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Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.
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FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homologue of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental and epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homologue fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental and epileptic encephalopathy and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental and epileptic encephalopathies associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental and epileptic encephalopathy cases.
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Proteínas Cdh1 , Epilepsia Generalizada , Epilepsia , Microcefalia , Ataxia , Proteínas Cdh1/genética , Criança , Epilepsia/genética , Epilepsia Generalizada/genética , Humanos , Mutação com Perda de Função , Microcefalia/genética , FenótipoRESUMO
AIM: To identify genetic causes for early infantile epileptic encephalopathies (EIEE) in Turkish children with mostly consanguineous parents. METHODS: In a selected EIEE group (N = 59) based on results of nongenetic and initial genetic testing with unexplained etiology, 49 patients underwent array-based comparative genomic hybridization (aCGH) and 49 patients underwent whole exome sequencing (WES) including 39 with negative aCGH results and 10 with WES-only. RESULTS: Diagnostic yield of aCGH and WES for pathogenic or likely pathogenic variants was 14.3% and 38.8%, respectively. Including de novo variants of uncertain significance linked to compatible phenotypes, increased the diagnostic yield of WES to 61.2%. Out of 38 positive variants, 18 (47.4%) were novel and 16 (42.1%) were de novo. Twenty-one (56.8%) patients had recessive variants inherited from mostly consanguineous healthy parents (85.7%). Fourteen (37.8%) of patients with diagnostic results had positive variants in established EIEE genes. Seizures started during neonatal period in 32.4% patients. Posture or movement disorders were comorbid with EIEE in 40.5% of diagnosed patients. We identified treatable metabolic disorders in 8.1% of patients and pathogenic variants in genes which support using targeted medicine in 19% of patients. CONCLUSIONS: Detailed electro-clinical phenotyping led to expansion of some of the known phenotypes with non-neurological and neurological findings in addition to seizures, as well as suggestion of candidate genes (SEC24B, SLC16A2 and PRICKLE2) and a copy number variant (microduplication of Xp21.1p11.4). The high ratio of recessive inheritance could be important for family counseling.
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Espasmos Infantis , Simportadores , Humanos , Sequenciamento do Exoma , Hibridização Genômica Comparativa , Espasmos Infantis/diagnóstico , Convulsões , Transportadores de Ácidos Monocarboxílicos/genética , Simportadores/genéticaRESUMO
BACKGROUND: Diagnosis and treatment of pseudotumor cerebri syndrome in children is still a challenge for clinicians. The aim of this study is to reveal the influence of presentation age and CSF opening pressure on long-term prognosis of pseudotumor cerebri and share our clinical data of the very young age (≤ 5-year) group. METHOD: This retrospective study includes the patients followed by the Marmara University Pediatric Neurology Clinic between years 2012 and 2020 diagnosed with definite, probable, or suggestive pseudotumor cerebri syndrome according to modified Friedman criteria. Patients were classified into three groups according to presentation age: group 1: ≤ 5 years old; group 2: 6-10 years; and group 3 > 10 years old. CSF opening pressure was also categorized into three groups as CSF < 20 cmH20; CSF 20-30 cmH20; and CSF > 30 cmH20. RESULTS: One hundred three patients, 62.1% female (n = 64), were enrolled in the study. Group 1 consisted of 16 patients (60% male), group 2 consisted of 30 patients (63.3% female), and group 3 consisted of 57 patients (66.7% female). The mean CSF opening pressure did not differ between the three age groups in our study (p > 0.05). Treatment response was not correlated with CSF opening pressure. Papilledema presence and level of CSF opening pressure were independent of age (p > 0.05). CONCLUSIONS: Age at presentation and CSF opening pressure at diagnosis are not any predictive factors that influence long-term prognosis of pseudotumor cerebri syndrome in children. Evaluation and follow-up of children should be done in personalized approach.
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Papiledema , Pseudotumor Cerebral , Pressão do Líquido Cefalorraquidiano/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Papiledema/diagnóstico , Prognóstico , Pseudotumor Cerebral/tratamento farmacológico , Pseudotumor Cerebral/terapia , Estudos RetrospectivosRESUMO
BACKGROUND: Respiratory failure is the leading cause of mortality in spinal muscular atrophy type 1 (SMA1) children. The current study aims to evaluate the effect of nusinersen treatment on respiratory outcome of the patients with SMA1. METHODS: In this retrospective, single-center study, 52 SMA1 patients treated with nusinersen were included in the analysis. Patients were divided into two groups based on their age at the time of their first nusinersen treatment (Group 1: ≤6 months, Group 2: >6 months). Respiratory outcome on the 180th day of treatment is defined as the type of ventilation support (spontaneous breathing, noninvasive ventilation (NIV), and tracheostomized or intubated on invasive mechanical ventilation). Demographic data, respiratory outcome, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores were obtained from medical records. RESULTS: On the 180th day of treatment, 46 of the 52 (88.4%) children were alive. Prevalence of the mortality was similar in both groups (P = 0.65). The comparison of respiratory outcome in patients between group 1 and group 2 was as follows: spontaneous breathing, 7 (43.7%) versus 4 (13.3%) (P = 0.03); NIV <16 h/day, 3 (18.7%) versus 4 (13.3%) (P = 0.68); invasive mechanical ventilation, 6 (37.5%) versus 22 (73.3%) (P = 0.01). There were no patients using NIV ≥16 h/day. There were significant improvements in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores of the patients at day 180 in comparison with the baseline (P < 0.001). CONCLUSIONS: Early initiation of nusinersen treatment in SMA1 patients may alter the disease's natural course.
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Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Criança , Humanos , Lactente , Oligonucleotídeos/uso terapêutico , Respiração Artificial , Estudos Retrospectivos , Atrofias Musculares Espinais da Infância/tratamento farmacológicoRESUMO
This study investigated the effect of the structured Neurodevelopmental Therapy Method-Bobath (NDT-B) approach on the feeding and swallowing activity of patients with cerebral palsy (CP) and feeding difficulties. In addition to feeding and oral motor intervention strategies (OMIS), and nutrition-related caregiver training (NRCT), and the NDT-B, which was structured to increase trunk and postural control, was added to the therapy program. Forty patients with CP, with a mean age of 3.25 ± 0.927 years, were classified using the Gross Motor Function Classification System, Eating and Drinking Ability Classification System, and Mini-Manual Ability Classification System. The patients were randomly assigned into two groups as OMIS + NRCT (n = 20) and OMIS + NRCT + NDT-B (n = 20). The program was applied for 6 weeks, 2 days/week, for 45 min. The patients were evaluated using the Trunk Impairment Scale, Schedule for Oral Motor Assessment, and the Pediatric Quality of Life Inventory before and after 6 weeks. The trunk control of the OMIS + NRCT + NDT-B group was superior to the other group (P = 0.026). Although there was an improvement in the groups according to the subcategories of SOMA, the OMIS + NRCT + NDT-B group was superior in the trainer cup and puree subcategories of SOMA (P = 0.05). A significant correlation was observed between trunk control and oral motor functions in children with CP, and the eating function of children in the OMIS + NRCT + NDT-B group further improved. NDT-B-based neck and trunk stabilization exercises should be added to the treatment programs.Trial Registration NCT04403113.
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Paralisia Cerebral , Paralisia Cerebral/complicações , Criança , Pré-Escolar , Deglutição , Terapia por Exercício , Humanos , Equilíbrio Postural , Qualidade de VidaRESUMO
OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is the second leading neurological cause of potential years of lifelost after stroke. Despite growing numbers of studies on social aspects of epilepsy, there is a paucity of research on the awareness of SUDEP among the parents of children with epilepsy (CWE), especially in Turkey. In this study, we aimed to evaluate the knowledge of parents of the CWE regarding SUDEP in the tertiary setting. MATERIAL AND METHODS: A total of 146 parents (108 female) aged 19 to 55â¯years (median age:34) of CWE were included at Marmara University, School of Medicine, Department of Pediatric Neurology outpatient clinic between May 2018 and September 2018. A total of 30 multiple-choice questions and a written survey were administered, which consisted of three sections. In the first section, the sociodemographics of parents and CWE were questioned. In the second section, the severity of epilepsy was evaluated. In the third section, the knowledge level and awareness of parents of CWE were assessed. RESULTS: Of 146 parents, only 16.6% previously heard about SUDEP, while 45% of them heard from their relatives. The presence of prior knowledge of SUDEP was associated with the presence of prolonged postictal confusion and longer duration of epilepsy (pâ¯<â¯0.05). Ninety-seven (66%) parents desired to be informed about SUDEP, while 76 (54.7%) of them agreed that this information should be given at the time of diagnosis. The degree of anxiety in parents regarding death of epilepsy-related causes was significantly related with prolonged postictal confusion (pâ¯<â¯0.001) and using three or more antiepileptic drugs (pâ¯=â¯0.005). CONCLUSION: Our data suggest that knowledge about SUDEP among parents with CWE found inadequate in Turkey. There should be much effort to inform parents and caregivers in epilepsy clinics on SUDEP, which may help to reduce the associated risk factors.
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Epilepsia/mortalidade , Epilepsia/psicologia , Pais/psicologia , Morte Súbita Inesperada na Epilepsia/epidemiologia , Inquéritos e Questionários , Centros de Atenção Terciária , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Cuidadores/psicologia , Criança , Epilepsia/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Morte Súbita Inesperada na Epilepsia/prevenção & controle , Turquia/epidemiologia , Adulto JovemRESUMO
PURPOSE: To investigate the relationships among the Infant Motor Profile (IMP), the Neuro-Sensory Motor Developmental Assessment (NSMDA), and the Alberta Infant Motor Scale (AIMS) in prematurely born infants. METHODS: Sixty-one preterm infants with a birth weight under 2500 g were assessed by the IMP, the NSMDA, and the AIMS. RESULTS: There was a significant correlation between the IMP total score and the AIMS percentile and between the IMP total score and the NSMDA functional levels. There were significant correlations between the AIMS percentile age and the NSMDA functional levels and between the AIMS total scores and the IMP total scores. In the infants with atypical development, the relationship was significant between the AIMS and the IMP; however, there was no relationship between the IMP and the NSMDA. CONCLUSIONS: The 3 movement analysis tests are related. The IMP was found to be consistent with other movement analysis tests.
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Avaliação da Deficiência , Recém-Nascido Prematuro/fisiologia , Movimento/fisiologia , Modalidades de Fisioterapia , Peso ao Nascer , Desenvolvimento Infantil , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Destreza Motora , Fatores SocioeconômicosRESUMO
BACKGROUND: Transient splenial lesions of the corpus callosum are rare radiological findings first described in association with epilepsy, antiepileptic drugs and viral encephalitis. However, subsequently more cases were described associated with diverse clinical conditions. CASE REPORT: We describe a 13-year-old girl suffering from migraine with aura presenting with headache, right-sided hemiparesis and encephalopathy. Brain magnetic resonance imaging revealed an ovoid lesion in the splenium of the corpus callosum. The patient's neurological symptoms resolved within 3 days without therapy and the lesion disappeared in follow up magnetic resonance images obtained 3 weeks after the onset of the symptoms. RESULTS: Migraine with aura was considered to be the cause of the lesion. To our knowledge the present case is the first report of a pediatric patient with a diagnosis of migraine with aura presenting with hemiparesis and encephalopathy. CONCLUSIONS: A diagnosis of transient lesion of the corpus callosum should be suspected in patients with migraine with aura presenting with hemiparesis and encephalopathy. A mild course and a good prognosis might be expected in the presence of a splenial lesion of the corpus callosum.
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Encefalopatias/diagnóstico por imagem , Corpo Caloso/diagnóstico por imagem , Imageamento por Ressonância Magnética , Enxaqueca com Aura/diagnóstico por imagem , Adolescente , Feminino , Seguimentos , Humanos , Remissão EspontâneaRESUMO
Pantothenate kinase-associated neurodegeneration (PKAN) syndrome is an autosomal-recessive neurodegenerative disease that causes progressive generalized dystonia. Currently, the disorder remains pharmacologically intractable. Herein we report the first case in which deep brain stimulation helped to relieve dystonic storm in a patient with PKAN syndrome who had homozygous c.628 2 T > G mutation of the PANK2 gene. A 10-year-old boy with PKAN disease presented with dystonic storm and was admitted to the emergency department. Examination revealed generalized dystonia and impaired breathing due to involvement of the respiratory muscles. The patient underwent surgery for bilateral globus pallidus internus deep brain stimulation. The patient showed marked response to treatment.
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Estimulação Encefálica Profunda , Mutação de Sentido Incorreto , Neurodegeneração Associada a Pantotenato-Quinase/terapia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Criança , Humanos , Masculino , Neurodegeneração Associada a Pantotenato-Quinase/genética , SíndromeRESUMO
PURPOSE: Developmental and Epileptic Encephalopathies (DEEs) are rare neurological disorders characterized by early-onset medically resistant epileptic seizures, structural brain malformations, and severe developmental delays. These disorders can arise from mutations in genes involved in vital metabolic pathways, including those within the brain. Recent studies have implicated defects in the mitochondrial malate aspartate shuttle (MAS) as potential contributors to the clinical manifestation of infantile epileptic encephalopathy. Although rare, mutations in MDH1, MDH2, AGC1, or GOT2 genes have been reported in patients exhibiting neurological symptoms such as global developmental delay, epilepsy, and progressive microcephaly. METHOD: In this study, we employed exome data analysis of a patient diagnosed with DEE, focusing on the screening of 1896 epilepsy-related genes listed in the HPO and ClinVar databases. Sanger sequencing was subsequently conducted to validate and assess the inheritance pattern of the identified variants within the family. The evolutionary conservation scores of the mutated residues were evaluated using the ConSurf Database. Furthermore, the impacts of the causative variations on protein stability were analyzed through I-Mutant and MuPro bioinformatic tools. Structural comparisons between wild-type and mutant proteins were performed using PyMOL, and the physicochemical effects of the mutations were assessed using Project Hope. RESULTS: Exome data analysis unveiled the presence of novel compound heterozygous mutations in the GOT2 gene coding for mitochondrial glutamate aspartate transaminase. Sanger sequencing confirmed the paternal inheritance of the p.Asp257Asn mutation and the maternal inheritance of the p.Arg262Cys mutation. The affected individual exhibited plasma metabolic disturbances, including hyperhomocysteinemia, hyperlactatemia, and reduced levels of methionine and arginine. Detailed bioinformatic analysis indicated that the mutations were located within evolutionarily conserved domains of the enzyme, resulting in disruptions to protein stability and structure. CONCLUSION: Herein, we describe a case with DEE82 (MIM: # 618721) with pathologic novel biallelic mutations in the GOT2 gene. Early genetic diagnosis of metabolic epilepsies is crucial for long-term neurodevelopmental improvements and seizure control as targeted treatments can be administered based on the affected metabolic pathways.
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Encefalopatias , Epilepsia Generalizada , Epilepsia , Humanos , Encefalopatias/genética , Epilepsia/genética , Mutação/genética , ConvulsõesRESUMO
BACKGROUND/AIM: Kelch-like protein 11 (KLHL11)-antibody may be found in paraneoplastic neurological disorders presenting with epileptic seizures. The aim of this study was to investigate the prevalence and clinical significance of KLHL11-antibody in epilepsy. PATIENTS AND METHODS: Sera of 42 pediatric and 59 adult patients with seizures of undetermined cause were screened using a cell-based assay. RESULTS: KLHL11-antibody was found in three of 168 control patients with paraneoplastic neurological disorders and four pediatric patients (4-8-year-old, 2 boys/2 girls) with seizures of unknown cause presenting with myoclonic-atonic epilepsy, generalized epilepsy or childhood epilepsy with centrotemporal spikes. In these four cases, seizures continued for 2-7 months, responded promptly and favorably to conventional anti-seizure drugs and did not recur in follow-up durations ranging between 2-5 years. Patients had normal brain MRI findings and motor-mental development before and after seizures. KLHL11-antibody was not detected in adult epilepsy patients with undetermined cause, MOG antibody-positive patients and healthy controls. CONCLUSION: KLHL11-antibody may be detected in pediatric epilepsy patients with a relatively benign disease course.
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Eletroencefalografia , Epilepsia , Masculino , Feminino , Humanos , Criança , Pré-Escolar , Progressão da Doença , Proteínas de TransporteRESUMO
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
Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late-onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone.
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Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Espasmos Infantis/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Convulsões Febris/genéticaRESUMO
PURPOSE: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. METHODS: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. KEY FINDINGS: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). SIGNIFICANCE: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.
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Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 2/genética , Epilepsia Generalizada/genética , Predisposição Genética para Doença/genética , Mapeamento Cromossômico , Família , Feminino , Ligação Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Linhagem , FenótipoRESUMO
Clobazam (CLB) is an effective anticonvulsant used as an adjunctive treatment for several seizures and epilepsy syndromes. Data are limited on efficacy and safety of CLB as add-on therapy for epileptic encephalopaties (EEs) other than Lennox-Gastaut syndrome (LGS). This retrospective study aimed to assess efficacy and safety of long-term CLB add-on therapy for various EE syndromes. Data on CLB add-on therapy were assessed in 74 children (60.8% male) after 3 months (early) and 12 months (late) follow-up as well as in 57 (77%) patients who had been on CLB therapy longer than 12 months (mean:39.11 ± 30.29; range:12-129 months) (very late) were reported. Data on CLB add-on therapy were assessed in 74 children (60.8% male) after 3 months (early) and 12 months (late) follow-up as well as in 57 (77%) patients who had been on CLB therapy longer than 12 months (mean:39.11 ± 30.29; range:12-129 months) (very late) were reported. Good response rate (> 50%) for seizures was achieved in 24% at early follow-up, 30% at late follow-up, and 35% during very late follow-up. Complete seizure remission was achieved for 15% seizures; 72.7% occurred at very late follow-up. Myoclonic seizures were the most responsive (35%); this response increased during late follow-up (46%), whereas 27.3% of myoclonic-atonic/atonic seizures had good response at early and very late follow-up. At late follow-up, comparison of mean effective doses of CLB did not show significant difference among types of seizures with good response. Adverse effects reported in 15% of patients did not require stopping CLB therapy. Generalized epileptogenic potentials significantly decreased while focal epileptogenic potentials significantly increased at first year of treatment in comparison to basal EEG findings (p < 0.001). CLB should be considered as an optional antiepileptic that is well tolerated, particularly in EEs with myoclonic and myoclonic-atonic/atonic seizures.
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Anticonvulsivantes/uso terapêutico , Clobazam/uso terapêutico , Epilepsia/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsia Generalizada/tratamento farmacológico , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Restless legs syndrome (RLS) and growing pains (GPs) share many common features and are sometimes overlapping diagnoses. The present study aims to investigate the shared features of patients with RLS, classified based on the 2013 diagnostic criteria of International Restless Legs Syndrome Study group and of patients with GPs, diagnosed based on the combined criteria proposed in 2013. METHODS: A cross-sectional population study was conducted in 7 Istanbul schools, which were selected randomly. A total of 4565 (56.1% female) children aged 9 to 18 years were included. In the first stage, candidates of RLS and GPs were identified based on 2 separate questionnaires, whose diagnoses were confirmed by a second survey applied to them under parental supervision. RESULTS: Out of 192 children (65.6% female) diagnosed as definite RLS (yearly prevalence: 4.2%), 30 (15.6%) reported bilateral leg muscle pain localized typical regions for GPs, which started <13 years of age in 17 children. An urge to move the legs to relieve unpleasant sensations or pain was present in 39.3% of 140 children (64.3% female) classified as GPs (yearly prevalence: 3.1%). Occurrence of symptoms at rest or when lying down was present in 36.4% of GPs children and relief by gross movements was in 21.4% children. Only 12 patients (9 with definite RLS and 3 with GPs) (0.03% of total cohort) were eligible for overlapping diagnosis of GPs and RLS. CONCLUSION: Although a considerable number of patients with RLS and GPs share some clinical features, a combined phenotype is very rare.
Assuntos
Síndrome das Pernas Inquietas , Adolescente , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Perna (Membro) , Masculino , Dor/diagnóstico , Síndrome das Pernas Inquietas/diagnóstico , Síndrome das Pernas Inquietas/epidemiologiaRESUMO
OBJECTIVE: Essential tremor is the most common movement disorder diagnosed during adolescence. However, there are insufficient data about its prevalence among adolescents. This study aims to determine the prevalence of potential essential tremor cases in Turkish adolescents. MATERIALS AND METHODS: This cross-sectional study was carried out in Istanbul, Turkey. A total of 5 high schools were visited. In the first step, the authors provided 5559 students (aged 14-18) with clinical information about tremors and essential tremors in their classrooms. After that, a 12-item questionnaire filled by adolescents and parental consent forms were collected. The response rate was 78% (n = 4330). According to the questionnaire answers, adolescents who complained of experiencing tremors in any part of their body were clinically evaluated in the second step of the study. Lastly, a neurological examination to classify essential tremors based on the Washington Heights Inwood Genetic Study of Essential Tremor (1998) diagnostic criteria was conducted by a specialist. RESULTS: The prevalence of tremor in the respondents aged 14-18 (median = 15) years was 1.2 % (n = 52/4330), and the prevalence of essential tremor was 0.41% (n = 18/4330). Male to female ratio for essential tremor was 5 : 1 (male = 15 and female = 1). Essential tremor cases were subclassified as following: 10 (55.5%) definite essential tremor, 3 (16.6%) probable essential tremor, and 5 (27.7%) possible essential tremor. CONCLUSION: The data support the claim that essential tremor is a prevalent movement disorder in Turkish adolescents.
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Introduction: In pediatric and adolescent population, autoimmune encephalitis (AE) may present with a wide variety of symptoms including cognitive regression accompanied with loss of language skills. Despite its high prevalence in AE, linguistic functions have not been investigated in extensive detail. Case: A 12-year-old girl with no significant premorbid history and normal school performance presented with fever, hypersomnia, nocturnal myoclonus and behavioral changes. Although neurological examination was normal, psychiatric evaluation revealed euphoria, mild irritability and visual hallucinations. Cranial MRI was normal, whereas cerebrospinal fluid (CSF) analysis showed elevated protein concentration and lymphocyte count, electroencephalogram (EEG) showed diffuse slow waves. A panel for anti-neuronal antibodies demonstrated glutamic acid decarboxylase (GAD) antibodies in the serum. Following immunotherapy, all neurological and behavioral symptoms vanished. However, the patient suffered from significant worsening of school performance. Psychiatric evaluation revealed severe depression. Assessment of intelligence done on the 10th and 18th month of follow-up yielded significantly low scores at mental retardation level. Linguistic assessment showed significant impairment in all domains but especially in semantics. Conclusion: Our case emphasizes the fact that AE may cause permanent cognitive dysfunction and language impairment even in patients with normal MRI/neurological examination findings and relatively mild treatment-responsive disease course.
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New molecular therapies are available for the treatment of spinal muscular atrophy (SMA) but early intervention is required. We report two cases that were diagnosed prenatally, where treatment with nusinersen was initiated within 7 h and three days respectively. The children were followed up for 13 months and almost six years respectively. Both children have developed within entirely normal centiles, indicating that initiating treatment immediately after birth, as in these cases, is essential for a good outcome.