RESUMO
Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.
Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda , Lisencefalia , Malformações do Sistema Nervoso , Humanos , Animais , Camundongos , Lisencefalia/genética , Alelos , Tubulina (Proteína)/genética , Fenótipo , Malformações do Sistema Nervoso/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genéticaRESUMO
BACKGROUND: ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. AIM: We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients. METHODS: A retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program. RESULTS: Patients (age 2.5-20â¯years) had symptom onset at an early age (6â¯days-1â¯year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3â¯years, range 6â¯weeks-4.8â¯years) with some improvements reported in all five. CONCLUSIONS: Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure-function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.
Assuntos
Encefalopatias , Epilepsia , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Mutação/genética , Estudos Retrospectivos , ATPase Trocadora de Sódio-Potássio/genética , Adulto JovemRESUMO
OBJECTIVE: Vagus nerve stimulation (VNS) Therapy is routinely indicated for people with drug-resistant epilepsy (DRE). We analyzed the baseline characteristics of individuals receiving the recently released VNS models and identified factors associated with early or late implantation. METHODS: The Comprehensive Outcomes Registry of subjects with Epilepsy (CORE-VNS), a prospective observational study evaluating the clinical and psychosocial outcomes of VNS Therapy®, is following participants for up to 60 months after VNS implantation. In this analysis, we used Cox proportional hazards model to identify baseline characteristics associated with the time from diagnosis to first implantation. RESULTS: Of the 819 enrolled, 792 (96.7%) participants implanted with a VNS device were evaluated. 529 (64.6%) underwent the first implantation and 263 (32.1%) a re-implantation. Participants' median age at first implant was 24 years; 492 (62.1%) were ≥18 years old and 166 (20.3%) were < 12 years old. The average number of failed ASMs prior to VNS implantation was 7.1, and 145 (17.7%) had undergone previous epilepsy-related surgery. Epilepsy was classified as focal in 47.7% of participants, generalized in 16.1% and combined focal and generalized in 34.2%. Many of the participants (40.9%) had epilepsy of unknown etiology. The median time from diagnosis to first implantation was 10.33 years and was significantly shorter in participants with combined focal and generalized epilepsy compared to those with focal epilepsy alone, and in participants with genetic and immune epilepsy compared to those with unknown etiologies. SIGNIFICANCE: In people with DRE, VNS Therapy is provided after multiple failures of ASMs and after failure of epilepsy surgery in one in six individuals. Time from diagnosis to first implantation is associated with epilepsy type and etiology, likely reflecting variable treatment pathways. Clearer guidelines on when and how non-drug therapies should be deployed in people with DRE related to different epilepsy factors are needed. PLAIN LANGUAGE SUMMARY: Neuromodulation can be a very helpful treatment in people who have seizures that do not respond to medications. The most widely utilized neuromodulation therapy is vagus nerve stimulation (VNS). We present data from a large, global study to show that people use an average of seven anti-seizure medications before attempting VNS Therapy and that it takes about 10 years for people to get their first VNS implant. We advocate for clearer treatment guidelines on how and when to consider VNS Therapy in people with seizures that are resistant to medication.
RESUMO
BACKGROUND: Responsibilities of Program Directors' (PDs) and Program Coordinators' (PCs) roles continue to evolve within Graduate Medical Education (GME). METHODS: In 2016, the authors conducted an anonymous electronic survey of Child Neurology and Neurodevelopmental Disabilities PDs (n = 76) and PCs (n = 68) to address workforce characteristics, challenges related to implementing Accreditation Council of Graduate Medical Education (ACGME) requirements, and institutional support. Responses were characterized with descriptive statistics. RESULTS: Response rate was 72% (46 of 76 PDs, 57 of 68 PCs). PD median clinical workloads were five half-day clinics weekly plus three months as hospital attending yearly. Most PDs (61%) reported having less, and many (43%) believed requirements were less, protected time than the ACGME requires. Most PCs have clerical titles (58%), no designated GME career path (79%), inaccurate job descriptions (86%), little to no formal GME training (61%), work-hours exceeding those scheduled (68%), and time allocation below ACGME recommendations (69%). More than half (54%) of hourly PCs reported responding to communications after hours, with nearly all (92%) unpaid for such work. Shared PD-PC concerns include faculty completion of resident evaluations (80%), inadequate protected time (71%), and low PC salary (70%). For both PDs and PCs, median time in the job was four years. CONCLUSIONS: Child neurology and neurodevelopmental disability residency PDs and PCs report problems that likely increase turnover and interfere with training. The ACGME should consider revising, formalizing, and disseminating requirements for protected time for PDs and PCs, based on realistic assessments of current administrative requirements, and monitoring compliance as part of program evaluations.
Assuntos
Internato e Residência/organização & administração , Papel Profissional , Docentes/psicologia , Humanos , Neurologia/educação , Pediatria/educação , Papel Profissional/psicologia , Inquéritos e Questionários , Recursos HumanosRESUMO
Intractable epilepsy is a common diagnosis among child neurology practitioners with medical management remaining unsatisfactory in many cases. GLUT1 deficiency syndrome (GLUT1-DS) is a disorder that should be considered in such situations. Evaluation by comparing serum to CSF glucose levels is a fast and relatively easy test, with hypoglycorrhachia being highly suggestive of GLUT1-DS. Furthermore, treatment with the ketogenic diet is well-established and can result in significant improvement in quality of life for these patients. The following case report outlines the presentation of one such patient and highlights common features that can be seen with GLUT1-DS. Of interest, she was found to have a spontaneous, novel mutation that has not been reported previously. Her case allows us to expand on the present literature and demonstrate the improvements that can be seen in a child with appropriate treatment.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Proteínas de Transporte de Monossacarídeos/deficiência , Ataxia/dietoterapia , Ataxia/genética , Erros Inatos do Metabolismo dos Carboidratos/dietoterapia , Erros Inatos do Metabolismo dos Carboidratos/genética , Dieta Cetogênica , Feminino , Humanos , Lactente , Proteínas de Transporte de Monossacarídeos/genética , Mutação/genética , Convulsões/dietoterapia , Convulsões/genéticaRESUMO
A colorimetric DNA hybridization-based assay has been evaluated against two conventional culture methods (FDA and USDA) for detection of Listeria spp. in dairy, Meat, and seafood products. A total of 1,300 samples representing 15 food types were analyzed in parallel by both the DNA hybridization (DNAH) and culture methods (FDA for dairy products and seafoods, USDA for meats). Samples included inoculated and naturally contaminated products and uninoculated controls. Fifteen strains representing five species of Listeria were used as inocula. Of 660 dairy and seafood samples tested, the FDA culture method detected 354 positives and the DNAH method detected 393 positives, 391 of which were confirmed. The DNAH method was statistically equivalent to the FDA method for eight of the nine products tested. In some trials, the DNAH method detected more positives than the FDA method for cheddar cheese and in some cases these differences were statistically significant. Of 540 meat samples tested, the USDA culture method detected 261 positives and the DNAH method detected 378 positives, all of which were confirmed. The DNAH method was statistically equivalent to the culture method for three of the six products tested. In some trials, the DNAH method detected more positives than the USDA method for roast beef, hot dogs, and fermented sausage. In some cases, these differences were statistically significant. Of 100 naturally contaminated products tested, the DNAH method detected 86 positives and the culture methods detected 84 positives. The DNAH method was statistically equivalent to the culture methods for these samples. The DNAH method gives a negative result 48 h after the start of sample enrichment, whereas the FDA and USDA methods require 3 to 4 days or longer. It is concluded that the DNAH assay is a rapid, accurate, and objective alternative to the culture procedures for the detection of Listeria spp. in foods.