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OBJECTIVE: This study aimed to assess the prevalence and characteristics of epilepsy in dystrophinopathies within a cohort of 142 patients at a tertiary neuromuscular center in Istanbul, Turkey. METHODS: We recorded the age at seizure onset, seizure type, family history, history of febrile seizures, treatment, and EEG results. Epilepsy was classified according to the latest International League Against Epilepsy (ILAE) classification. RESULTS: Of the 142 DMD patients, 8 experienced epileptic seizures (5.6 %). The median age of the patients was 11 years (8.0-15.2). The median age for the first DMD symptoms was 24 months (16.5-37.5). All seizures were consistent with generalized tonic-clonic seizures. Three patients are currently on anti-seizure medication. SIGNIFICANCE: The prevalence of epilepsy in our study (5.6 %) exceeds that of the general pediatric population (0.5-1 %). However, the frequency of febrile seizures in children with dystrophinopathy is similar to that of the general population.
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Epilepsia , Convulsões Febris , Humanos , Criança , Pré-Escolar , Estudos Retrospectivos , Epilepsia/complicações , Epilepsia/epidemiologia , Epilepsia/diagnóstico , Convulsões , Anamnese , EletroencefalografiaRESUMO
OBJECTIVES: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant neurodegenerative disease, which is characterized by iron accumulation in the basal ganglia. BPAN is associated with pathogenic variation in WDR45, which has been reported almost exclusively in females most probably due to male lethality in the hemizygous state. METHODS: Whole exome sequencing (WES) and targeted deep sequencing were performed for a male with a clinical diagnosis of BPAN at the age of 37. RESULTS: The novel frameshift variant in WDR45 detected by WES was further analyzed with targeted resequencing to detect a mosaic variant with a level of 85.5% in the blood sample of the proband. DISCUSSION: Although the main role of WDR45 remains elusive, recent studies show that WDR45 may contribute to neurodegeneration through defects in autophagy, iron storage and ferritin metabolism, mitochondria organization, and endoplasmic reticulum homeostasis. The extend of spatiotemporal haploinsufficiency of WDR45 frameshifting variants caused by mosaicism in males may lead to variable clinical severity, which may be hard to elaborate clinically. Promising genetic analysis strategies using targeted deep sequencing may help determine the clinical outcome of somatic mosaicism in neurological disorders including BPAN. Additionally, we suggest that deep sequencing should be conducted in cerebrospinal fluid samples to provide more reliable results in terms of reflecting the mosaicism level in the brain for future studies.
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In this study, we aimed to determine the genetic basis of a Turkish family related to hereditary spastic paraplegia (HSP) by exome sequencing. HSP is a progressive neurodegenerative disorder and displays genetic and clinical heterogeneity. The major symptoms are muscle weakness and spasticity, especially in the lower extremities. We studied seven affected and seven unaffected family members, as well as a clinically undetermined member, to identify the disease-causing gene. Exome sequencing was performed for four affected and two unaffected individuals. The variants were firstly filtered for HSP-associated genes, and we found a common variant in the ZFYVE27 gene, which has been previously implied for association with HSP. Due to the incompletely penetrant segregation pattern of the ZFYVE27 variant, revealed by Sanger sequencing, with the disease in this family, filtering was re-performed according to the mode of inheritance and allelic frequencies. The resulting 14 rare variants were further evaluated in terms of their cellular functions, and three candidate variants in ATAD3C, VPS16, and MYO1H genes were selected as possible causative variants, which were analyzed for their familial segregation. ATAD3C and VPS16 variants were eliminated due to incomplete penetrance. Eventually, the MYO1H variant NM_001101421.3:c.2972_2974del (p.Glu992del, rs372231088) was found as the possible disease-causing deletion for HSP in this family. This is the first study reporting the possible role of a MYO1H variant in HSP pathogenesis. Further studies on the cellular roles of Myo1h protein are needed to validate the causality of MYO1H gene at the onset of HSP.
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Miosina Tipo I , Paraplegia Espástica Hereditária , Humanos , Padrões de Herança , Mutação , Miosina Tipo I/genética , Linhagem , Proteínas/genética , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Proteínas de Transporte Vesicular/genética , Sequenciamento do ExomaRESUMO
OBJECTIVE: The link between headache and epilepsy is more prominent in patients with idiopathic/genetic epilepsy (I/GE). We aimed to investigate the prevalence of headache and to cluster patients with regard to their headache and epilepsy features. METHODS: Patients aged 6-40 years, with a definite diagnosis of I/GE, were consecutively enrolled. The patients were interviewed using standardized epilepsy and headache questionnaires, and their headache characteristics were investigated by experts in headache. Demographic and clinical variables were analyzed, and patients were clustered according to their epilepsy and headache characteristics using an unsupervised K-means algorithm. RESULTS: Among 809 patients, 508 (62.8%) reported having any type of headache; 87.4% had interictal headache, and 41.2% had migraine. Cluster analysis revealed two distinct groups for both adults and children/adolescents. In adults, subjects having a family history of headache, ≥5 headache attacks, duration of headache ≥ 24 months, headaches lasting ≥1 h, and visual analog scale scores > 5 were grouped in one cluster, and subjects with juvenile myoclonic epilepsy (JME), myoclonic seizures, and generalized tonic-clonic seizures (GTCS) were clustered in this group (Cluster 1). Self-limited epilepsy with centrotemporal spikes and epilepsy with GTCS alone were clustered in Cluster 2 with the opposite characteristics. For children/adolescents, the same features as in adult Cluster 1 were clustered in a separate group, except for the presence of JME syndrome and GTCS alone as a seizure type. Focal seizures were clustered in another group with the opposite characteristics. In the entire group, the model revealed an additional cluster, including patients with the syndrome of GTCS alone (50.51%), with ≥5 attacks, headache lasting >4 h, and throbbing headache; 65.66% of patients had a family history of headache in this third cluster (n = 99). SIGNIFICANCE: Patients with I/GE can be clustered into distinct groups according to headache features along with seizures. Our findings may help in management and planning for future studies.
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Epilepsia Generalizada , Epilepsia Mioclônica Juvenil , Adolescente , Adulto , Criança , Análise por Conglomerados , Estudos de Coortes , Eletroencefalografia , Epilepsia Generalizada/diagnóstico , Cefaleia/epidemiologia , Humanos , ConvulsõesRESUMO
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurological disease with childhood or adult onset. It is a subtype of clinically and genetically heterogeneous group of disorders, collectively known as neurodegeneration with brain iron accumulation . MPAN is generally associated with biallelic pathogenic variants in C19orf12. Herein, we describe genetic and clinical findings of two MPAN cases from Turkey. In the first case, we have identified the relatively common pathogenic variant of C19orf12 in the homozygous state, which causes late-onset MPAN. The second case was homozygous for an essential splice-site variation.
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Membranas Mitocondriais , Proteínas Mitocondriais , Encéfalo/patologia , Seguimentos , Humanos , Proteínas Mitocondriais/genética , MutaçãoRESUMO
OBJECTIVE: The purpose of this paper is to describe a child with auditory neuropathy spectrum disorder (ANSD) associated with Brown-Vialetto-Van Laere (BVVL) syndrome, which is a rare, inherited, neurodegenerative disorder that is caused by defects in riboflavin transporter genes. DESIGN: We report the audiological and clinical profile of a child who presented with a complaint of sudden loss of speech understanding associated with an atypical form of ANSD. He was later diagnosed with BVVL. STUDY SAMPLE: An 11-year-old boy with ANSD associated with BVVL. RESULTS: The patient's severe neurological symptoms improved within a year of supplementation with high doses of riboflavin. His fluctuating hearing loss and 0% WDS remained unchanged. The patient was able to use hearing aids without any discomfort after treatment initiation, but he stopped using them again due to a lack of benefit in speech understanding. Although cochlear implantation was recommended, the patient and his family decided not to consider it for another year since they still had hope for complete recovery. CONCLUSIONS: Sudden-onset ANSD can be the earliest sign of undetected BVVL syndrome. Early detection of BVVL is crucial since all symptoms can be reversible with an early intervention of high doses of riboflavin supplementation.
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Paralisia Bulbar Progressiva , Perda Auditiva Neurossensorial , Paralisia Bulbar Progressiva/diagnóstico , Paralisia Bulbar Progressiva/tratamento farmacológico , Paralisia Bulbar Progressiva/genética , Criança , Perda Auditiva Central , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Mutação , Riboflavina/genética , Riboflavina/uso terapêuticoRESUMO
BACKGROUND: Genetic defects of monoamine neurotransmitters are rare neurological diseases amenable to treatment with variable response. They are major causes of early parkinsonism and other spectrum of movement disorders including dopa-responsive dystonia. OBJECTIVES: The objective of this study was to conduct proteomic studies in cerebrospinal fluid (CSF) samples of patients with monoamine defects to detect biomarkers involved in pathophysiology, clinical phenotypes, and treatment response. METHODS: A total of 90 patients from diverse centers of the International Working Group on Neurotransmitter Related Disorders were included in the study (37 untreated before CSF collection, 48 treated and 5 unknown at the collection time). Clinical and molecular metadata were related to the protein abundances in the CSF. RESULTS: Concentrations of 4 proteins were significantly altered, detected by mass spectrometry, and confirmed by immunoassays. First, decreased levels of apolipoprotein D were found in severe cases of aromatic L-amino acid decarboxylase deficiency. Second, low levels of apolipoprotein H were observed in patients with the severe phenotype of tyrosine hydroxylase deficiency, whereas increased concentrations of oligodendrocyte myelin glycoprotein were found in the same subset of patients with tyrosine hydroxylase deficiency. Third, decreased levels of collagen6A3 were observed in treated patients with tetrahydrobiopterin deficiency. CONCLUSION: This study with the largest cohort of patients with monoamine defects studied so far reports the proteomic characterization of CSF and identifies 4 novel biomarkers that bring new insights into the consequences of early dopaminergic deprivation in the developing brain. They open new possibilities to understand their role in the pathophysiology of these disorders, and they may serve as potential predictors of disease severity and therapies. © 2020 International Parkinson and Movement Disorder Society.
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Erros Inatos do Metabolismo dos Aminoácidos , Distúrbios Distônicos , Biomarcadores , Humanos , Proteômica , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Epilepsy is highly prevalent in patients with tuberous sclerosis complex (TSC). Everolimus showed higher efficacy than placebo for seizures in the primary analysis of the EXIST-3 study. Here, we present the long-term outcomes of everolimus at the end of the postextension phase (PEP; data cutoff date: October 25, 2017). METHODS: After completion of the extension phase, patients were invited to continue everolimus in the PEP with everolimus (targeted trough concentration = 5-15 ng/ml, investigator-judged). Efficacy assessments included changes in seizure status during the PEP collected at 12-week intervals as parent/caregiver-reported data through a structured questionnaire. RESULTS: Among 361 patients, 343 entered the extension phase and 249 entered the PEP. After 12 weeks in the PEP, 18.9% (46/244) of patients were seizure-free since the last visit of the extension phase and 64.8% (158/244) had a stable/improved seizure status. At 24 weeks, the corresponding percentages were 18.2% (42/231) and 64.5% (149/231). Among 244 patients, the response rate was 32.8% (80/244) during the 12-week maintenance period of the core phase and 63.9% (156/244) at the end of the extension phase. Of the 149 responders at the end of the extension phase, 70.5% were seizure-free or had stable/improved seizure status. Long-term efficacy data showed persistent responses were observed in 183 of 361 patients (50.7%); 63.9% of these patients had a response that lasted at least 48 weeks. The most frequent Grade 3-4 adverse events (≥2% incidence) reported throughout the study were pneumonia, status epilepticus, seizure, stomatitis, neutropenia, and gastroenteritis. Four patients died during the study. SIGNIFICANCE: The final analysis of EXIST-3 demonstrated the sustained efficacy of everolimus as adjunctive therapy in patients with TSC-associated treatment-refractory seizures, with a tolerable safety profile.
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Epilepsia , Esclerose Tuberosa , Terapia Combinada , Epilepsia/tratamento farmacológico , Everolimo/efeitos adversos , Humanos , Convulsões/induzido quimicamente , Convulsões/etiologia , Resultado do Tratamento , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológicoRESUMO
BACKGROUND: Although the courses of self-limited focal epilepsies of childhood are considered as benign, a handful of studies suggested that these children may suffer from cognitive problems. Implementing tailor-made educational strategies would aid these children to reach their full potentials. Therefore, it is crucial to understand and differentiate the complete neuropsychological and behavioral profiles of these rather common syndromes. We aimed to examine the distinct cognitive and behavioral profiles of the Panayiotopoulos syndrome (PS) and the Gastaut syndrome (GS), comparatively. METHOD: Twenty patients with PS, 20 patients with GS, and 20 healthy controls have been recruited. The testing protocol included Wechsler Intelligence Scale for Children-Revised, Conner's Continuous Performance Test, Verbal Fluency Test, Stroop Color and Word Test, Color Trails Test, Tower of London Test, Symbol Digit Modalities Test, California Verbal Learning Test-Children's Version, Rey Complex Figure Test, Benton Face Recognition Test, Benton Judgment of Line Orientation, Peabody Picture Vocabulary Test, Reading and Writing Test, Child Behavior Checklist, Conner's Parent Rating Scale-48, and Behavior Rating Inventory of Executive Function. Demographical, clinical, electrophysiological data, and imaging findings have also been evaluated. RESULTS: With regard to intelligence, the patients with PS scored less in all scales compared to the healthy controls. However, only the performance IQ (intelligence quotient) scores differed significantly between the patient groups, with the patients with PS scoring lower than the patients with GS. Verbal memory problems were eminent in both of the patient groups; whereas, visual memory was impaired only in the group with PS. Psychomotor speed was affected in both groups. Reading problems were prominent only in the patients with PS. Writing and arithmetic skills were defective in both patient groups. There were no noteworthy behavioral problems in comparison to healthy subjects. CONCLUSION: Using neuropsychological profiles, this study demonstrated that the GS and the PS are two distinct entities. Cognitive dysfunction is a more prominent and widespread feature of the patients with PS; whereas, the patients with GS suffer only from milder and isolated cognitive problems.
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Epilepsias Parciais/diagnóstico , Síndrome de Lennox-Gastaut/diagnóstico , Testes Neuropsicológicos , Adolescente , Estudos de Casos e Controles , Criança , Comportamento Infantil , Cognição , Diagnóstico Diferencial , Epilepsias Parciais/fisiopatologia , Epilepsias Parciais/psicologia , Feminino , Humanos , Testes de Inteligência , Síndrome de Lennox-Gastaut/fisiopatologia , Síndrome de Lennox-Gastaut/psicologia , Masculino , Desempenho PsicomotorRESUMO
Tuberous sclerosis (TSC) is an autosomal dominantly inherited genetic disorder that chiefly affects the central nervous system, along with the other multiple systems. While phenomenology and symptom severity may vary greatly from one individual to another, the most common neurological presentation is epilepsy, which may be refractory in a considerable number of patients. Convulsive SE is seen frequently in TSC patients due to the high ratio of refractory seizures in well-studied cohorts. Status epilepticus (SE) is a life-threating condition and requires urgent medical care. Non-convulsive status epilepticus (NCSE) is an epileptic state with no convulsive seizures but impaired consciousness and corresponding electrophysiological findings. Due to its heterogeneity of clinical features, it is generally hard to recognize, and thus difficult to treat promptly. The relationship between TSC and NCSE is a relatively less emphasized issue in the literature. Here, we present two cases of TSC with NCSE with a view to increasing clinicians' awareness of the association between refractory epilepsy and NCSE.
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Estado Epiléptico/etiologia , Esclerose Tuberosa/complicações , Criança , Humanos , Masculino , Estado Epiléptico/diagnósticoRESUMO
INTRODUCTION: Pathogenic variations in C19orf12 are responsible for two allelic diseases: mitochondrial membrane protein-associated neurodegeneration (MPAN); and spastic paraplegia type 43 (SPG43). MPAN is an orphan disease, which presents with spasticity, dystonia, peripheral nerve involvement, and dementia. The pattern of iron accumulation on brain MRI may be a clue for the diagnosis of MPAN. SPG43, on the other hand, is characterised by progressive lower limb spasticity without brain iron accumulation. We here present clinical and genetic findings of MPAN patients with potentially pathogenic C19orf12 variants. MATERIALS AND METHODS: Patients from 13 different families having progressive motor symptoms with irritative pyramidal signs and brain iron accumulation were screened for C19orf12 gene variants. RESULTS: C19orf12 screening identified seven variants associated with MPAN in eight patients from seven families. We associated two pathogenic variants (c.24G > C; p.(Lys8Asn) and c.194G > A; p.(Gly65Glu)) with the MPAN phenotype for the first time. We also provided a genetic diagnosis for a patient with an atypical MPAN presentation. The variant c.32C > T; p.(Thr11Met), common to Turkish adult-onset MPAN patients, was also detected in two unrelated late-onset MPAN patients. CONCLUSIONS: Genetic analysis along with thorough clinical analysis supported by radiological findings will aid the differential diagnosis of MPAN within the neurodegeneration with brain iron accumulation spectrum as well as other disorders including hereditary spastic paraplegia. Dystonia and parkinsonism may not be the leading clinical findings in MPAN patients, as these are absent in the atypical case. Finally, we emphasise that the existence of frameshifting variants may bias the age of onset toward childhood.
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Doenças Raras , Adulto , Humanos , Proteínas Mitocondriais , Mutação , Fenótipo , TurquiaRESUMO
OBJECTIVE: The present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin ) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin . METHODS: A model-based approach was used to predict patients' daily Cmin . Time-normalized Cmin (TN-Cmin ) was calculated as the average predicted Cmin in a time interval. TN-Cmin was used to link exposure to efficacy and safety end points via model-based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure-response relationship for seizure frequency (SF). An extended Cox regression model was used to link exposure to the time to first adverse event. RESULTS: There was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN-Cmin and SF, regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN-Cmin were not associated with statistically significant increases in the risk of stomatitis or infections. SIGNIFICANCE: The recommended TDM is to target everolimus Cmin within a range of 5-7 ng/mL initially and 5-15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP3A4/P-glycoprotein inducers/inhibitors.
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Monitoramento de Medicamentos/métodos , Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/etiologia , Esclerose Tuberosa/complicações , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Indutores do Citocromo P-450 CYP3A/farmacocinética , Indutores do Citocromo P-450 CYP3A/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Everolimo/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto JovemRESUMO
Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal storage disorder involving the white matter of the peripheral and the central nervous systems. It is caused by a deficiency of galactocerebrosidase enzyme activity. The most common manifestation is the classical early onset KD that leads to patient's loss before the age of 2. Herein, we report the evaluation of a consanguineous family with three affected children manifesting severe neurological findings that ended with death before the age of 2, in an attempt to provide genetic diagnosis to the family. One of the children underwent detailed physical and neurological examinations, including brain magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) evaluations. GALC genetic testing on this child enabled identification of a novel homozygous variant (NM_000153.3: c.1394C>T; p.(Thr465Ile)), which confirmed diagnosis as KD. Familial segregation of this variant was performed by PCR amplification and Sanger sequencing that revealed the parents as heterozygous carriers. We believe this novel GALC variant will not only help in genetic counseling to this family but will also aid in identification of future KD cases.
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Galactosilceramidase/genética , Homozigoto , Leucodistrofia de Células Globoides/enzimologia , Leucodistrofia de Células Globoides/genética , Mutação , Encéfalo/diagnóstico por imagem , Consanguinidade , Família , Evolução Fatal , Feminino , Humanos , Lactente , Leucodistrofia de Células Globoides/diagnóstico por imagem , MasculinoRESUMO
INTRODUCTION: DBS is initially used for treatment of essential tremor and Parkinson's disease in adults. In 1996, a child with severe life-threatening dystonia was offered DBS to the internal globus pallidus (GPi) with lasting efficacy at 20 years. Since that time, increasing number of children benefited from DBS. PATIENTS AND METHODS: We retrospectively evaluated our database of patients who underwent DBS from 2011 to 2017. All patients ≤ 17 years of age at the time of implantation of DBS were included in this series. Subjective Benefit Rating Scale (SBRS), Hoehn Yahr Scale (HYS), Fahn Marsden Rating Scale (FMRS), Clinical Global Impressions Scales (CGI), and Yale Global Tic Severity Scale (YGT) were used to evaluate clinical outcome. RESULTS: Between May 2014 and October 2017, 11 children underwent DBS procedure in our institution. Six of them were female and five of them were male. Mean age at surgery was 11.8 ± 4.06 years (range 5-17 years). In our series, four patients had primary dystonia (PDY) (36.3%), three patients had secondary dystonia (SDY) (27.2%), two patients had JP (18.1%), and two patients had Tourette Syndrome (TS) (18.1%). Two JP patients underwent bilateral STN DBS while the other nine patients underwent bilateral GPi DBS. SBRS scores were 1.75 ± 0.5 for patients with PDY, 3 ± 0 for patients with JP, 2.5 ± 0.7 for patients with TS, and 2 ± 1 for patients with SDY. Mean FMRS reduction rate was 40.5 for patients with dystonia. Significant improvement was also defined in patients with TS and JP after DBS. None of the patients experienced any intracerebral hemorrhage or other serious adverse neurological effect related to the DBS. Wound complications occurred in two patients. CONCLUSION: There are many literatures that support DBS as a treatment option for pediatric patients with medically refractory neurological disorders. DBS has replaced ablative procedures as a treatment of choice not only for adult patients, but also for pediatric patients. Wound-related complications still remain the most common problem in pediatric patients. Development of smaller and more flexible hardware will improve quality of children's life and minimize wound-related complications in the future.
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Estimulação Encefálica Profunda/métodos , Distonia/cirurgia , Globo Pálido/cirurgia , Transtornos Parkinsonianos/cirurgia , Síndrome de Tourette/cirurgia , Adolescente , Criança , Pré-Escolar , Distonia/diagnóstico por imagem , Feminino , Globo Pálido/diagnóstico por imagem , Humanos , Masculino , Transtornos Parkinsonianos/diagnóstico por imagem , Estudos Retrospectivos , Síndrome de Tourette/diagnóstico por imagemRESUMO
Charcot-Marie-Tooth (CMT) disease is a hereditary neurologic disease which affects the sensorial and motor fibers of the peripheral nerves. CMTX1 is an X-linked dominantly inherited subtype of CMT and is caused by mutations in gap junction beta 1 gene (GJB1). A small proportion of GJB1 mutations are associated with recurrent central nervous system findings. We describe a 15-year-old male patient with CMTX1 who had stroke-like findings along with foot deformities and peripheral neuropathy. Strokes and stroke-like attacks are rarely seen in children and adolescents. Herein, neurological signs, MRI findings and genetic results of a CMTX1 case are presented and discussed.
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Doença de Charcot-Marie-Tooth/genética , Ataque Isquêmico Transitório , Acidente Vascular Cerebral , Adolescente , Conexinas , Humanos , Ataque Isquêmico Transitório/genética , Masculino , MutaçãoRESUMO
Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined. Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein. We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation.
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Proteínas Reguladoras de Apoptose/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Proteínas Mitocondriais/genética , Mutação/genética , Adolescente , Adulto , Células Cultivadas , Criança , Pré-Escolar , Deficiência de Citocromo-c Oxidase , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Lactente , Leucoencefalopatias/enzimologia , Imageamento por Ressonância Magnética , Masculino , Mitocôndrias/metabolismo , Mioblastos/metabolismo , Mioblastos/patologiaRESUMO
BACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2-65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01713946. FINDINGS: Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2-22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3-37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5-49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1-21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8-41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0-48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group. INTERPRETATION: Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures. FUNDING: Novartis Pharmaceuticals Corporation.
Assuntos
Anticonvulsivantes/uso terapêutico , Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Convulsões/tratamento farmacológico , Esclerose Tuberosa/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Terapia Combinada , Relação Dose-Resposta a Droga , Método Duplo-Cego , Everolimo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To examine the incidence of restless legs syndrome (RLS) among children with iron deficiency, or iron deficiency anemia, or both, and the relationship between RLS prevalence and serum ferritin levels. METHODS: This prospective, cross-sectional, case controlled study was carried out between January and June 2013, and included 98 iron deficiency and/or iron deficiency anemia, and 102 healthy children referred to the Neurology and Pediatric Departments of the Medical Faculty of Bezmialem Vakif University, Istanbul, Turkey. Both groups were evaluated according to the International Restless Legs Syndrome Study Group diagnostic criteria. RESULTS: The range of ferritin levels was 0.01-12 mg/ml in patients while it was 12.3-91.8 mg/mL in the control group. Restless legs syndrome was detected in 61.2% of children with iron deficiency anemia, and in 37.3% of children with normal biochemistry values. A statistically significant correlation was found between serum ferritin levels and frequency of RLS. In patients with serum ferritin levels higher than 50 ng/ml, 92.3% had no RLS, while 55.2% of patients with serum ferritin levels lower than 50 ng/ml had RLS. The patients with serum ferritin levels of > 50 ng/ml had a significantly higher incidence of RLS. Serum ferritin levels were significantly different between the 2 groups. CONCLUSION: The incidence of RLS, also known as Willis-Ekbom Disease, is high in children aged between 8-18 years with iron deficiency, or iron deficiency anemia, or both. This finding supports the importance of iron replacement therapy especially during the growth and development of children.
Assuntos
Anemia Ferropriva/complicações , Ferritinas/sangue , Síndrome das Pernas Inquietas/sangue , Síndrome das Pernas Inquietas/epidemiologia , Adolescente , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Humanos , Imunoensaio , Incidência , Medições Luminescentes , Masculino , Estudos Prospectivos , Turquia/epidemiologiaRESUMO
BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a late complication of measles infection. Immune dysfunction related to genetic susceptibility has been considered in disease pathogenesis. A functional single nucleotide polymorphism (SNP) of granzyme B gene (GZMB) reported in several pathologies may also be involved in susceptibility to SSPE. PATIENTS AND METHODS: An SNP (rs8192917, G â A, RâQ) was screened in 118 SSPE patients and 221 healthy controls (HC) by polymerase chain reaction-restriction fragment length polymorphism. Frequencies were compared between groups. In vitro production of GZMB was measured in controls with different genotypes. RESULTS: The SNP had a minor allele (G) frequency of 0.22 in patients and 0.31 in controls. GG genotype was significantly less frequent in patients (odds ratio, 0.23). G allele carriers produced relatively higher levels of GZMB, when stimulated in vitro. CONCLUSION: These findings implicate possible effect of this genetic polymorphism in susceptibility to SSPE which needs to be confirmed in bigger populations.
Assuntos
Predisposição Genética para Doença/genética , Granzimas/genética , Polimorfismo de Nucleotídeo Único/genética , Panencefalite Esclerosante Subaguda/genética , Adolescente , Adulto , Antígenos CD , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Adulto JovemRESUMO
PURPOSE: In Developmental and Epileptic Encephalopathies (DEEs), identifying the precise genetic factors guides the clinicians to apply the most appropriate treatment for the patient. Due to high locus heterogeneity, WES analysis is a promising approach for the genetic diagnosis of DEE. Therefore, the aim of the present study is to evaluate the utility of WES in the diagnosis and treatment of DEE patients. METHODS: The exome data of 29 DEE patients were filtrated for destructive and missense mutations in 1896 epilepsy-related genes to detect the causative variants and examine the genotype-phenotype correlations. We performed Sanger sequencing with the available DNA samples to follow the co-segregation of the variants with the disease phenotype in the families. Also, the structural effects of p.Asn1053Ser, p.Pro120Ser and p.Glu1868Gly mutations on KCNMA1, NPC2, and SCN2A proteins, respectively, were evaluated by molecular dynamics (MD) and molecular docking simulations. RESULTS: Out of 29, nine patients (31%) harbor pathological (P) or likely pathological (LP) mutations in SCN2A, KCNQ2, ATP1A2, KCNMA1, and MECP2 genes, and three patients have VUS variants (10%) in SCN1A and SCN2A genes. Sanger sequencing results indicated that three of the patients have de novo mutations while eight of them carry paternally and/or maternally inherited causative variants. MD and molecular docking simulations supported the destructive effects of the mutations on KCNMA1, NPC2, and SCN2A protein structures. CONCLUSION: Herein we demonstrated the effectiveness of WES for DEE with high locus heterogeneity. Identification of the genetic etiology guided the clinicians to adjust the proper treatment for the patients.