guide was based on current literature, drug labels, and drug interaction resources. We summarized the available data related to the potential implications of anti-COVID-19 co-medication in patients treated with ASMs. Our recommendations refer to drug selection, dosing, and patient monitoring. Given the limited availability of data, some recommendations are based on general pharmacokinetic or pharmacodynamic principles and might apply to additional future drug combinations as novel treatments emerge. They do not replace evidence-based guidelines, should those become available. Awareness to drug characteristics that increase the risk of interactions can help adjust anti-COVID-19 and ASM treatment for patients with epilepsy.
Asunto(s)
Anticonvulsivantes , Antivirales , Tratamiento Farmacológico de COVID-19 , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia , Administración del Tratamiento Farmacológico , Anticonvulsivantes/clasificación , Anticonvulsivantes/farmacología , Antivirales/clasificación , Antivirales/farmacología , Comorbilidad , Monitoreo de Drogas/métodos , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Quimioterapia Combinada/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Humanos , Israel/epidemiología , Administración del Tratamiento Farmacológico/normas , Administración del Tratamiento Farmacológico/tendencias , Selección de Paciente , Guías de Práctica Clínica como Asunto , Ajuste de Riesgo/métodos , Ajuste de Riesgo/tendencias , SARS-CoV-2RESUMEN
A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.
Asunto(s)
Anestésicos por Inhalación/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/fisiopatología , Isoflurano/farmacología , Losartán/farmacología , Imagen por Resonancia Magnética/métodos , Estado Epiléptico/diagnóstico por imagen , Estado Epiléptico/fisiopatología , Anestesia por Inhalación , Anestésicos por Inhalación/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Animales , Biomarcadores , Barrera Hematoencefálica/efectos de los fármacos , Modelos Animales de Enfermedad , Electrocorticografía , Isoflurano/administración & dosificación , Losartán/administración & dosificación , Masculino , Estudios Prospectivos , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/tratamiento farmacológicoRESUMEN
BACKGROUND: A syndrome of profound hypotonia, intellectual disability, intrauterine growth retardation with subsequent failure to thrive, dyskinesia and epilepsy was diagnosed in Bedouin Israeli families. Mild dysmorphism was evident: plagiocephaly, broad forehead with prominent nose, smooth philtrum and congenital esotropia. We set out to decipher the molecular basis of this syndrome. METHODS: Genome-wide linkage analysis and fine mapping were done. Whole exome sequencing data were filtered for candidate variants within locus. Validation and segregation of the mutation was assayed via Sanger sequencing. UNC80 expression pattern was analysed through reverse transcription PCR. RESULTS: Homozygosity mapping followed by fine mapping identified a 7.5â Mb disease-associated locus (logarithm of odds score 3.5) on chromosome 2. Whole exome and Sanger sequencing identified a single homozygous nonsense mutation within this locus, segregating within the families as expected for recessive heredity and not found in a homozygous state in 150 Bedouin controls: c.151C>T, p.(R51*) in UNC80. CONCLUSIONS: The syndrome described is caused by a mutation in UNC80, truncating most of the 3258 amino acids highly conserved encoded protein, that has no known motifs. UNC80 bridges between UNC79 and the cation channel NALCN, enabling NALCN's role in basal Na(+) leak conductance in neurons, essential for neuronal function. The phenotype caused by the UNC80 mutation resembles that previously described for homozygous NALCN mutations.
Asunto(s)
Proteínas Portadoras/genética , Cationes/metabolismo , Codón sin Sentido/genética , Discinesias/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Hipotonía Muscular/genética , Canales de Sodio/genética , Epilepsia/genética , Exoma/genética , Femenino , Ligamiento Genético/genética , Homocigoto , Humanos , Canales Iónicos , Masculino , Neuronas , SíndromeRESUMEN
The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin.
Asunto(s)
Anticonvulsivantes/efectos adversos , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Árabes , Hipersensibilidad a las Drogas/epidemiología , Hipersensibilidad a las Drogas/etnología , Epilepsia/tratamiento farmacológico , Epilepsia/etnología , Femenino , Humanos , Incidencia , Israel/epidemiología , Israel/etnología , Judíos , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: The new Diagnostic Statistical Manual (DSM) requires the presence of fewer symptoms to make a diagnosis of adult ADHD while the criteria for diagnosis in childhood are unchanged as compared to previous editions. This study examines the prevalence of adults meeting the revised DSM-5 symptoms cutoff as compared to the previous DSM-IV symptoms cutoff. METHOD: This study is part of a larger nationwide study that evaluated the use of, and the attitudes toward, ADHD medications by university students. 445 students from four major university faculties were surveyed and filled out questionnaires for our study. RESULTS: The proportion of participants that met the minimum threshold of six out of nine current symptoms in either of the two DSM-IV symptom domains (inattentive presentation and hyperactive/impulsive presentation) for ADHD was 12.7% while the proportion that met the minimum threshold of five symptoms in either of the DSM-5 symptom domains was 21%. CONCLUSION: Since the new DSM requires fewer current symptoms for a diagnosis of ADHD, a significant increase (65%) was observed in the number of participants meeting the new cutoff as compared to the old DSM-IV symptoms cutoff. This increase in the number of adults meeting symptoms cutoff may affect the rates of adults diagnosed with ADHD. Using the new criteria may identify more adults with ADHD and fewer diagnoses will be missed. However, meeting the new symptoms cutoff should be considered within the overall clinical context to prevent over-diagnosis.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Adolescente , Adulto , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Docentes , Femenino , Humanos , Masculino , Proyectos Piloto , Prevalencia , Estudiantes/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
OBJECTIVES: To compare seizure burden between newborn infants treated with therapeutic hypothermia (TH) and those that were not and to compare the need for antiseizure medications (ASM) in a cohort of infants who were diagnosed with neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: This was a retrospective cohort study on infants born after 35 weeks' gestation, diagnosed with moderate to severe HIE, monitored with amplitude-integrated electroencephalography (aEEG) and eligible for TH. Infants born before the implementation of TH in 2008 were compared with infants born thereafter who received TH. Seizure burden was assessed from aEEG as total time in minutes of seizures activity per hour of recording. Other clinical and demographic data were retrieved from a prospective local database of infants with HIE. RESULTS: Overall, 149 of 207 infants were included in the study: 112 exposed to TH and 37 not exposed. Cooled infants had a lower seizure burden overall (0.4 vs 2.3 min/h, P < 0.001) and were also less likely to be treated with ASM (74% vs 100%, P < 0.001). In multivariable regression models, not exposed to TH, having a depressed aEEG background, and having higher Apgar scores were associated with higher seizure burden (incidence rate ratio: 4.78 for noncooled infants, P < 0.001); also, not exposed to TH was associated with a higher likelihood of multidrug ASM (odds ratio: 4.83, P < 0.001). CONCLUSIONS: TH in infants with moderate to severe HIE is associated with significant reduction of seizure burden and ASM therapy.
Asunto(s)
Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Recién Nacido , Lactante , Humanos , Estudios Retrospectivos , Estudios Prospectivos , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/diagnóstico , Convulsiones/terapia , Convulsiones/tratamiento farmacológico , Hipotermia Inducida/efectos adversos , ElectroencefalografíaRESUMEN
Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by PLP1 mutations. A similar autosomal-recessive phenotype, Pelizaeus-Merzbacher-like disease (PMLD), has been shown to be caused by homozygous mutations in GJC2 or HSPD1. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD in which linkage to PLP1, GJC2, and HSPD1 was excluded. Through genome-wide homozygosity mapping and mutation analysis, we demonstrated in all affected individuals a homozygous frameshift mutation that fully abrogates the main active domain of AIMP1, encoding ARS-interacting multifunctional protein 1. The mutation fully segregates with the disease-associated phenotype and was not found in 250 Bedouin controls. Our findings are in line with the previously demonstrated inability of mutant mice lacking the AIMP1/p43 ortholog to maintain axon integrity in the central and peripheral neural system.
Asunto(s)
Citocinas/genética , Homocigoto , Mutación , Proteínas de Neoplasias/genética , Enfermedad de Pelizaeus-Merzbacher/genética , Proteínas de Unión al ARN/genética , Adolescente , Adulto , Animales , Preescolar , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Masculino , Ratones , LinajeRESUMEN
OBJECTIVE: We assessed the neurologic manifestation of influenza among hospitalized children with influenza (neuro-flu), comparing their demographic and clinical characteristics to hospitalized children without neurologic manifestation (classic-flu). METHODS: A retrospective, cohort study. All children with laboratory confirmed influenza (PCR), admitted to the Soroka University Medical Center (SUMC) between 2016 and 2019 were included. RESULTS: Overall, 951 patients were identified: 201 with neuro-flu, and 750 with classic-flu. Seizures (n = 125) were the most common neurological manifestation of neuro-flu (seizure-flu): 73 simple febrile seizures, 45 atypical febrile seizures, and 7 afebrile seizures. Neurological comorbidities rates were significantly higher in neuro-flu versus classic-flu (13.0% vs. 6.0%), while respiratory and cardiac comorbidities were less common in neuro-flu (4.5% and 0.5% vs. 8.0% and 4.5%, respectively). Neuro-flu (compared with classic-flu) was associated with leukocytosis (21.0% vs. 13.0%, P < 0.001) and lower C-reactive protein (CRP) levels (2.4 ± 4.1 vs. 3.3 ± 5.4, P = 0.03). Notably, patients with classic flu had a more prominent respiratory disease, as they had more chest radiographs (CXR) performed (60.5% vs. 45.0%, P < 0.001), higher rates of pneumonia (27.0% vs. 12.0%, P < 0.001), and antibiotic (antibacterial) treatment (60.0% vs. 42.0%, P < 0.001). CONCLUSIONS: Influenza can appear as a neurologic disease, manifested mainly with febrile seizures. Children with neuro-flu have more neurologic comorbidities, suggesting that neuro-flu is mainly driven by host-factors, rather than by pathogen-factors. The relatively lower rates of pneumonia in neuro-flu suggests that these patients are admitted in the early stage of the influenza infection, which triggers the neurologic response.
Asunto(s)
Gripe Humana , Convulsiones Febriles , Humanos , Niño , Lactante , Gripe Humana/complicaciones , Gripe Humana/epidemiología , Estudios de Cohortes , Estudios Retrospectivos , Convulsiones/etiología , Convulsiones/complicacionesRESUMEN
BACKGROUND: Onasemnogene abeparvovec-xioi (OA) has been available since 2019 as a gene replacement therapy for individuals with spinal muscular atrophy (SMA) under age two years. We aim to expand upon the sparse knowledge about its safety and clinical efficacy. METHODS: The clinical outcome data of all the individuals with SMA who were treated with gene therapy in four tertiary hospitals in Israel were retrieved and analyzed. RESULTS: The study participants included 25 individuals who received the gene therapy between age 11 days and 23 months and whose median follow-up duration was 18.0 (interquartile range [IQR], 12.4 to 18.3) months. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores increased by a median (IQR) of 13 (8 to 20) points at the last follow-up compared with baseline. None of the patients experienced regression in motor abilities after gene therapy, which was generally well tolerated. There was gradual improvement in motor function, especially among presymptomatic patients (P ≤ 0.001) whose disease duration was shorter (≤8 months) before receiving gene therapy (P ≤ 0.001) and who did not experience recurrent infections and illnesses in the months following treatment (P ≤ 0.001). CONCLUSIONS: OA was well tolerated and led to favorable functional motor outcomes at six to 24 months after treatment initiation. Better progress in motor function was observed in individuals who received OA earlier and who were presymptomatic, irrespective of the SMN2 copy number or type. Our results further strengthen the clinical efficacy of OA and reinforce the importance of early recognition of SMA via newborn screening programs.
Asunto(s)
Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Lactante , Niño , Recién Nacido , Humanos , Preescolar , Atrofias Musculares Espinales de la Infancia/genética , Atrofias Musculares Espinales de la Infancia/terapia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Resultado del Tratamiento , Terapia Genética/efectos adversos , Tamizaje NeonatalRESUMEN
BACKGROUND: This study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death, and the identification of a gene involved in the pathogenesis of the disease. METHODS: Homozygosity mapping was performed using Affymetrix Human Mapping 250k NspI arrays. Sequencing of all coding exons of the candidate genes was performed with primer sets designed using the Primer3 program. Fluorescence activated cell sorting was performed using conjugated antibody to CD59. Staining, acquisition and analysis were performed on a FACSCalibur flow cytometer. RESULTS: Using homozygosity mapping, the study mapped the disease locus to 18q21.32-18q22.1 and identified the disease-causing mutation, c.2126GâA (p.Arg709Gln), in PIGN, which encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1, a protein involved in GPI-anchor biosynthesis. Arginine at the position 709 is a highly evolutionarily conserved residue located in the PigN domain. The expression of GPI linked protein CD59 on fibroblasts from patients as compared to that in a control individual showed a 10-fold reduction in expression, confirming the pathogenic consequences of the mutation on GPI dependent protein expression. CONCLUSIONS: The abundant expression of PIGN in various tissues is compatible with the diverse phenotypic features observed in the patients and with the involvement of multiple body systems. The presence of developmental delay, hypotonia, and epilepsy combined with multiple congenital anomalies, especially anorectal anomalies, should lead a clinician to suspect a GPI deficiency related disorder.
Asunto(s)
Anomalías Múltiples/genética , Antígenos CD59/genética , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 18/química , Glicosilfosfatidilinositoles/metabolismo , Fosfotransferasas/genética , Transferasas/genética , Anomalías Múltiples/etnología , Árabes/etnología , Secuencia de Bases , Antígenos CD59/metabolismo , Preescolar , Trastornos de los Cromosomas/etnología , Mapeo Cromosómico , Consanguinidad , Exones , Femenino , Citometría de Flujo , Homocigoto , Humanos , Lactante , Israel/epidemiología , Pérdida de Heterocigocidad , Masculino , Datos de Secuencia Molecular , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Alineación de Secuencia , SíndromeAsunto(s)
Antibacterianos/administración & dosificación , Encefalopatías , Brucella/aislamiento & purificación , Brucelosis , Meningitis Bacterianas , Anticonvulsivantes/administración & dosificación , Árabes , Encéfalo/diagnóstico por imagen , Encefalopatías/diagnóstico , Encefalopatías/microbiología , Encefalopatías/fisiopatología , Encefalopatías/terapia , Brucelosis/complicaciones , Brucelosis/diagnóstico , Niño , Angiografía por Tomografía Computarizada/métodos , Diagnóstico Diferencial , Electroencefalografía/métodos , Resultado Fatal , Escala de Coma de Glasgow , Humanos , Israel , Masculino , Meningitis Bacterianas/diagnóstico , Meningitis Bacterianas/microbiología , Meningitis Bacterianas/fisiopatología , Meningitis Bacterianas/terapia , Examen Neurológico/métodos , Respiración Artificial/métodos , Tiempo de TratamientoRESUMEN
Carbon monoxide (CO) poisoning is a serious health problem. The main pathophysiological mechanism of acute CO poisoning is hypoxia due to the formation of carboxyhemoglobin (COHb). Delayed neuropsychiatric sequel (DNPS) occurs following an interval of several days to several weeks post-CO exposure and can present in many different manifestations, ranging from behavioral and mood disorders to encephalopathy and seizures and cause long-term neuropsychiatric sequel. The pathogenesis of DNPS following CO poisoning is a complex one that encompasses hypoxia-induced encephalopathy as well as inflammation, direct cellular changes and damage. The incidence varies and treatment is debated. We display a case of a previously healthy 13-year-old boy suffering from DNPS, presenting with seizures and encephalopathy and later developing optic nerve damage. Increased awareness to this condition might help diagnose future patients and aid in the understanding of the pathogenesis and treatment options for this poorly understood condition.
RESUMEN
We aimed to confirm or reject previous reports on the association of prenatal antibiotic exposure and development of epilepsy in offspring by accounting for known and unidentified confounding factors. In a retrospective cohort investigation, we enrolled children aged 3-18 years born between 1998 and 2012 at a single regional hospital and their mothers. A computerized medication database was linked with hospital records. The exposed group included children whose mothers purchased 1 or more antibiotic medications for use during pregnancy. Epilepsy was defined by epilepsy diagnosis and/or by chronic dispensing of antiepileptic drugs. We analyzed maternal exposure to antibiotics 2 years after delivery (but not during pregnancy and/or the 2 years following delivery) as part of the specificity analysis. We enrolled 88 899 children and their 74 416 mothers. The group exposed prenatally to antibiotics comprised 36 622 children (41.2%). Of them, 326 (0.9%) developed epilepsy compared with 370 of 52 277 (0.7%) in the unexposed group (relative risk [RR], 1.24; 95% confidence interval [CI], 1.07-1.44: P = .004). Exposure during the first, second, and third trimesters was characterized by incidence of epilepsy in 0.8% (P = .943), 0.9% (P = .266), and 0.9% (P = .073) of children, respectively, compared with the unexposed group, with an RR of 1.01 (95%CI, 0.83-1.23), 1.12 (95%CI, 0.92-1.36), and 1.19 (95%CI, 0.98-1.45), respectively. Similarly, prenatal exposure by antibiotic class was associated with epilepsy. Nevertheless, the specificity analysis strongly suggested the possibility of confounding by indication. Our findings indicated that pregnant women should receive the indicated antibiotic treatment with no fear of the development of epilepsy in their children.
Asunto(s)
Antibacterianos/administración & dosificación , Epilepsia/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Adolescente , Anticonvulsivantes/administración & dosificación , Niño , Preescolar , Femenino , Humanos , Masculino , Embarazo , Trimestres del Embarazo , Estudios Retrospectivos , Riesgo , Factores SociodemográficosRESUMEN
BACKGROUND: The incidence of seizures in the neonatal period is thought to be high due to a lower seizure threshold of the immature brain. Data on seizures in extremely premature infants are scarce. OBJECTIVES: The aim of this study was to determine whether seizures are an independent risk factor for in-hospital death and to determine the incidence of seizures in extremely premature infants. METHODS: This was a retrospective cohort study. Included were infants born under 28 weeks' gestation and monitored with amplitude-integrated electroencephalography (aEEG) over the first 3 days of life. The number and duration of seizures was retrieved from aEEG recordings together with clinical data. The association of seizures and other parameters with mortality was assessed using univariable analyses methods. Relevant parameters were used for a multivariable Cox regression analysis. RESULTS: Overall, 229 infants were included in the study. Forty-six infants had at least one seizure episode yielding an incidence of 20%. In univariable analyses, gestational age (p < 0.001), birthweight Z-score (p < 0.001), seizures (p = 0.025), suppressed background aEEG (p < 0.001), and severe intraventricular hemorrhage (IVH; p < 0.001) were associated with death before discharge. In multivariable analysis, gestational age (HR = 0.61, p < 0.001), background aEEG activity (HR = 0.30, p < 0.001), birth weight Z-score (HR = 0.51, p = 0.04), and severe IVH (HR = 2.60, p < 0.001) were found to be significant predictors of mortality while the presence of seizures in the first 3 days of life trended to significantly predict an increased risk of mortality (HR = 1.53, p = 0.09). CONCLUSIONS: Although seizure incidence was relatively high in this cohort of extremely preterm infants and infants with seizures were more likely to die, seizures alone are not a predictor for early death. However, they may be an important indicator of pathologies that are not immediately diagnosed yet could eventually lead to death among this vulnerable population.
Asunto(s)
Encéfalo/fisiopatología , Recien Nacido Extremadamente Prematuro , Convulsiones/epidemiología , Peso al Nacer , Hemorragia Cerebral/mortalidad , Hemorragia Cerebral/fisiopatología , Electroencefalografía , Femenino , Edad Gestacional , Humanos , Incidencia , Recién Nacido , Israel/epidemiología , Masculino , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Convulsiones/mortalidadRESUMEN
BACKGROUND: Most Israeli males aged 16-17 undergo a thorough medical examination prior to recruitment into the army. During the last 50 years, extensive data have been gathered enabling a study of time trends in the prevalence of common diseases in this age group. OBJECTIVES: To examine the current prevalence of common diseases, compare the results with those of previous cohorts, and assess the influence of the massive immigration during the 1990s. METHODS: The health examination at the recruitment centers includes a medical history, complete physical examination, and review of medical documentation provided by the family physician. If needed, additional tests and referral to specialists are ordered. The prevalence of selected diseases and severity was drawn from the computerized database of the classification board. Two cohorts, 1992-94 and 2003-04, were examined and compared with three previous cohort studies in 1957-61, 1977-78 and 1982-84. Data were stratified according to origin and country of birth. RESULTS: The prevalence of asthma increased dramatically during the years from 10.2 per 1000 examinees in 1957-61 to 111.6 per 1000 examinees in 2003-04. The prevalence of tuberculosis declined and then increased from 0.6 per 1000 adolescents in 1982-84 to 2.4 per 1000 adolescents in 2003-04. The prevalence of type 1 diabetes mellitus increased from 0.2 cases per 1000 examinees in 1957-61 to 0.8 cases in 1977-78 and 1982-84 and 0.9 cases per 1000 examinees in 2003-04. The prevalence of severe heart defects and severe epilepsy declined in the last 20 years (1.4 and 1.7 cases per 1000 examinees in the 1982-84 cohort to 0.4 and 0.3 cases per 1000 examinees in the 2003-4 cohort respectively). The patterns of disease prevalence were different for immigrants: tuberculosis was more common while asthma and allergic rhinitis were less prevalent. CONCLUSIONS: The prevalence of common diseases among adolescents in Israel has changed over the last 50 years. There is a different pattern for immigrants and for those born in Israel.