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Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.
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Transtorno do Espectro Autista/genética , Barreira Hematoencefálica/fisiopatologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Mutação , Aminoácidos/administração & dosagem , Aminoácidos/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Transportador 1 de Aminoácidos Neutros Grandes/genética , Masculino , Camundongos , Camundongos Knockout , Linhagem , Biossíntese de Proteínas , Receptor TIE-2/genéticaRESUMO
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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INTRODUCTION: Vagus nerve stimulation (VNS) has been used as an adjunctive therapy for both children and adults with refractory epilepsy, over the last two decades. In this study, we aimed to evaluate the long-term effects and tolerability of VNS in the pediatric drug-resistant epilepsy (DRE) and to identify the predictive factors for responsiveness to VNS. METHODS: We retrospectively reviewed the medical records of pediatric patients who underwent VNS implantation between 1997 and 2018. Patients with ≥50% reduction of seizure frequency compared with the baseline were defined as "responders". The clinical characteristics of responders and nonresponders were compared. RESULTS: A total of 58 children (male/female: 40/18) with a mean follow-up duration of 5.7â¯years (3â¯months to 20â¯years) were included. The mean age at implantation was 12.4â¯years (4.5 to 18.5â¯years). Approximately half (45%) of our patients were responders, including 3 patients (5.8%) who achieved seizure freedom during follow-up. The age of seizure-onset, duration of epilepsy, age at implantation, and etiologies of epilepsy showed no significant difference between responders and nonresponders. Responders were more likely to have focal or multifocal epileptiform discharges (63%) on interictal electroencephalogram (EEG), when compared to nonresponders (36%) (pâ¯=â¯.07). Vocal disturbances and paresthesias were the most common side effects, and in two patients, VNS was removed because of local reaction. CONCLUSION: Our series had a diverse etiological profile and patients with transition to adult care. Long-term follow-up showed that VNS is an effective and well-tolerated treatment modality for refractory childhood onset epilepsy. Age at implantation, duration of epilepsy and underlying etiology are not found to be predictors of responsiveness to VNS. Higher response rates were observed for a subset of patients with focal epileptiform discharges.
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Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/terapia , Eletroencefalografia/tendências , Estimulação do Nervo Vago/tendências , Adolescente , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletrodos Implantados/tendências , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: The distribution of hippocampal sclerosis (HS) subtypes, according to the classification of the International League Against Epilepsy (ILAE), has been reported mainly in adult patients. We aimed to review the pathological findings in children who had anterior temporal lobectomy accompanied with amygdalohippocampectomy, in view of the current classification, and evaluate postsurgical outcome with respect to HS subtypes in childhood. METHODS: Seventy children who underwent temporal resections for treatment of medically refractory epilepsy, with a minimum follow-up of 2â¯years, were included; the surgical hippocampus specimens were re-evaluated under the HS ILAE classification. RESULTS: Neuropathological evaluations revealed HS type 1 in 38 patients (54.3%), HS type 2 in 2 (2.8%), HS type 3 in 21 patients (30%), and no HS in 9 patients (12.9%). Of 70 patients, 23 (32.9%) had dual pathology, and the most common pattern was HS type 3 with low-grade epilepsy-associated brain tumors (LEAT). The distribution of HS types with respect to age revealed that HS type 3 and no HS subgroups had significantly more patients younger than 12â¯years, compared with those of HS type 1 (90.5%, 77.8% vs 47.4%, respectively). History of febrile seizures was higher in HS type 1. Prolonged/recurrent febrile seizures were most common in patients 12â¯years and older, whereas LEAT was the most common etiology in patients under 12â¯years of age (pâ¯<â¯0.001). Patients with HS type 1 had longer duration of epilepsy and an older age at the time of surgery compared with patients with HS type 3 and no HS (p: 0.031, p: 0.007). At final visit, 74.3% of the patients were seizure-free. Seizure outcome showed no significant difference between pathological subtypes. CONCLUSIONS: Our study presents the distribution of HS ILAE subtypes in an exclusively pediatric series along with long-term seizure outcome. The study reveals that the leading pathological HS subgroup in children is HS type 1, similar with adult series. Hippocampal sclerosis type 2 is significantly less in children compared with adults; however, HS type 3 emerges as the second most predominant group because of dual pathology, particularly LEAT. Further studies are required regarding clinicopathological features of isolated HS in pediatric cohort. Seizure-free outcome was favorable and similar in all HS types in children. The proportion of HS types may be better defined in pediatric patients with temporal resections, as the current HS ILAE classification becomes more widely used, and may help reveal the surgical and cognitive outcome with respect to HS types.
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Epilepsia do Lobo Temporal , Adulto , Idoso , Lobectomia Temporal Anterior , Criança , Consenso , Epilepsia do Lobo Temporal/etiologia , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/cirurgia , Hipocampo/patologia , Humanos , Estudos Retrospectivos , Esclerose/patologia , Resultado do TratamentoRESUMO
X-linked adrenoleukodystrophy (X-ALD), a progressive neurometabolic disorder that is caused by a defect in the gene ABCD1 (ATP-binding cassette, subfamily D, member 1), which encodes the peroxisomal ABC half-transporter ALD protein. Recently, allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only therapy known to prevent disease progression. In this study, we would like to present our experience of alloHSCT for X-ALD from a HLA matched related sibling by the use of reduced intensity conditioning regimen composed of fludarabine, busulfan and ATG which allows us to reduce procedure-related toxicity and prevent mortality while achieving a curative effect.
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Adrenoleucodistrofia/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adulto , Humanos , MasculinoRESUMO
Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.
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Proteína 2 de Ligação a Metil-CpG/genética , Mosaicismo , Mutação , Fenótipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Alelos , Biópsia , Criança , Fácies , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , MasculinoRESUMO
MBOAT7 gene codes O-acyltransferase domain containing seven proteins which is one of four enzymes involved in remodeling of phosphoinositol phosphate (PIP) in LANDs cycle. We present clinical, neuroimaging, and genetic findings of 12 patients from 7 families with MBOAT7 gene defect, a recently defined novel phospholipid remodelling disease. To the best of our knowledge, our case series is the second report on patients with MBOAT7 gene defect. The patients present with global developmental delay particularly in speech and language skills, intellectual disability, stereotypical behavior, ataxic gait, early onset epilepsy with well response to medical treatment, strabismus and similar facial features. Common neuroimaging findings of the patients were folium dysgenesis of the cerebellum with a particular appearance, mild-to-moderate cerebellar atrophy, T2 hyperintensity of bilateral globus pallidius and dentate nuclei, enlarged perivascular areas, and mild thinning of the corpus callosum. Genome-wide genotyping and exome sequencing identified five different types of homozygous mutations in the MBOAT7 gene in all seven families which are p.Arg87*, p.Leu227ProfsX65, p.Gln376Lys, p.Trp426*, and chr19:54.666.173-54.677.766/11594 bp del. We conclude that clinical and neuroimaging findings of MBOAT7 gene defect may suggest the diagnosis and guide genetic tests.
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Aciltransferases/genética , Encéfalo/patologia , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Fosfolipídeos/metabolismo , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Análise Mutacional de DNA , Família , Feminino , Homozigoto , Humanos , Lactente , Masculino , Mutação , Neuroimagem , Linhagem , Fenótipo , TurquiaRESUMO
Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain â¼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.
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Proteínas de Ciclo Celular/genética , Doenças Cerebelares/genética , Cílios/genética , Síndrome de Ellis-Van Creveld/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Retina/anormalidades , Anormalidades Múltiplas , Adolescente , Animais , Cerebelo/anormalidades , Criança , Pré-Escolar , Cílios/patologia , Éxons , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Lactente , Masculino , Fenótipo , Análise de Sequência de DNA , Adulto Jovem , Peixe-Zebra/genéticaRESUMO
BACKGROUND: Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. METHODS: Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. RESULTS: Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. CONCLUSIONS: Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).
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Córtex Cerebral/anormalidades , Análise Mutacional de DNA/métodos , Malformações do Desenvolvimento Cortical/genética , Mutação , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Humanos , Lisencefalia/genética , Imageamento por Ressonância Magnética , Malformações do Desenvolvimento Cortical/patologia , Heterotopia Nodular Periventricular/genéticaRESUMO
Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder with a great variation in clinical spectrum and age at presentation. Clinical features of 10 NPC patients who presented in the newborn period between 1993 and 2015 at our center were retrospectively analyzed. Males and females were equally distributed; there was a history of parental consanguinity (n = 8) and first-degree relative with NPC (n = 3). Patients were symptomatic between 1 and 10 days (mean 3.6 ± 2.6 days). Age at diagnosis was between 1 and 30 days (mean 14.6 ± 13.3 days). Laboratory work-up included bone marrow aspiration (n = 8) and/or filipin staining (n = 4). Confirmation was done by molecular analysis, indicating NPC1 (n = 8) and NPC2 (n = 2) mutations. All patients had neonatal cholestasis and hepatosplenomegaly. Pulmonary involvement (n = 9) and fetal ascites (n = 2) were additional accompanying features. All but one died due to pulmonary complications (n = 6) and liver insufficiency (n = 3) between 1.5 and 36 months of age (mean 8.1 ± 10.8 months). Currently, one patient is alive at the age of 11 months without any neurological deficit. CONCLUSIONS: Neonatal presentation is a rare form of NPC with exclusively visceral involvement in the newborn period and poor prognosis leading to premature death due to pulmonary complications and liver failure. What is known: ⢠Neonatal presentation is a rare form of NPC with exclusively visceral involvement in the newborn period and poor prognosis leading to premature death. ⢠Progressive liver disease is the most common cause of death among neonatal-onset NPC patients. What is new: ⢠Natural course of neonatal-onset NPC may show variations. ⢠Pulmonary involvement should be considered as an important cause of death in neonatal-onset cases, and appropriate precautions should be taken to prevent complications of respiratory insufficiency and airway infections.
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Doença de Niemann-Pick Tipo C/diagnóstico , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Falência Hepática/etiologia , Falência Hepática/mortalidade , Pneumopatias/etiologia , Pneumopatias/mortalidade , Masculino , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/mortalidade , Prognóstico , Estudos RetrospectivosRESUMO
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 , LinhagemAssuntos
Âmnio/enzimologia , Vilosidades Coriônicas/enzimologia , Ensaios Enzimáticos/métodos , Sangue Fetal/enzimologia , Doenças por Armazenamento dos Lisossomos/diagnóstico , Diagnóstico Pré-Natal/métodos , Amniocentese , Âmnio/citologia , Células Sanguíneas/enzimologia , Células Sanguíneas/metabolismo , Células Cultivadas , Amostra da Vilosidade Coriônica , Feminino , Sangue Fetal/citologia , Humanos , Recém-Nascido , Doenças por Armazenamento dos Lisossomos/enzimologia , Doenças por Armazenamento dos Lisossomos/patologia , Masculino , Triagem Neonatal , Gravidez , Cultura Primária de Células/métodos , Estudos Retrospectivos , Doença de Sandhoff/diagnóstico , Doença de Sandhoff/enzimologia , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/enzimologia , TurquiaRESUMO
OBJECTIVE: To evaluate clinical characteristics and long-term outcomes in patients with guanidinoacetate methyltransferase (GAMT) deficiency with a special emphasis on seizures and electroencephalography (EEG) findings. METHODS: We retrospectively analyzed the clinical and molecular characteristics, seizure types, EEG findings, neuroimaging features, clinical severity scores, and treatment outcomes in six patients diagnosed with GAMT deficiency. RESULTS: Median age at presentation and diagnosis were 11.5 months (8-12 months) and 63 months (18 months -11 years), respectively. Median duration of follow-up was 14 years. Global developmental delay (6/6) and seizures (5/6) were the most common symptoms. Four patients presented with febrile seizures. The age at seizure-onset ranged between 8 months and 4 years. Most common seizure types were generalized tonic seizures (n = 4) and motor seizures resulting in drop attacks (n = 3). Slow background activity (n = 5) and generalized irregular sharp and slow waves (n = 3) were the most common EEG findings. Burst-suppression and electrical status epilepticus during slow-wave sleep (ESES) pattern was present in one patient. Three of six patients had drug-resistant epilepsy. Post-treatment clinical severity scores showed improvement regarding movement disorders and epilepsy. All patients were seizure-free in the follow-up. CONCLUSIONS: Epilepsy is one of the main symptoms in GAMT deficiency with various seizure types and non-specific EEG findings. Early diagnosis and initiation of treatment are crucial for better seizure and cognitive outcomes. This long-term follow up study highlights to include cerebral creatine deficiency syndromes in the differential diagnosis of patients with global developmental delay and epilepsy and describes the course under treatment.
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Eletroencefalografia , Guanidinoacetato N-Metiltransferase/deficiência , Transtornos do Desenvolvimento da Linguagem , Transtornos dos Movimentos/congênito , Humanos , Masculino , Feminino , Pré-Escolar , Lactente , Criança , Estudos Retrospectivos , Convulsões/diagnóstico , Convulsões/fisiopatologia , Convulsões/etiologia , Convulsões/tratamento farmacológico , Transtornos dos Movimentos/diagnóstico , Seguimentos , Deficiências do Desenvolvimento/etiologiaRESUMO
Introduction: Sepiapterin reductase deficiency (SRD) is an exceedingly rare neurotransmitter disease caused by an enzyme error involved in the synthesis of tetrahydrobiopterin (BH4). It has been described in nearly 60 cases so far. The clinical manifestations include motor and speech delay, axial hypotonia, dystonia, weakness, oculogyric crises, diurnal fluctuation, and improvement of symptoms during sleep. Molecular genetic analysis can demonstrate pathogenic mutations in the SPR gene, allowing for a definitive diagnosis. Levodopa/carbidopa and 5-hydroxytryptophan are used for treatment. Case Presentation: We present a 19-year-old male patient who was evaluated for dysarthria, axial hypotonia, limb dystonia, and movement disorder. The parents described the current patient's history with febrile seizures since 9 months of age, as well as speech and neuromotor developmental retardation, which indicated that the disease began in infancy. The basal metabolic work-up was normal except for hyperprolactinemia. The definitive diagnosis of SRD was confirmed by whole exome sequencing (WES) analysis, which revealed a homozygous pathogenic mutation c.655C>T (p.Arg219*) (rs779204655) in the SPR gene. After treatment, we noted significant improvements in dystonia, axial hypotonia, and dysarthria. Conclusion: WES analysis offers a more expeditious and dependable method for diagnosing difficult cases exhibiting neurodevelopmental problems and thus renders the possibilities of early management.
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The aim of this study was to evaluate the health-related quality of life (HRQoL) in adolescents with psychogenic nonepileptic seizures (PNESs) and to identify factors affecting the quality of life in these patients. Thirty-four adolescents with PNESs were compared to 30 adolescents without any psychiatric disorder. The Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Version (K-SADS-PL) was applied to determine comorbid psychiatric disorders in the study group and to rule out any psychiatric disorder in the control group. The Pediatric Quality-of-Life Inventory (PedsQL) was used to assess the HRQoL. Physical HRQoL and psychosocial HRQoL, including emotional and school functioning, were found to be significantly lower in adolescents with PNESs. In the group with PNESs, the physical HRQoL and total HRQoL of adolescents with somatoform disorders other than PNESs and the emotional functioning of adolescents with major depressive disorder were worse than those of the adolescents without these comorbid psychiatric disorders. Seizure frequency and the duration of symptoms were not correlated with HRQoL scores. Treatment strategies in adolescents with PNESs should regard comorbid unexplained somatic symptoms and psychiatric disorders in addition to the reduction or cessation of seizures.
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Transtornos Psicofisiológicos/complicações , Qualidade de Vida , Convulsões/complicações , Convulsões/psicologia , Transtornos Somatoformes/complicações , Adolescente , Criança , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Transtornos Somatoformes/psicologia , Estatísticas não Paramétricas , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background. METHODS: Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 (KCTD7) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue. RESULTS: Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7. DISCUSSION: These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.
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Mutação , Epilepsias Mioclônicas Progressivas/genética , Canais de Potássio/genética , Animais , Western Blotting , Química Encefálica , Células Cultivadas , Mapeamento Cromossômico , Homozigoto , Humanos , Espaço Intracelular , Camundongos , Microscopia de Fluorescência , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , TurquiaRESUMO
Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.
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Fatores de Ribosilação do ADP/genética , Córtex Cerebral/fisiologia , Fatores de Troca do Nucleotídeo Guanina/genética , Proteínas de Saccharomyces cerevisiae , Adolescente , Sequência de Aminoácidos , Animais , Divisão Celular , Movimento Celular , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Mutação , Neurônios/fisiologiaRESUMO
Joubert syndrome is a congenital brain malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation (crossing in the brain) affecting the corticospinal tract and superior cerebellar peduncles. Individuals with Joubert syndrome have motor and behavioral abnormalities, including an inability to walk due to severe clumsiness and 'mirror' movements, and cognitive and behavioral disturbances. Here we identified a locus associated with Joubert syndrome, JBTS3, on chromosome 6q23.2-q23.3 and found three deleterious mutations in AHI1, the first gene to be associated with Joubert syndrome. AHI1 is most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicates that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors.
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Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Deficiências do Desenvolvimento/genética , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular , Animais , Encéfalo/anormalidades , Encéfalo/embriologia , Encéfalo/metabolismo , Tronco Encefálico/anormalidades , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Filogenia , SíndromeRESUMO
OBJECTIVE: Non-epileptic paroxysmal events (NEPEs) are common in pediatric patients and may be misdiagnosed as epileptic seizures. We aimed to study the distribution of NEPEs across age groups and with different comorbidities, and to correlate the patients' presenting symptoms with their final diagnosis after video-EEG. METHODS: We retrospectively analyzed video-EEG recordings of children aged one month to 18 years who were admitted between March 2005 and March 2020. Patients who experienced any NEPE while under video-EEG monitorization were evaluated in this study. Subjects with concomitant epilepsy were also included. The patients were first divided into 14 groups according to the basic characteristics of symptoms they reported at admission. The events captured on video-EEG were then classified into six NEPE categories based on the nature of the events. These groups were compared according to video-EEG results. RESULTS: We retrospectively evaluated 1338 records of 1173 patients. The final diagnosis was non-epileptic paroxysmal event in 226 (19.3%) of 1173 patients. The mean age of the patients was 105.4 ± 64.4 months at the time of the monitoring. The presenting symptoms were motor in 149/226 (65.9%) patients, with jerking being the most common (n = 40, 17.7%). Based on video-EEG, the most common NEPE was psychogenic non-epileptic seizures (PNES) (n = 66, 29.2%), and the most common PNES subtype was major motor movements (n = 19/66, 28.8%). Movement disorders (n = 46, 20.4%) were the second most common NEPE and the most common NEPE (n = 21/60, 35%) in children with developmental delay (n = 60). Other common NEPEs were physiological motor movements during sleep (n = 33, 14.6%), normal behavioral events (n = 31, 13.7%), and sleep disorders (n = 15, 6.6%). Almost half of the patients had a prior diagnosis of epilepsy (n = 105, 46.5%). Following the diagnosis of NEPE, antiseizure medication (ASM) was discontinued in 56 (24.8%) patients. CONCLUSION: Non-epileptiform paroxysmal events can be difficult to distinguish from epileptic seizures in children, especially in patients with developmental delay, epilepsy, abnormal interictal EEG, or abnormal MRI findings. Correct diagnosis of NEPEs by video-EEG prevents unnecessary ASM exposure in children and guides appropriate management of NEPEs.
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Epilepsia , Humanos , Criança , Estudos Retrospectivos , Diagnóstico Diferencial , Epilepsia/diagnóstico , Convulsões/diagnóstico , Convulsões/psicologia , Eletroencefalografia/métodos , Gravação em Vídeo/métodosRESUMO
Conversion disorder (CD) in children remains a major challenge both in pediatric and mental health clinics and is still a prevalent psychiatric disorder in developing countries. The authors describe a 10-year-old boy with the complaints of inability to walk, speak or eat, excessive drooling, urinary and fecal incontinence, disturbance from light and sound, and expression of needs only by eye movements. The patient diagnosed with CD was followed by the Department of Child and Adolescent Psychiatry with play therapy, individual psychotherapy and family therapy. At the end of three months, the patient was discharged. This is one of the most challenging cases of CD in children. The most important aim of the treatment is to understand the need for conversion symptoms and to constitute a healthy psychological environment for the child rather than to remove the physical symptoms.