RESUMO
UNLABELLED: We describe a 5-year-old girl with marked hypotonia, poor feeding and reduced facial expression since birth. Congenital myopathy was suspected; muscle biopsy showed unspecific type 1 fibre predominance. The possibility of a ryanodine receptor 1 gene (RYR1)-associated myopathy was considered, but not further investigated. At the age of 2 years, she presented with exophthalmos. Brain MRI revealed optic pathway glioma. On clinical examination, she had six café-au-lait spots, thus fulfilling the diagnostic criteria for neurofibromatosis type 1 (NF1). The hypotonia was then attributed to NF1. At the age of 3 years, she developed scoliosis and had an unusually severe motor delay for NF1, as she was not able to walk independently. Dual pathology was suspected, and muscle MRI showed the typical pattern for RYR1-related myopathy. This was genetically confirmed with the discovery of two heterozygous mutations. CONCLUSION: NF1 is one of the most frequent genetic diseases in children. RYR1-related myopathy is one of the most frequent causes of congenital myopathy. The combination of these two pathologies has not yet been described. In cases of unusual presentations or clinical course, the possibility of genetic "double trouble" should be considered.
Assuntos
Anormalidades Múltiplas , DNA/genética , Genes da Neurofibromatose 1 , Mutação de Sentido Incorreto , Miopatia da Parte Central/genética , Neurofibromatose 1/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Biópsia , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética , Miopatia da Parte Central/diagnóstico , Miopatia da Parte Central/metabolismo , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/metabolismo , Fenótipo , Músculo Quadríceps/metabolismo , Músculo Quadríceps/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismoRESUMO
Sunflower epilepsy is a rare photosensitive and commonly pharmacoresistant reflex epilepsy characterized by stereotyped seizures involving turning of the head towards light, similar to a sunflower turning towards the sun, and waving of the hands in front of the eyes, sometimes followed by absence seizures, myoclonic jerks, and tonic-clonic seizures. In the original description, seizures in sunflower epilepsy have been perceived as self-induced, but contemporary case series suggest that hand waving corresponds to an ictal phenomenon and not to a precipitating factor. We describe a nine-year-old girl featuring absence seizures with eye rolling or fluttering associated with hand waving movements. The chronological sequence of events based on a video-EEG-documented episode of our patient adds to the controversy surrounding the hypothesis of "self-induced" epileptic seizures in sunflower epilepsy. Shortly after epilepsy diagnosis, our patient presented with an EEG pattern of continuous spike waves in slow-wave sleep, an EEG feature that has not been described before and may relate to the cognitive deficit observed in some patients with sunflower epilepsy. Continuous spike waves in slow-wave sleep resolved, and lasting seizure freedom was achieved by a combination of ethosuximide and lamotrigine, which may be a possible alternative to valproic acid, particularly in girls and women of childbearing age. However, an attempt to taper anti-seizure drugs two years later led to seizure recurrence. We suggest performing sleep EEG recordings for sunflower epilepsy, particularly in patients with developmental stagnation or regression, to timely diagnose and treat continuous spike waves in slow-wave sleep syndrome.
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Epilepsia Reflexa , Sono de Ondas Lentas , Criança , Eletroencefalografia , Epilepsia Tipo Ausência , Feminino , Humanos , ConvulsõesRESUMO
The neurophysiological mechanisms underlying executive function deficits in very preterm born children still remain unclear. Moreover, evidence on factors that can be modified by behavior and exert an influence on these deficits is lacking. The present case-control study examined the association between very preterm birth and neurophysiological indices of response inhibition (i.e. the N200-P300 complex) as well as the potential mediation of this association by aspects of physical fitness. 54 children born very preterm completed a submaximal cycling ergometer test and a motor skill test battery. Event-related potentials elicited by a Go/NoGo task were recorded using electroencephalography. Cases were then matched to full-term children (age: 11 ± 0.7 y). A higher error rate on NoGo trials was found in children born very preterm compared to those born full-term. Path-analyses further revealed that very preterm birth was associated with decreased NoGo P300 amplitude. Motor skills, but not aerobic fitness, fully mediated this association. In early adolescence, very preterm birth is associated with less effective recruitment of attentional resources for stimulus evaluation processes. The improvement of motor skills rather than cardiorespiratory fitness appears promising for reducing this specific impairment in cognitive control.
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Destreza Motora , Nascimento Prematuro , Adolescente , Criança , Cognição , Potenciais Evocados , Feminino , Humanos , Aptidão Física , GravidezRESUMO
Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3-1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.
Assuntos
Cromossomos Humanos Par 1/genética , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Di-Hidrouracila Desidrogenase (NADP)/genética , Rearranjo Gênico , Deleção de Sequência , Sequência de Bases , Pré-Escolar , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Dados de Sequência Molecular , Pirimidinas/análiseRESUMO
BACKGROUND AND OBJECTIVES: Neonatal arterial ischemic stroke (NAIS) is associated with considerable lifetime burdens such as cerebral palsy, epilepsy, and cognitive impairment. Prospective epidemiologic studies that include outcome assessments are scarce. This study aimed to provide information on the epidemiology, clinical manifestations, infarct characteristics, associated clinical variables, treatment strategies, and outcomes of NAIS in a prospective, population-based cohort of Swiss children. METHODS: This prospective study evaluated the epidemiology, clinical manifestations, vascular territories, associated clinical variables, and treatment of all full-term neonates diagnosed with NAIS and born in Switzerland between 2000 and 2010. Follow-up was performed 2 years (mean 23.3 months, SD 4.3 months) after birth. RESULTS: One hundred neonates (67 boys) had a diagnosis of NAIS. The NAIS incidence in Switzerland during this time was 13 (95% confidence interval [CI], 11-17) per 100,000 live births. Seizures were the most common symptom (95%). Eighty-one percent had unilateral (80% left-sided) and 19% had bilateral lesions. Risk factors included maternal risk conditions (32%), birth complications (68%), and neonatal comorbidities (54%). Antithrombotic and antiplatelet therapy use was low (17%). No serious side effects were reported. Two years after birth, 39% were diagnosed with cerebral palsy and 31% had delayed mental performance. CONCLUSIONS: NAIS in Switzerland shows a similar incidence as other population-based studies. About one-third of patients developed cerebral palsy or showed delayed mental performance 2 years after birth, and children with normal mental performance may still develop deficits later in life.
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Isquemia Encefálica , Acidente Vascular Cerebral , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/epidemiologia , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Estudos Prospectivos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Suíça/epidemiologia , Resultado do TratamentoRESUMO
Array genomic hybridization (AGH) has recently been implemented as a diagnostic tool for the detection of submicroscopic copy number variants (CNVs) in patients with developmental disorders. However, there is no consensus regarding the choice of the platform, the minimal resolution needed and systematic interpretation of CNVs. We report our experience in the clinical diagnostic use of high resolution AGH up to 100 kb on 131 patients with chromosomal phenotypes but previously normal karyotype. We evaluated the usefulness in our clinics and laboratories by the detection rate of causal CNVs and CNVs of unknown clinical significance and to what extent their interpretation would challenge the systematic use of high-resolution arrays in clinical application. Prioritizing phenotype-genotype correlation in our interpretation strategy to criteria previously described, we identified 33 (25.2%) potentially pathogenic aberrations. 16 aberrations were confirmed pathogenic (16.4% syndromic, 8.5% non-syndromic patients); 9 were new and individual aberrations, 3 of them were pathogenic although inherited and one is as small as approx 200 kb. 13 of 16 further CNVs of unknown significance were classified likely benign, for 3 the significance remained unclear. High resolution array allows the detection of up to 12.2% of pathogenic aberrations in a diagnostic clinical setting. Although the majority of aberrations are larger, the detection of small causal aberrations may be relevant for family counseling. The number of remaining unclear CNVs is limited. Careful phenotype-genotype correlations of the individual CNVs and clinical features are challenging but remain a hallmark for CNV interpretation.
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Anormalidades Múltiplas/genética , Transtorno Autístico/genética , Aberrações Cromossômicas , Cromossomos Humanos , Deficiências do Desenvolvimento/genética , Hibridização de Ácido Nucleico/métodos , Estudos de Associação Genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de Ácido Caínico/genética , Receptor de GluK2 CainatoRESUMO
OBJECTIVE: To assess quality of life (QoL) and psychological adjustment in children and adolescents with neurofibromatosis type 1 (NF1). STUDY DESIGN: Forty-six patients with NF1 were investigated between the ages of 7 and 16 years (mean, 11.6 years), with children and parents used as informants. TNO-AZL Questionnaire for Children's Health-Related Quality of Life and Child Behavior Checklist scores were compared with healthy reference groups. Predictive values of sociodemographic variables, illness-related variables, and family-related variables for quality of life and psychological adjustment were assessed. RESULTS: Most dimensions of QoL in NF1 children and adolescents were different from reference values. Deviations in the NF1 group were an impairment of motor, cognitive, and social functioning and a reduction of positive and negative emotions. Also, psychological adjustment in patients with NF1 was significantly impaired compared with normal subjects. Illness-related variables had a negative impact on the emotional domain of QoL. Good family relationships positively affected both QoL and psychological adjustment. CONCLUSIONS: QoL and psychological adjustment are impaired in children and adolescents with NF1. Illness-related variables and the quality of family relationships are important predictors.