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Genomic repeat sequences are patterns of nucleic acids that exist in multiple copies throughout the genome. More than 60 Mendelian disorders are caused by the expansion or contraction of these repeats. Various specific methods for determining tandem repeat variations have been developed. However, these methods are highly specific to the genomic region being studied and sometimes require specialized tools. In this study, we have investigated the use of Optical Genome Mapping (OGM) as a diagnostic tool for detecting repeat disorders. We evaluated 19 patients with a prediagnosis of repeat disorders and explained the molecular etiology of 9 of them with OGM (5 patients with Facioscapulohumeral Muscular Dystrophy (FSHD), 2 patients with Friedreich's Ataxia (FA), 1 patient with Fragile X Syndrome (FXS), and 1 patient with Progressive Myoclonic Epilepsy 1A (EPM1A)). We confirmed OGM results with more widely used fragment analysis techniques. This study highlights the utility of OGM as a diagnostic tool for repeat expansion and contraction diseases such as FA, FXS, EPM1A, and FSHD.
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PURPOSE: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants. METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.
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Encefalopatias , Distonia , Transtornos dos Movimentos , Humanos , Animais , Ratos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/genética , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Transtornos dos Movimentos/genética , Aminas , Encéfalo/metabolismoRESUMO
BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.
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Deficiência Intelectual , Tabagismo , Humanos , Deficiência Intelectual/genética , Lisina/genética , Tabagismo/genética , Testes Genéticos , Canais Iônicos/genéticaRESUMO
BACKGROUND AND OBJECTIVE: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. METHODS: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. RESULTS: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. CONCLUSIONS: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Coreia , Distonia , Distúrbios Distônicos , Transtornos dos Movimentos , Criança , Humanos , Hipercinese , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/diagnóstico , Distúrbios Distônicos/genética , Coreia/diagnóstico , Coreia/genética , Proteínas do Tecido Nervoso , Fatores de Transcrição Forkhead , Diester Fosfórico Hidrolases , ATPase Trocadora de Sódio-Potássio , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genéticaRESUMO
Hereditary lower motor neuron diseases (LMND) other than 5q-spinal muscular atrophy (5q-SMA) can be classified according to affected muscle groups. Proximal and distal forms of non-5q-SMA represent a clinically and genetically heterogeneous spectrum characterized by significant overlaps with axonal forms of Charcot-Marie-Tooth (CMT) disease. A consensus for the best approach to molecular diagnosis needs to be reached, especially in light of continuous novel gene discovery and falling costs of next-generation sequencing (NGS). We performed exome sequencing (ES) in 41 families presenting with non-5q-SMA or axonal CMT, 25 of which had undergone a previous negative neuromuscular disease (NMD) gene panel analysis. The total diagnostic yield of ES was 41%. Diagnostic success in the cohort with a previous NMD-panel analysis was significantly extended by ES, primarily due to novel gene associated-phenotypes and uncharacteristic phenotypic presentations. We recommend early ES for individuals with hereditary LMND presenting uncharacteristic or significantly overlapping features. As mitochondrial dysfunction was the underlying pathomechanism in 47% of the solved individuals, we highlight the sensitivity of the anterior horn cell and peripheral nerve to mitochondrial imbalance as well as the necessity to screen for mitochondrial disorders in individuals presenting predominant lower motor neuron symptoms.
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Doença de Charcot-Marie-Tooth , Atrofia Muscular Espinal , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mitocôndrias/genética , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genéticaRESUMO
PURPOSE: Sulthiame (STM) has been recommended as an effective antiepileptic drug (AED) in children with epileptic encephalopathy with status epilepticus in sleep (ESES). The aim of this study is to evaluate the efficacy of STM add-on treatment in children with pattern of ESES with respect to the etiologic subgroup. METHODS: Twenty-nine children with ESES pattern with three different etiologic subgroups (epileptic syndromes: 14, structural/infectious: 9, unknown: 6) who were given STM as add-on treatment were included into the study. The efficacy of STM was evaluated in terms of seizure control, electroencephalography (EEG) findings, need of the new AEDs after add-on STM, and behavioral and cognitive improvement. RESULTS: The range of the follow-up duration after add-on STM treatment was between 5 and 51 months. At the end of 1 year of STM treatment, the most successful electrophysiologic improvement was identified in the well-defined epileptic syndrome group; epileptic syndrome, 71.4% (10/14); structural/infectious, 33.3% (3/9); and unknown, 0% (0/6). Patients who had complete response or persistent ESES pattern at the 3rd month were still in the same condition at the 6th and 12th months. However, the ESES pattern reappeared in 35.2% of the patients who had partial electrophysiological improvement at the 3rd month. In the epilepsy syndrome group, eight out of ten patients who had either complete or partial EEG response after 1 year of STM treatment displayed behavioral and cognitive improvement. CONCLUSION: Sulthiame might be a valid add-on treatment of ESES especially in children with epilepsy syndromes.
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Transtornos do Sono-Vigília , Estado Epiléptico , Tiazinas , Anticonvulsivantes/uso terapêutico , Criança , Eletroencefalografia , Humanos , Estudos Retrospectivos , Sono , Transtornos do Sono-Vigília/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Tiazinas/uso terapêuticoRESUMO
AIM: Developmental and epileptic encephalopathies (DEEs) are a group of devastating disorders caused by epileptic activity, resulting in deterioration in developmental, cognitive, and motor functions. The number of genes identified as being responsible for DEEs has been increasing rapidly. However, despite a comprehensive molecular analysis, a molecular diagnosis can only be established in 50% of cases. The aim of this project is to use whole exome sequencing (WES) to determine the molecular etiology of DEEs in undiagnosed patients with a pedigree suggestive of an autosomal recessive single gene disease. METHODS: Three DEE families, having either consanguineous parents of an affected individual and/or having more than one affected offspring, were enrolled in the project. Prior to this project, the families had been evaluated using a next-generation sequencing panel including 16 DEE genes in a previous study; however, no molecular diagnosis could be established. In five cases from the three selected DEEs families in our study, the genetic etiology was investigated using WES. RESULTS: All patients in the study group had infantile onset epileptic seizures; however, semiologies varied. All patients presented with severe developmental delay. WES revealed biallelic disease causing mutations in DENDD5A, GRN, and TBCD genes in family 1, family 2, and family 3, respectively. In each family, the identified variants associated with the disease were segregated. Reverse phenotyping supported the molecular analysis. CONCLUSION: This study provided a valuable contribution to the genotype-phenotype relationship by determining rare epilepsy syndromes in undiagnosed patients previously. WES is a useful diagnostic alternative, particularly in consanguineous families.
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Encefalopatias , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas Associadas aos Microtúbulos , Mutação/genética , Linhagem , Fenótipo , Sequenciamento do ExomaRESUMO
Craniocervical arterial dissection is an important cause of arterial ischemic stroke in children. Recognition of dissections is of particular importance both in determining the risk of recurrence and in bringing about different treatment alternatives. We report a 10-year-old girl who presented with acute ischemic stroke due to spontaneous long segment dissection involving the parasellar internal carotid artery up to the distal M1 portion of the middle cerebral artery. Three-dimensional digital subtraction angiography with flat panel detector revealed the presence of major vessels originating from both true and false lumens and had a critical role in the treatment decision of the case.
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Isquemia Encefálica , Dissecação da Artéria Carótida Interna , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/etiologia , Dissecação da Artéria Carótida Interna/complicações , Dissecação da Artéria Carótida Interna/diagnóstico por imagem , Angiografia Cerebral , Criança , Dissecação , Feminino , Humanos , Angiografia por Ressonância Magnética , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologiaRESUMO
Biotinidase deficiency is characterized by severe neurological manifestations as hypotonia, lethargy, ataxia, hearing loss, seizures and developmental retardation in its classical form. Late-onset biotinidase deficiency presents distinctly from the classical form such as limb weakness and vision problems. A 14-year-old boy presented with progressive vision loss and upper limb weakness. The patient was initiated steroid therapy with a preliminary diagnosis of neuromyelitis optica spectrum disorder due to the craniospinal imaging findings demonstrating optic nerve, brainstem and longitudinally extensive spinal cord involvement. Although the patient exhibited partial clinical improvement after pulse steroid therapy, craniocervical imaging performed one month after the initiation of steroid therapy did not show any regression. The CSF IgG index was <0.8 (normal: <0.8), oligoclonal band and aquaporin-4 antibodies were negative. Metabolic investigations revealed a low biotinidase enzyme activity 8% (0.58 nmoL/min/mL; normal range: 4.4 to 12). Genetic testing showed c.98-104delinsTCC and p.V457 M mutations in biotinidase (BTD) gene. At the third month of biotin replacement therapy, control craniospinal MRI demonstrated a complete regression of the lesions. The muscle strength of the case returned to normal. His visual acuity was 7/10 in the left eye and 9/10 in the right. The late-onset form of the biotinidase deficiency should be kept in mind in all patients with myelopathy with or without vision loss, particularly in those with inadequate response to steroid therapy. The family screening is important to identify asymptomatic individuals and timely treatment.
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Biotina/uso terapêutico , Deficiência de Biotinidase/diagnóstico por imagem , Neuromielite Óptica/diagnóstico por imagem , Doenças da Medula Espinal/diagnóstico por imagem , Transtornos da Visão/diagnóstico por imagem , Adolescente , Deficiência de Biotinidase/complicações , Deficiência de Biotinidase/tratamento farmacológico , Diagnóstico Diferencial , Humanos , Masculino , Neuromielite Óptica/complicações , Neuromielite Óptica/tratamento farmacológico , Doenças da Medula Espinal/complicações , Doenças da Medula Espinal/tratamento farmacológico , Resultado do Tratamento , Transtornos da Visão/complicações , Transtornos da Visão/tratamento farmacológicoRESUMO
The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.
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Encefalopatias/genética , Encéfalo/anormalidades , Análise Mutacional de DNA/métodos , Proteínas do Tecido Nervoso/genética , Animais , Sequência de Bases , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Encefalopatias/patologia , Proteínas de Ciclo Celular , Feminino , Genes Recessivos , Humanos , Masculino , Camundongos , Microcefalia/genética , Microcefalia/patologia , Dados de Sequência Molecular , Mutação , Proteínas do Tecido Nervoso/metabolismo , LinhagemRESUMO
BACKGROUND: Ictal urinary urge is a rare autonomic symptom usually lateralizing to the non-dominant hemisphere and localizing to the temporal lobe. CASE REPORT: A 12-year-old boy was referred with desire to void and contraction of the left arm. The history of the case revealed tickling and an unpleasant rising feeling in the stomach and sense of fear lasting for 1 year. He had been evaluated and treated several times with the diagnosis of gastroesophageal reflux and cystitis. His cranial MRI displayed an intra-axial mass formation on the right temporal lobe. Pathological findings were consistent with a low-grade glial mass. CONCLUSION: Ictal urinary urge has a considerable value both for localization and lateralization of seizures.
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Epilepsia do Lobo Temporal/complicações , Lateralidade Funcional , Lobo Temporal/fisiopatologia , Incontinência Urinária de Urgência/etiologia , Criança , Epilepsia do Lobo Temporal/patologia , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
BACKGROUND: Accurate classification is essential for addressing childhood movement disorders (MD), but the common coexistence of multiple MDs complicates this process. OBJECTIVE: The aim was to assess inter-rater agreement on classifying hyperkinetic MDs among pediatric neurologists with expertise in MDs. METHODS: Five pediatric neurologists were requested to examine 112 videos of 66 pediatric patients. Based on the Movement Disorder-Childhood Rating Scale, 3 queries were posed: (Q1) Is there more than 1 MD? (Q2) What is the (predominant) MD? (Q3) What is the other MD (if present)? RESULTS: The final agreement rates were 57.5% for Q1, 66.6% for Q2, and 43.9% for absolute agreement. All videos with absolute agreement at the first evaluation featured 1 MD, whereas only 2 videos with multiple MDs could totally agree in the final review. CONCLUSIONS: This study reveals significant discordance in classification even among pediatric neurologists with expertise in MDs and highlights the necessity for a standardized approach.
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BACKGROUND: To compare the amplitude-integrated electroencephalography (aEEG) monitoring (short-term versus prolonged-period) for neonatal seizure detection and outcome. METHODS: The aEEG monitoring in a historical cohort (n = 88, preterm:42, and term:46) with neonatal encephalopathy between 2010-2022 was re-evaluated for neonatal seizures (electrographic, electro-clinical, and clinical seizures) and EEG background scoring. The cohort was dichotomized: group I (short-period with 6-12 h, n = 36) and group II (prolonged-period with 24-48 h, n = 52). Both monitoring types were evaluated for the diagnostic accuracy of the "patients with seizures" and for outcome characteristics (early death as well as adverse outcomes at 12 months of age). RESULTS: A total of 67 (76 %) neonates of the cohort were diagnosed as "patients with seizures": electrographic-only seizures in 10 (15 %), electro-clinical seizures in 22 (33 %), and clinical-only seizures in 35 (52 %). The aEEG provides the "patients with seizures" in neonates with a 36.5 % rate with both types of monitoring: 17/36 (47.2 %) with short-term and 15/52 (28.8 %) with prolonged-period monitoring. The prolonged period aEEG had higher diagnostic values for seizure detection (sensitivity = 0.73 and negative predictivity value = 0.81). However, the aEEG background scores were similar for both types of aEEG monitoring, respectively (the mean ± SD: 4.73 ± 2.9 versus 4.4 ± 4. p = 0.837). The aEEG scoring was correlated with the magnitude of brain injury documented with MRI, the early death, and the adverse outcome at 12 months of age. CONCLUSIONS: Both aEEG types are valuable for monitoring the "patients with seizures" and outcome characteristics.
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Eletroencefalografia , Convulsões , Humanos , Eletroencefalografia/métodos , Recém-Nascido , Masculino , Feminino , Convulsões/diagnóstico , Convulsões/fisiopatologia , Estudos de Coortes , Encefalopatias/diagnóstico , Encefalopatias/fisiopatologia , Fatores de Tempo , Lactente , Estudos RetrospectivosRESUMO
BACKGROUND: To evaluate the utility of genetic testing for etiology-specific diagnosis (ESD) in infantile epileptic spasms syndrome (IESS) with a step-based diagnostic approach in the next-generation sequencing (NGS) era. METHODS: The study cohort consisted of 314 patients with IESS, followed by the Pediatric Neurology Division of Ege University Hospital between 2005 and 2021. The ESD was evaluated using a step-based approach: step I (clinical phenomenology), step II (neuroimaging), step III (metabolic screening), and step IV (genetic testing). The diagnostic utility of genetic testing was evaluated to compare the early-NGS period (2005 to 2013, n = 183) and the NGS era (2014 to 2021, n = 131). RESULTS: An ESD was established in 221 of 314 (70.4%) infants with IESS: structural, 40.8%; genetic, 17.2%; metabolic, 8.3%; immune-infectious, 4.1%. The diagnostic yield of genetic testing increased from 8.9% to 41.7% in the cohort during the four follow-up periods. The rate of unknown etiology decreased from 34.9% to 22.1% during the follow-up periods. The genetic ESD was established as 27.4% with genetic testing in the NGS era. The genetic testing in the NGS era increased dramatically in subgroups with unknown and structural etiologies. The diagnostic yields of the epilepsy panels increased from 7.6% to 19.2%. However, the diagnostic yield of whole exome sequencing remained at similar levels during the early-NGS period at 54.5% and in the NGS era at 59%. CONCLUSIONS: The more genetic ESD (27.4%) was defined for IESS in the NGS era with the implication of precision therapy (37.7%).
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Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Espasmos Infantis , Humanos , Espasmos Infantis/genética , Espasmos Infantis/diagnóstico , Lactente , Masculino , Feminino , Estudos de CoortesRESUMO
BACKGROUND: Various etiologies may underlie optic neuritis, including autoantibody-mediated disorders described in the last decade. We re-examined demographic, clinical, laboratory features and prognostic factors in pediatric patients with autoimmune optic neuritis according to current knowledge. METHODS: Cases of pediatric ON from 27 centers in Türkiye diagnosed between 2009 and 2022 were included for retrospective evaluation. RESULTS: The study included 279 patients, 174 females and 105 males, with a female-to-male ratio of 1.65. The average age at onset was 12.8 ± 3.4 years, and mean follow-up, 2.1 years (range: 1-12.1 years). Patients <10 years old were grouped as "prepubertal" and those ≥10 years old as "others". The diagnoses made at the end of follow-up were multiple sclerosis associated optic neuritis (n = 90, 32.3 %), single isolated optic neuritis (n = 86, 31 %), clinically isolated syndrome (n = 41, 14.7 %), myelin oligodendrocyte glycoprotein antibody associated optic neuritis (n = 22, 7.9 %), and relapsing isolated optic neuritis (n = 18, 6.5 %). Predominant diagnoses were myelin oligodendrocyte glycoprotein antibody associated optic neuritis and acute disseminated encephalomyelitis associated optic neuritis in the prepubertal group and multiple sclerosis associated optic neuritis in the older group. Recurrences were observed in 67 (24 %) patients, including 28 with multiple sclerosis associated optic neuritis, 18 with relapsing isolated optic neuritis, 11 with myelin oligodendrocyte glycoprotein antibody associated optic neuritis, 8 with aquaporin-4 antibody related optic neuritis, and 2 with chronic relapsing inflammatory optic neuropathy. Recurrences were more common among female patients. Findings supporting the diagnosis of multiple sclerosis included age of onset ≥ 10 years (OR=1.24, p = 0.027), the presence of cranial MRI lesions (OR=26.92, p<0.001), and oligoclonal bands (OR=9.7, p = 0.001). Treatment in the acute phase consisted of intravenous pulse methylprednisolone (n = 46, 16.5 %), pulse methylprednisolone with an oral taper (n = 212, 76 %), and combinations of pulse methylprednisolone, plasmapheresis, or intravenous immunoglobulin (n = 21, 7.5 %). Outcome at 12 months was satisfactory, with 247 out of 279 patients (88.5 %) demonstrating complete recovery. Thirty-two patients exhibited incomplete recovery and further combination treatments were applied. Specifically, patients with relapsing isolated optic neuritis and aquaporin-4 antibody related optic neuritis displayed a less favorable prognosis. CONCLUSION: Our results suggest optic neuritis is frequently bilateral in prepubertal and unilateral in peri or postpubertal patients. Age of onset 10 or older, presence of oligoclonal bands, and brain MRI findings reliably predict the development of multiple sclerosis. The risk of developing multiple sclerosis increases mostly during the second and third years of follow-up. Relapsing isolated optic neuritis remains a separate group where the pathogenesis and outcome remain unclear. Investigation of predisposing and diagnostic biomarkers and long follow-up could help to define this group.
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Aquaporinas , Esclerose Múltipla , Neuromielite Óptica , Neurite Óptica , Humanos , Masculino , Adolescente , Feminino , Criança , Estudos Retrospectivos , Glicoproteína Mielina-Oligodendrócito , Bandas Oligoclonais , Turquia/epidemiologia , Neurite Óptica/diagnóstico , Esclerose Múltipla/complicações , Autoanticorpos , Metilprednisolona , Aquaporina 4 , Neuromielite Óptica/complicaçõesRESUMO
Cerebral folate deficiency (CFD) syndrome is a rare treatable neurometabolic disorder with low levels of the active form of folaten in cerebrospinal fluid (CSF) arising from different causes such as FOLR1 gene mutations or autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus. It is characterized by late infantile onset refractory seizures, ataxia, movement disorder, and unexplained global developmental delay. Here, we report a patient diagnosed with autistic spectrum disorder, followed by refractory myoclonic-atonic seizures, ataxia, and loss of motor skills over time. A homozygous missense (c.665A > G) mutation in FOLR1 gene and extremely low CSF 5-methyltetrahydrofolate level led to the diagnosis of CFD. Although she was initiated on combined oral and intravenous high doses of folinic acid treatment at 6 years of age, mild improvement was achieved in terms of epileptic seizures and motor skills. It is important that CFD should be kept in mind in cases with refractory myoclonic-atonic seizure and folinic acid treatment should be started as soon as possible.
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Deficiência de Ácido Fólico , Feminino , Humanos , Leucovorina/uso terapêutico , Leucovorina/genética , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/tratamento farmacológico , Deficiência de Ácido Fólico/genética , Mutação/genética , Ataxia , Receptor 1 de Folato/genética , Receptor 1 de Folato/uso terapêuticoRESUMO
OBJECTIVE: The aim of this study was to evaluate the adaptability of pediatric residents to the current seizure classification of the International League Against Epilepsy-2017 (ILAE-2017) using a modular education program (MEP). MATERIALS AND METHODS: The MEP design consisted of 8 modules, including 5 modules for the current version of the ILAE-2017 seizure classification and 3 modules for the older ILAE-1981 version. The MEP was implemented with a group of pediatric residents, and it comprised 50 illustrative pediatric seizure videos along with an instruction manual kit that included a seizure determinator. Following a 3-month follow-up period, a posttest was conducted using 58 new videos in the MEP. RESULTS: The overall success rates of the participants were similar both ILAE-2017 (41%) and ILAE-1981 (38.5%) seizure classifications in the post-MEP test. Regarding the ILAE-2017 mod- ules, the participants demonstrated a higher proficiency in classifying focal nonmotor seizures (56.3%) compared to focal motor seizures (34.9%). However, when it came to generalized seizures, the participants had significantly lower accuracy rates for generalized nonmotor seizures (26%) compared to generalized motor seizures (46%) with the ILAE-2017 classifica- tion. The seizure types that were most commonly misclassified, with an error rate exceeding 50%, were automatisms and myoclonic seizures within the focal seizure modules and atypical absences in generalized seizure modules of ILAE-2017. CONCLUSION: The single-day MEP yielded modest results, with a success rate of 41% in terms of the initial adaptability of pediatric residents to the ILAE-2017 seizure classification. However, to ensure successful implementation of the ILAE-2017 classification in clinical practice, additional booster applications of the MEP are required.
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OBJECTIVE: The aim of the study was to identify the predominant predictors of seizure relapse following discontinuation of ASM in epileptic children. METHODS: The study cohort consisted of 403 epileptic children who had a withdrawal process of ASM (monotherapy: 344; dual therapy or polytherapy: 59) after at least a 2-year seizure-free period. Patients were categorized if they had a well-defined epileptic syndrome. Epileptic children with ongoing ketogenic diet, vagal nerve stimulation, or surgery were excluded from the cohort due to the additional withdrawal process related to other therapy modalities. RESULTS: The cohort's seizure relapse rate was 12.7% (51/403). The highest rates of seizure relapse were defined for genetic etiology at 25% and structural etiology at 14.9%. An epilepsy syndrome was defined in 183 of 403 children (45.4%). There was no difference in the seizure relapse rate between the subgroups of well-defined epileptic syndromes; 13.8% for self-limited focal epileptic syndromes, 11.7% for developmental and epileptic encephalopathies, and 7.1% for generalized epileptic syndromes. Five predictors were defined as the most powerful predictors of seizure relapse in univariate analysis: age at epilepsy diagnosis >2 years (hazard ratio [HR]: 1.480; 95% confidence interval [CI]: 1.134-1.933), defined etiology (HR: 1.304; 95% CI: 1.003-1.696), focal seizure (HR: 1.499; 95% CI: 1.209-1.859), ≤3 months duration of the withdrawal process (HR: 1.654; 95% CI: 1.322-2.070), and a history of neonatal encephalopathy with or without seizures (HR: 3.140; 95% CI: 2.393-4.122). In multivariate analysis, the main predictor of seizure relapse was a history of neonatal encephalopathy with or without seizures (HR: 2.823; 95% CI: 2.067-3.854). SIGNIFICANCE: The duration of seizure freedom before discontinuation of ASM was not a predominant risk factor for seizure relapse: 2-3 years versus >3 years. The predictive values of five predictors of seizure relapse rate should be evaluated for patients with different epilepsy subgroups.
Assuntos
Epilepsia Generalizada , Epilepsia , Síndromes Epilépticas , Recém-Nascido , Humanos , Criança , Pré-Escolar , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia Generalizada/tratamento farmacológico , Síndromes Epilépticas/tratamento farmacológico , RecidivaRESUMO
BACKGROUND: The aim of this study was to investigate the frequency of sleep problems in adolescents with epilepsy and their caregivers. We also examined the behavioural difficulties in adolescents with epilepsy and compared these behaviors with healthy controls. METHODS: This observational case-control study included 37 adolescents with epilepsy and their caregivers, and 43 healthy age-matched adolescents and their caregivers. The Children`s Sleep Habits Questionnaire (CSHQ), DSM-5 Level 2 Sleep Disorders Scale for Children, and Strengths & Difficulties Questionnaire (SDQ) were used to evaluate sleep habits, sleep problems, and behavioural difficulties in adolescents. The DSM-5 sleep disorder scale for adults was used to evaluate the caregivers` sleep problems. RESULTS: Adolescents with epilepsy had higher sleep problem scores such as daytime sleepiness and overall sleep problems compared with healthy controls. The psychopathological symptoms such as conduct problems, hyperactivity/inattention, and total behavior were also more frequent in adolescents with epilepsy. There was a nonsignificant increase in DSM-5 sleep disturbance score in caregivers of adolescents with epilepsy. Sleep onset delay had a significant negative correlation with total behavioral difficulties (r = -0.44, p < 0.01), and emotional problems (r = -0.47, p < 0.05) in adolescents with epilepsy. Sleep duration was negatively correlated with conduct problems (r = -0.33, p < 0.05), but positively correlated with prosocial score (r = 0.46, p < 0.01) in adolescents with epilepsy. Night waking was positively correlated with total behavioral difficulties (r = 0.35, p < 0.05) and hyperactivity score (r = 0.38, p < 0.05) in adolescents with epilepsy. CONCLUSIONS: Adolescents with epilepsy have more frequent sleep disturbances and maladaptive behaviors such as hyperactivity/inattention, and conduct problems compared with healthy controls, and their caregivers are more vulnerable to sleep problems. Moreover, we also demonstrated a strong association between sleep disturbances and behavioral problems in adolescents with epilepsy.