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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: 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: 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
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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OBJECTIVES: To evaluate clinical characteristics, imaging features and etiological profile of Radiologically Isolated Syndrome (RIS) along with clinical and radiological follow-up. METHODS: Demographic, clinical and radiological data of patients younger than 18 years fulfilling the criteria for RIS were retrospectively analyzed. RIS was defined by the detection of lesions meeting the revised 2010 McDonald Criteria for dissemination in space on magnetic resonance imaging (MRI) in the absence of any symptoms of demyelinating disease or an alternative cause for the MRI findings. RESULTS: There were total 69 patients (38 girls, 31 boys). The median age at index MRI was 15.7 years, and median follow-up time was 28 months. The most common reason for neuroimaging was headache (60.9%). A first clinical event occurred with median 11 months in 14/69 (20%) of cases. Those with oligoclonal bands (OCB) in cerebrospinal fluid (CSF) and follow-up longer than 3 years were more likely to experience a clinical event (p<0.05): 25% of those with OCB manifested clinical symptoms within the first year and 33.3% within the first two years compared to 6.3% and 9.4%, respectively in those without OCB. Radiological evolution was not associated with any variables: age, sex, reason for neuroimaging, serum 25-hydroxyvitamin D level, elevated IgG index, OCB positivity, total number and localization of lesions, presence of gadolinium enhancement, achievement of 2005 criteria for DIS and duration of follow-up. CONCLUSION: Children and adolescents with RIS and CSF OCB should be followed-up for at least 3 years in order to detect any clinical symptoms suggestive of a demyelinating event. Because disease-modifying treatments are not approved in RIS and no consensus report justifies their use especially in pediatric RIS, close follow-up of OCB-positive patients is needed for early recognition of any clinical event and timely initiation of specific treatment.
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Doenças Autoimunes do Sistema Nervoso , Doenças Desmielinizantes , Esclerose Múltipla , Masculino , Feminino , Humanos , Criança , Adolescente , Esclerose Múltipla/diagnóstico , Estudos Retrospectivos , Meios de Contraste , Gadolínio , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/líquido cefalorraquidiano , Bandas Oligoclonais/líquido cefalorraquidiano , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS) mostly presenting as optic neuritis and acute myelitis. NMOSD can be associated with seropositivity for aquaporin 4 antibody (AQP4 IgG), myelin oligodendrocyte glycoprotein antibody (MOG IgG), or can be seronegative for both. In this study, we retrospectively examined our seropositive and seronegative pediatric NMOSD patients. METHOD: Data were collected from all participating centres nationwide. Patients diagnosed with NMOSD were divided into three subgroups according to serology: AQP4 IgG NMOSD, MOG IgG NMOSD, and double seronegative (DN) NMOSD. Patients with at least six months of follow-up were compared statistically. RESULTS: The study included 45 patients, 29 female and 16 male (ratio:1.8), mean age 15.16 ± 4.93 (range 5.5-27) years. Age at onset, clinical manifestations, and cerebrospinal fluid findings were similar between AQP4 IgG NMOSD (n = 17), MOG IgG NMOSD (n = 10), and DN NMOSD (n = 18) groups. A polyphasic course was more frequent in the AQP4 IgG and MOG IgG NMOSD groups than DN NMOSD (p = 0.007). The annualized relapse rate and rate of disability were similar between groups. Most common types of disability were related to optic pathway and spinal cord involvement. Rituximab in AQP4 IgG NMOSD, intravenous immunoglobulin in MOG IgG NMOSD, and azathioprine in DN NMOSD were usually preferred for maintenance treatment. CONCLUSION: In our series with a considerable number of double seronegatives, the three major serological groups of NMOSD were indistinguishable based on clinical and laboratory findings at initial presentation. Their outcome is similar in terms of disability, but seropositive patients should be more closely followed-up for relapses.
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Neuromielite Óptica , Masculino , Feminino , Humanos , Aquaporina 4 , Estudos Retrospectivos , Imunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Autoanticorpos/líquido cefalorraquidianoRESUMO
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.
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Epilepsia , Transtornos do Sono-Vigília , Criança , Humanos , Adolescente , Estudos de Casos e Controles , Cuidadores , Epilepsia/complicações , Epilepsia/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia , Inquéritos e QuestionáriosRESUMO
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.
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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: Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle. OBJECTIVE: The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort. METHODS: Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated. RESULTS: Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment. CONCLUSIONS: The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature.
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Miotonia Congênita , Masculino , Humanos , Criança , Adolescente , Idoso , Lactente , Pré-Escolar , Feminino , Miotonia Congênita/genética , Estudos Retrospectivos , Canais de Cloreto/genética , Mutação , Músculo EsqueléticoRESUMO
BACKGROUND: To evaluate the clinical features, demographic features, and treatment modalities of pediatric-onset chronic inflammatory demyelinating polyneuropathy (CIDP) in Turkey. METHODS: The clinical data of patients between January 2010 and December 2021 were reviewed retrospectively. The patients were evaluated according to the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society Guideline on the management of CIDP (2021). In addition, patients with typical CIDP were divided into two groups according to the first-line treatment modalities (group 1: IVIg only, group 2: IVIg + steroid). The patients were further divided into two separate groups based on their magnetic resonance imaging (MRI) characteristics. RESULTS: A total of 43 patients, 22 (51.2%) males and 21 (48.8%) females, were included in the study. There was a significant difference between pretreatment and post-treatment modified Rankin scale (mRS) scores (P < 0.05) of all patients. First-line treatments include intravenous immunoglobulin (IVIg) (n = 19, 44.2%), IVIg + steroids (n = 20, 46.5%), steroids (n = 1, 2.3%), IVIg + steroids + plasmapheresis (n = 1, 2.3%), and IVIg + plasmapheresis (n = 1, 2.3%). Alternative agent therapy consisted of azathioprine (n = 5), rituximab (n = 1), and azathioprine + mycophenolate mofetil + methotrexate (n = 1). There was no difference between the pretreatment and post-treatment mRS scores of groups 1 and 2 (P > 0.05); however, a significant decrease was found in the mRS scores of both groups with treatment (P < 0.05). The patients with abnormal MRI had significantly higher pretreatment mRS scores compared with the group with normal MRI (P < 0.05). CONCLUSIONS: This multicenter study demonstrated that first-line immunotherapy modalities (IVIg vs IVIg + steroids) had equal efficacy for the treatment of patients with CIDP. We also determined that MRI features might be associated with profound clinical features, but did not affect treatment response.
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Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Masculino , Feminino , Criança , Humanos , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Azatioprina/uso terapêutico , Estudos Retrospectivos , MetotrexatoRESUMO
OBJECTIVE: The aim of this study is to evaluate the prognostic factors in a single-center pediatric cohort with autoimmune encephalitis. MATERIALS AND METHODS: The study group consisted of 23 pediatric autoimmune encephalitis patients (seropositive autoimmune encephalitis: 15, seronegative autoimmune encephalitis: 8). Five group prognostic parameters were evaluated: clinical manifestations, elect roenc ephal ograp hy features, magnetic resonance imaging characteristics, biomarkers, and treatment modalities. Three scoring models were applied: the Antibody Prevalence in Epilepsy and Response to Immunotherapy in Epilepsy for predicting autoimmune-related epilepsy in the whole cohort and the anti-N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status score for overall outcome in patients with anti-N-methyl-d-aspartate receptor encephalitis. RESULTS: The initial clinical spectrum of the disease was similar in the seronegative and seropositive groups. Almost half of the patients (48%) recovered without any complications with first-line immunotherapy. The patients with movement disorders in the acute phase of the disease needed more likely second-line immunotherapy (P = .039). The presence of status epilepticus at admission was significantly associated with adverse outcomes and the development of autoimmune-related epilepsy (P = .019). Autoimmune-related epilepsy was defined in an equal proportion of patients (91.5%) with 2 immune epilepsy scores (Antibody Prevalence in Epilepsy and Response to Immunotherapy in Epilepsy). The N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status score and the modified Rankin score assessed for the first-year prognosis were strongly correlated among the patients with anti-N-methyl-d-aspartate receptor encephalitis (P = .03, Spearmen's rho = 0.751). CONCLUSIONS: The presence of status epilepticus was the most important prognostic factor in the patients with the adverse outcome. The studied scoring models (Anti-N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status, Antibody Prevalence in Epilepsy, and Response to Immunotherapy in Epilepsy) have also been proven to be applicable to the pediatric age group for predicting overall outcome and autoimmune-related epilepsy.
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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
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
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
BACKGROUND: The discovery of anti-myelin oligodendrocyte glycoprotein (MOG)-IgG and anti-aquaporin 4 (AQP4)-IgG and the observation on certain patients previously diagnosed with multiple sclerosis (MS) actually have an antibody-mediated disease mandated re-evaluation of pediatric MS series. AIM: To describe the characteristics of recent pediatric MS cases by age groups and compare with the cohort established before 2015. METHOD: Data of pediatric MS patients diagnosed between 2015 and 2021 were collected from 44 pediatric neurology centers across Türkiye. Clinical and paraclinical features were compared between patients with disease onset before 12 years (earlier onset) and ≥12 years (later onset) as well as between our current (2015-2021) and previous (<2015) cohorts. RESULTS: A total of 634 children (456 girls) were enrolled, 89 (14%) were of earlier onset. The earlier-onset group had lower female/male ratio, more frequent initial diagnosis of acute disseminated encephalomyelitis (ADEM), more frequent brainstem symptoms, longer interval between the first two attacks, less frequent spinal cord involvement on magnetic resonance imaging (MRI), and lower prevalence of cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCBs). The earlier-onset group was less likely to respond to initial disease-modifying treatments. Compared to our previous cohort, the current series had fewer patients with onset <12 years, initial presentation with ADEM-like features, brainstem or cerebellar symptoms, seizures, and spinal lesions on MRI. The female/male ratio, the frequency of sensorial symptoms, and CSF-restricted OCBs were higher than reported in our previous cohort. CONCLUSION: Pediatric MS starting before 12 years was less common than reported previously, likely due to exclusion of patients with antibody-mediated diseases. The results underline the importance of antibody testing and indicate pediatric MS may be a more homogeneous disorder and more similar to adult-onset MS than previously thought.
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Encefalomielite Aguda Disseminada , Esclerose Múltipla , Neuromielite Óptica , Masculino , Feminino , Humanos , Esclerose Múltipla/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito , Imageamento por Ressonância Magnética , Autoanticorpos , Imunoglobulina GRESUMO
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.
Assuntos
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
PURPOSE: To compare the effects of chloral hydrate and melatonin on sleep EEG recordings in children by using standard EEG sleep stages and the bispectral index scores (BIS). METHODS: A total of 86 children were randomly assigned to two groups: (1) melatonin group (n = 43) and (2) chloral hydrate group (n = 43). BIS monitoring scores and sleep EEGs were recorded simultaneously. The effect of two drugs on sleep EEG recording was evaluated with sleep stages of EEG and BIS. RESULTS: There was no statistically significant difference between the groups with regard to time to sleep onset and the need for a second drug ( P = 0.432; P = 1.000). Eight patients (18.6%) in chloral hydrate group reported side effects while there were no reported side effects in the melatonin group ( P = 0.006). Mean BIS values during EEG recordings were similar in both groups (59.72 ± 18.69 minutes and 66.17 ± 18.44 minutes, respectively, P = 1.000). The average time to achieve N2 sleep was 32.38 minutes in the chloral hydrate group and 43.25 minutes in the melatonin group ( P < 0.001). Both "time spent in wakefulness" and "N1 sleep" were found to be significantly higher in the melatonin group ( P < 0.001 and P = 0.005). BIS scores higher than 75 were found to be suggestive for wakefulness; 75 to 66 for N1, 65 to 46 for N2, and values lower than 46 were found to be indicative for N3 sleep with a good strength of agreement in weighted Kappa analysis (95% confidence interval; weighted Kappa = 0.67). CONCLUSIONS: Melatonin is reliable and at least as effective as chloral hydrate for sleep EEG acquisition in children.
Assuntos
Hidrato de Cloral , Melatonina , Criança , Humanos , Hidrato de Cloral/farmacologia , Melatonina/farmacologia , Hipnóticos e Sedativos/farmacologia , Fases do Sono , Eletroencefalografia , SonoRESUMO
OBJECTIVE: The study aimed to evaluate the patients with a diagnosis of cerebral sinovenous thrombosis in terms of clinical findings, etiology and underlying risk factors, imaging findings, treatment, and prognosis in the long term. MATERIALS AND METHODS: Medical records of 19 patients whose ages ranged between 0 days and 17 years with clinical and radiological cerebral sinovenous thrombosis in Ege University Department of Child Neurology were retrospectively evaluated. RESULTS: Nine of nineteen cases were female (47.3%). The median age was 84 months (0-201 months). The most common complaint at the presentation was headache (n=12) and the most common physical examination finding was papilledema (n=11). In etiology, otitis/mastoiditis in three cases, iron deficiency anemia in three cases, sinusitis in two cases, catheter use in four cases, Behçet's disease in three cases were determined. The most common observed genetic factors causing thrombosis was methylenetetrahydrofolate reductase mutation. The transverse sinus (68.4%) is the sinus where thrombosis is most frequently observed. As a result of an average follow-up of 12 months (2-72 months), hemiparesis (n=3/19, 15.7%) and epilepsy (n=5/19, 26.3%) were recorded as sequelae findings, and no mortality was observed. CONCLUSION: In cases presenting with headache, evaluation of papilledema on funduscopic examination should not be skipped. Neurological imaging should be performed in the change of consciousness of poor feeding infants and children with infections in the head and neck area or underlying chronic diseases. When cerebral sinovenous thrombosis is detected, anticoagulant therapy should be started immediately.
RESUMO
PURPOSE: To assess the spike characteristics and temporal spike evolution on serial EEG of children with childhood epilepsy with centrotemporal spikes (CECTS) treated with anti-seizure medication. METHODS: The study cohort consisted of 127 children with CECTS divided into three groups based on anti-seizure medication responsiveness: group I: seizure-free with monotherapy (n: 61, 48%), group II: seizure-controlled with monotherapy (n: 52, 41%) and group III: seizure-controlled with dual therapy (n: 14, 11%). The clinical profiles and sequential four-year follow-up visual EEG recordings of the children were evaluated. Each EEG was reanalyzed with three spike characteristics on the epochs: (1) spike-wave rate, (2) spike topography, and (3) spike localization. We calculated the spike clearance velocity, which is defined as a decrease in the spike-wave rate over time in four-year sequential follow-up EEGs. RESULTS: There was no statistical significance across the study groups with respect to initial EEG spike characteristics (spike-wave rate, spike localization, and spike topography). Seizure recurrence occurred in 15 patients (12.8%) who discontinued anti-seizure medication. There was no statistically significant difference between the spike characteristics on EEG just before the discontinuation of anti-seizure medication and seizure recurrence. However, the spike clearance velocity was significantly slower in group III than in group I in four-year sequential follow-up EEGs (pâ¯=â¯0.002). A statistically significant decrease in the mean spike-wave rate was observed in group I in the first year of anti-seizure medication (p<0.001). The spike clearance velocity was also more prominent during the second year of treatment in group II and the third year of treatment in group III. However, the spike clearance velocity was not different across the anti-seizure medication groups (oxcarbazepine, valproic acid, and levetiracetam). CONCLUSION: Spike clearance velocity might be a valuable EEG marker to guide anti-seizure medication in children with CECTS.
Assuntos
Epilepsia Rolândica , Criança , Eletroencefalografia , Epilepsia Rolândica/tratamento farmacológico , Humanos , Levetiracetam , Recidiva , Convulsões/tratamento farmacológicoRESUMO
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.