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INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is classified according to neurophysiological and histological findings, the inheritance pattern, and the underlying genetic defect. The objective of these guidelines is to offer recommendations for the diagnosis, prognosis, follow-up, and treatment of this disease in Spain. MATERIAL AND METHODS: These consensus guidelines were developed through collaboration by a multidisciplinary panel encompassing a broad group of experts on the subject, including neurologists, paediatric neurologists, geneticists, physiatrists, and orthopaedic surgeons. RECOMMENDATIONS: The diagnosis of CMT is clinical, with patients usually presenting a common or classical phenotype. Clinical assessment should be followed by an appropriate neurophysiological study; specific recommendations are established for the parameters that should be included. Genetic diagnosis should be approached sequentially; once PMP22 duplication has been ruled out, if appropriate, a next-generation sequencing study should be considered, taking into account the limitations of the available techniques. To date, no pharmacological disease-modifying treatment is available, but symptomatic management, guided by a multidiciplinary team, is important, as is proper rehabilitation and orthopaedic management. The latter should be initiated early to identify and improve the patient's functional deficits, and should include individualised exercise guidelines, orthotic adaptation, and assessment of conservative surgeries such as tendon transfer. The follow-up of patients with CMT is exclusively clinical, and ancillary testing is not necessary in routine clinical practice.
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INTRODUCTION: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a biallelic mutation of the SMN1 gene, located on the long arm of chromosome 5, and predominantly affects the motor neurons of the anterior horn of the spinal cord, causing progressive muscle weakness and atrophy. The development of disease-modifying treatments is significantly changing the natural history of SMA, but uncertainty remains about which patients can benefit from these treatments and how that benefit should be measured. METHODOLOGY: A group of experts specialised in neurology, neuropediatrics, and rehabilitation and representatives of the Spanish association of patients with SMA followed the Delphi method to reach a consensus on 5 issues related to the use of these new treatments: general aspects, treatment objectives, outcome assessment tools, requirements of the treating centres, and regulation of their use. Consensus was considered to be achieved when a response received at least 80% of votes. RESULTS: Treatment protocols are useful for regulating the use of high-impact medications and should guide treatment, but should be updated regularly to take into account the most recent evidence available, and their implementation should be assessed on an individual basis. Age, baseline functional status, and, in the case of children, the type of SMA and the number of copies of SMN2 are characteristics that should be considered when establishing therapeutic objectives, assessment tools, and the use of such treatments. The cost-effectiveness of these treatments in paediatric patients is mainly influenced by early treatment onset; therefore, the implementation of neonatal screening is recommended. CONCLUSIONS: The RET-AME consensus recommendations provide a frame of reference for the appropriate use of disease-modifying treatments in patients with SMA.
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Atrofia Muscular Espinal , Doenças Neurodegenerativas , Criança , Consenso , Técnica Delphi , Humanos , Recém-Nascido , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , EspanhaRESUMO
BACKGROUND AND PURPOSE: Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA-binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2. METHODS: Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses of EGR2 were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two-hybrid assay. RESULTS: A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of the EGR2 gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB-EGR2 protein interactions can result in dramatic neuropathy. CONCLUSION: Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission.
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Doença de Charcot-Marie-Tooth/genética , Proteína 2 de Resposta de Crescimento Precoce/genética , Animais , Homozigoto , Humanos , Mutação , Fatores de Transcrição/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.
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Aconselhamento Genético , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/genética , Guias de Prática Clínica como Assunto/normas , Transtornos de Deglutição , Seguimentos , Humanos , Distrofia Miotônica/complicaçõesRESUMO
INTRODUCTION: Some epileptic syndromes are characterised by seizures that are difficult to control and are associated to delayed neuropsychomotor development, which results in a deterioration in the patient's quality of life as well as in that of his or her family. AIM: To evaluate the use of cannabidiol as adjuvant therapy in patients with refractory epilepsies. PATIENTS AND METHODS: An observational study was conducted by means of a survey addressed to the patient's caregiver. Data collected included information about the patient and the caregiver, changes observed in the seizures, neuropsychological effects, side effects and the family's overall perception following the use of cannabidiol. RESULTS: The evaluation examined 15 patients with refractory epilepsies, who received cannabidiol over a period ranging from one month to one year. The frequency of seizures decreased in 40% of the patients, 60% of the patients were seen to have control over 50% of their seizures and in 27% of them the seizures disappeared completely. Neurocognitive changes were also reported: behaviour improved in 73%; 60% reported an improvement in language; in 50% sleep improved; 43% reported improvements in eating habits; and 100% said their mood had improved. The overall perception of the illness was that there had been improvements in 73% of respondents. The most common side effects were drowsiness and fatigue. CONCLUSIONS: These results suggest a possible beneficial effect of cannabidiol on the control of seizures and on the improvement of certain neurocognitive aspects in patients with refractory epilepsies.
TITLE: Cannabidiol: uso en epilepsias refractarias.Introduccion. Algunos sindromes epilepticos se caracterizan por crisis de dificil control y asocian un retraso en el desarrollo neuropsicomotor, lo que conlleva un deterioro en la calidad de vida del paciente y su familia. Objetivo. Evaluar el uso del cannabidiol como tratamiento adyuvante en pacientes con epilepsias refractarias. Pacientes y metodos. Se realizo un estudio observacional por medio de una encuesta dirigida a la persona cuidadora del paciente. Se valoro la informacion sobre el paciente y el cuidador, cambios observados sobre las crisis, efectos neuropsicologicos, efectos adversos y percepcion global de la familia tras el uso del cannabidiol. Resultados. Se evaluo a 15 pacientes con epilepsias refractarias, quienes recibieron cannabidiol durante un periodo de un mes a un año. En el 40% de los pacientes hubo una disminucion en la frecuencia de las crisis, en el 60% de los pacientes se observo un control de mas del 50% de las crisis y en el 27% las crisis desaparecieron totalmente. Tambien se comunicaron cambios neurocognitivos: en el 73% hubo una mejoria del comportamiento; el 60% notifico una mejoria en el lenguaje; el 50%, en el sueño; el 43%, en la alimentacion; y el 100%, en el estado de animo. La percepcion global sobre la enfermedad notifico una mejoria en el 73%. Los efectos adversos mas frecuentes fueron somnolencia y fatiga. Conclusiones. Estos resultados sugieren un posible efecto beneficioso del cannabidiol sobre el control de las crisis y en la mejoria de ciertos aspectos neurocognitivos en pacientes con epilepsias refractarias.
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Canabidiol/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Adulto JovemRESUMO
The new treatments of spinal muscular atrophy (SMA) due by SMN1 gene deletions are reviewed. There are several ways to increase the protein SMN, its activity and persistence in the tissues. Neuroprotective drugs as olesoxime or riluzole, and drugs acting by epigenetic mechanisms, as histone deacetylase inhibitors, have shown positive effects in preclinical studies but no clear efficacy in clinical trials. They might give in the future added benefits when used associated to other genetic modifying drugs. The best improvements in murine models of SMA and in clinical trials have been reached with antisense oligonucleotides, drugs that modify the splicing of SMN2, and they are expected to get better in the near future. Nusinersen, a methoxi-ethyl phosphotioate antisense oligonucleotide has recently approved for treatment of patients with SMA type 1 after having proved its efficacy in clinical trial phase 3. The results of nusinersen are reviewed. New modifications of antisense oligonucleotides with better access to brain, spinal cord and peripheral tissues are on the way. There are data of the efficacy of the genetic therapy with SMN1 gene through adenoassociated virus, now in phase 1 trial. A constant feature of these new treatments is that the earlier the treatment, the best are the results, and they are even better in presymptomatic stage. The general standards of care, particularly nutrition and respiratory management are needed in order to reach optimal results with the new therapies.
TITLE: Posibilidades de tratamiento en la atrofia espinal infantil.Se revisan los nuevos tratamientos de la atrofia muscular espinal (AME) producida por delecion del gen SMN1. Se describen las diferentes posibilidades de incrementar la proteina SMN, de su actividad y persistencia en el organismo. Farmacos neuroprotectores, como olesoxime y riluzol, y farmacos que actuan epigeneticamente, como inhibidores de histona deacetilasa, han mostrado cierto efecto positivo en fases preclinicas pero no han conseguido eficacia en los ensayos clinicos. Podrian proporcionar en un futuro un beneficio añadidos a otros farmacos modificadores geneticos. Los mayores cambios en estudios de modelos del raton SMA y en fases clinicas se han encontrado con oligonucleotidos antisentido que modifican el splicing del gen SMN2, y se espera que mejoren en el futuro proximo. Recientemente se ha aprobado el nusinersen, un metoxietilo fosforotioato-oligonucleotido antisentido, para uso en pacientes con AME de tipo I una vez demostrada su eficacia en pacientes en el ensayo en fase 3. Se revisan los resultados de este farmaco. Estan en marcha modificaciones de oligonucleotidos antisentido que amplien la liberacion en el sistema nervioso y en tejidos perifericos. Hay datos que sugieren eficacia de la terapia genica introduciendo el gen SMN1 mediante virus adenoasociados, actualmente en fase clinica 1. Una constante en estos nuevos tratamientos es que los resultados se optimizan en las etapas precoces de la enfermedad y, mejor aun, en estadio presintomatico. Se subraya la importancia de los cuidados generales optimos, especialmente nutricionales y respiratorios, para conseguir los mejores resultados con las nuevas terapias.
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Atrofias Musculares Espinais da Infância/terapia , Terapias em Estudo , Animais , Criança , Ensaios Clínicos como Assunto , Dependovirus/genética , Modelos Animais de Doenças , Epigênese Genética , Deleção de Genes , Terapia Genética , Vetores Genéticos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Camundongos , Camundongos Mutantes Neurológicos , Estudos Multicêntricos como Assunto , Fármacos Neuroprotetores/uso terapêutico , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , Cuidados Paliativos , Células-Tronco Pluripotentes/transplante , Splicing de RNA , Proteínas Recombinantes/genética , Atrofias Musculares Espinais da Infância/genética , Proteína 1 de Sobrevivência do Neurônio Motor/biossíntese , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/biossíntese , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaRESUMO
BACKGROUND AND PURPOSE: Pompe disease is a rare inheritable muscle disorder for which enzyme replacement therapy (ERT) has been available since 2006. Uniform criteria for starting and stopping ERT in adult patients were developed and reported here. METHODS: Three consensus meetings were organized through the European Pompe Consortium, a network of experts from 11 European countries in the field of Pompe disease. A systematic review of the literature was undertaken to determine the effectiveness of ERT in adult patients on a range of clinical outcome measures and quality of life. A narrative synthesis is presented. RESULTS: Consensus was reached on how the diagnosis of Pompe disease should be confirmed, when treatment should be started, reasons for stopping treatment and the use of ERT during pregnancy. This was based on expert opinion and supported by the literature. One clinical trial and 43 observational studies, covering a total of 586 individual adult patients, provided evidence of a beneficial effect of ERT at group level. At individual patient level, the response to treatment varied, but factors associated with a patient's response to ERT were not described in many studies. Eleven observational studies focused on more severely affected patients, suggesting that ERT can also be beneficial in these patients. There are no studies on the effects of ERT in pre-symptomatic patients. CONCLUSIONS: This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.
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Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Qualidade de Vida , Adulto , Consenso , Esquema de Medicação , Europa (Continente) , Humanos , Guias de Prática Clínica como AssuntoRESUMO
INTRODUCTION: Variant detection protocols for clinical next-generation sequencing (NGS) need application-specific optimization. Our aim was to analyze the performance of single nucleotide variant (SNV) and copy number (CNV) detection programs on an NGS panel for a rare disease. METHODS: Thirty genes were sequenced in 83 patients with hereditary spastic paraplegia. The variant calls obtained with LifeScope, GATK UnifiedGenotyper and GATK HaplotypeCaller were compared with Sanger sequencing. The calling efficiency was evaluated for 187 (56 unique) SNVs and indels. Five multiexon deletions detected by multiple ligation probe assay were assessed from the NGS panel data with ExomeDepth, panelcn.MOPS and CNVPanelizer software. RESULTS: There were 48/51 (94%) SNVs and 1/5 (20%) indels consistently detected by all the calling algorithms. Two SNVs were not detected by any of the callers because of a rare reference allele, and one SNV in a low coverage region was only detected by two algorithms. Regarding CNVs, ExomeDepth detected 5/5 multi-exon deletions, panelcn.MOPs 4/5 and only 3/5 deletions were accurately detected by CNVPanelizer. CONCLUSIONS: The calling efficiency of NGS algorithms for SNVs is influenced by variant type and coverage. NGS protocols need to account for the presence of rare variants in the reference sequence as well as for ambiguities in indel calling. CNV detection algorithms can be used to identify large deletions from NGS panel data for diagnostic applications; however, sensitivity depends on coverage, selection of the reference set and deletion size. We recommend the incorporation of several variant callers in the NGS pipeline to maximize variant detection efficiency.
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Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Paraplegia Espástica Hereditária/genética , Humanos , Doenças Raras/genéticaRESUMO
INTRODUCTION: Ischaemic stroke is rare during childhood. Congenital and acquired heart diseases are one of the most important risk factors for arterial ischaemic stroke (AIS) in children. PATIENTS AND METHODS: We conducted a retrospective study of all children with AIS and heart disease diagnosed between 2000 and 2014. RESULTS: We included 74 children with heart disease who were eligible for inclusion. 60% were boys with a mean stroke age of 11 months. 20% of the patients died during the study period. 90% of the patients had a congenital heart disease, while cyanotic heart disease was identified in 60%. Hypoplastic left heart syndrome was the most frequent heart disease. In 70% of patients AIS was directly associated with heart surgery, catheterisation or ventricular assist devices. Most patients with AIS were in the hospital. Seizures and motor deficit were the most frequent symptoms. Most patient diagnoses were confirmed by brain CT. The AIS consisted of multiple infarcts in 33% of the cases, affected both hemispheres in 27%, and involved the anterior and posterior cerebral circulation in 10%. CONCLUSIONS: Arterial ischaemic strokes were mainly associated with complex congenital heart diseases, and heart procedures and surgery (catheterisation). AIS presented when patients were in-hospital and most of the patients were diagnosed in the first 24hours.
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Cardiopatias/complicações , Cardiopatias/epidemiologia , Acidente Vascular Cerebral/etiologia , Circulação Cerebrovascular , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
Infantile-onset Pompe disease has a fatal prognosis in the short term unless it is diagnosed at an early stage and enzyme replacement therapy is not started as soon as possible. A group of specialists from different disciplines involved in this disease have reviewed the current scientific evidence and have drawn up an agreed series of recommendations on the diagnosis, treatment and follow-up of patients. We recommend establishing enzyme treatment in any patient with symptomatic Pompe disease with onset within the first year of life, with a clinical and enzymatic diagnosis, and once the CRIM (cross-reactive immunological material) status is known.
TITLE: Guia clinica de la enfermedad de Pompe infantil.La enfermedad de Pompe infantil tiene un pronostico fatal a corto plazo si no se diagnostica precozmente ni se inicia un tratamiento enzimatico sustitutivo lo antes posible. Un grupo de especialistas de las diferentes disciplinas involucradas en esta enfermedad ha revisado la evidencia cientifica actual y ha elaborado por consenso una serie de recomendaciones para el diagnostico, el tratamiento y el seguimiento de los pacientes. Se recomienda instaurar tratamiento enzimatico en todo paciente con enfermedad de Pompe sintomatica de comienzo en el primer año de vida, con diagnostico clinico y enzimatico, y una vez conocido el estado CRIM (material inmunologico con reactividad cruzada).
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Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/terapia , Idade de Início , Humanos , LactenteRESUMO
Visuospatial functions are very important in learning process and development of abstract thought during childhood. Several studies show that preterm and low birth weight infants obtain lower scores in test that assess cognitive functions, specially in the first year of life. These differences are attenuated over time, but a developmental delay that affects working memory and visuospatial process still persists. It is unclear what factors are involved in development of these functions, and pre- or perinatal factors may interfere with the proper conduct of the same, but have been described anatomical and physiological differences between the preterm and term brain that could explain somewhere in these alterations. The different selective vulnerability to hypoxia between immature brain in which preoligodendrocytes and subplate neurons predominate, and mature brain, determine differences in the pattern of injury from hypoxia with greater involvement of the periventricular white matter in preterm children. This lesional pattern leaves to a dysfunction in attentional and visuospatial process, due to the increased vulnerability of the regions involved in the dorsal pathway of visual processing.
TITLE: Funciones visuoespaciales y prematuridad.Durante la infancia, las funciones visuoespaciales son importantes en los procesos de aprendizaje y en el desarrollo del pensamiento abstracto. Diferentes estudios muestran que los niños prematuros o con bajo peso al nacer obtienen menores puntuaciones en los tests que valoran las funciones cognitivas, siendo estas diferencias mas pronunciadas durante el primer año de vida. Con el tiempo, estas diferencias se van atenuando, pero persiste un retraso madurativo que afecta a la memoria de trabajo y a los procesos visuoespaciales. No esta claro cuales son los factores implicados en el desarrollo de estas funciones y que factores pre o perinatales pueden interferir en su buen desarrollo, pero se han descrito diferencias anatomicas y fisiologicas entre el cerebro del niño pretermino y el termino que podrian explicar, en parte, alguna de estas alteraciones. La diferente vulnerabilidad selectiva a la hipoxia entre el cerebro inmaduro, en el que predominan las neuronas de la subplaca y los preoligodendrocitos, y el cerebro maduro del niño nacido a termino determinan diferencias en el patron de lesion por hipoxia con mayor afectacion de la sustancia blanca periventricular en el niño pretermino. Este patron lesional conlleva una disfuncion en los procesos atencionales y visuoespaciales debido a la mayor vulnerabilidad de las regiones que intervienen en la ruta dorsal del procesamiento visual.
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Encéfalo/patologia , Doenças do Prematuro/psicologia , Recém-Nascido Prematuro/psicologia , Leucomalácia Periventricular/psicologia , Percepção Espacial/fisiologia , Vias Visuais/patologia , Percepção Visual/fisiologia , Encéfalo/embriologia , Encéfalo/fisiopatologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Hipóxia Fetal/patologia , Hipóxia Fetal/fisiopatologia , Humanos , Hipóxia Encefálica/patologia , Hipóxia Encefálica/fisiopatologia , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido Prematuro/fisiologia , Doenças do Prematuro/patologia , Doenças do Prematuro/fisiopatologia , Deficiências da Aprendizagem/etiologia , Deficiências da Aprendizagem/fisiopatologia , Leucomalácia Periventricular/patologia , Leucomalácia Periventricular/fisiopatologia , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Neurônios/patologia , Oligodendroglia/patologia , Vias Visuais/fisiopatologiaRESUMO
INTRODUCTION: Tuberous sclerosis complex (TSC) is one of the most frequent neurocutaneous disorders. Cortical tubers are the most common pathological changes in TSC and they are directly related to the disease's main clinical manifestations: seizures, mental retardation, and autistic behaviour. OBJECTIVE: The aim of this study is to establish a correlation between tuber size and the severity of clinical features in TSC. MATERIAL AND METHODS: We performed a retrospective study of the clinical and imaging findings from 45 TSC patients (22 females and 23 males) and compared the clinical features with the location, size, and number of the cortical tubers in each patient. RESULTS: Four patients had voluminous tubers located in 1 or both cerebral hemispheres. All of these patients had intractable seizures and severe mental retardation; 3 of these cases also presented with autistic behaviour, despite tubers having been resected in all 4 patients. Thirteen patients had tubers of large-to-average size, and all patients in this group showed intractable seizures and mental retardation. Nine patients who had experienced infantile spasms during the first year of life presented autistic behaviour. Multiple tubers of small to average size were found in 28 patients. In general, this group had seizures that responded well to antiepileptic drugs and a low prevalence of autism. In 3 patients who all presented good seizure control and normal intelligence, single cortical/subcortical tubers were located in the frontal or occipital lobes. Of the total of 45 patients, 13 had cerebellar as well as cerebral tubers; these were generally present in cases with more severe clinical features. CONCLUSIONS: Although large tubers are less common than small to medium-sized ones, they are much more likely to be accompanied by severe clinical symptoms (seizures, mental retardation and autistic behaviour), even when the smaller tubers are quite numerous.
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Esclerose Tuberosa/patologia , Transtorno Autístico/etiologia , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Encéfalo/patologia , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/psicologia , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Convulsões/etiologia , Convulsões/fisiopatologia , Convulsões/psicologia , Esclerose Tuberosa/fisiopatologiaRESUMO
Mutations in the SPG7 gene were initially reported in patients with autosomal recessive hereditary spastic paraplegia (HSP). Recent works suggested a dominant effect for some SPG7 mutations. To characterize the SPG7 mutational spectrum in a large cohort of Spanish HSP patients, we sequenced the whole SPG7 gene in a total of 285 Spastic Paraplegia patients. Large gene rearrangements were also ascertained in some patients. We found a total of 14 SPG7 mutations (12 new) in 14 patients; 2 were large deletions. All the mutation carriers had an adult onset age but only five (35%) had a complicated phenotype. We identified a single mutation in 13 patients. Familial analysis suggested a dominant inheritance for one (p.Leu78*) of these mutations. Carriers of the rare p.A510V variant were significantly more frequent in patients vs healthy controls (3% vs 1%), suggesting a pathogenic role for this SPG7 variant. We reported a high frequency of patients with only one SPG7 mutation, and a putative pathogenic role for the p.A510V variant.
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Substituição de Aminoácidos , Metaloendopeptidases/genética , Mutação , Paraplegia Espástica Hereditária/genética , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Frequência do Gene , Genes Dominantes , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Humanos , Lactente , Pessoa de Meia-Idade , Fenótipo , Espanha , Paraplegia Espástica Hereditária/diagnóstico , Adulto JovemRESUMO
Before 2006, Pompe disease or glycogenosis storage disease type II was an incurable disease whose treatment was merely palliative. The development of a recombinant human alpha-glucosidase enzymatic replacement therapy has become the first specific treatment for this illness. The aim of this guide is to serve as reference for the management of the late-onset Pompe disease, the type of Pompe disease that develops after one year of age. In the guide a group of Spanish experts make specific recommendations about diagnosis, follow-up and treatment of this illness. With regard to diagnosis, the dried blood spots method is essential as the first step for the diagnosis of Pompe disease. The confirmation of the diagnosis of Pompe disease must be made by means of an study of enzymatic activity in isolated lymphocytes or a mutation analysis of the alpha-glucosidase gene. With regard to treatment with enzymatic replacement therapy, the experts say that is effective improving or stabilizating the motor function and the respiratory function and it must be introduced when the first symptoms attributable to Pompe disease appear.
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Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/terapia , Algoritmos , Doença de Depósito de Glicogênio Tipo II/complicações , HumanosRESUMO
INTRODUCTION: Intrauterine infection due to cytomegalovirus is the most common of the intrauterine viral/parasitic infections that affect the central nervous system and cause permanent lesions in the cortex as well as the subcortical white matter. Studies using brain magnetic resonance imaging (MRI) are limited. MATERIAL AND METHODS: Six patients (4 females and 2 males) were studied in the first months of life in order to make a diagnosis of congenital cytomegalovirus, and identify the cortical and subcortical lesions using the necessary MRI sequences. RESULTS: The six patients showed malformations of cortical development (MDC) (schizencephaly, polymicrogyria or lissencephaly-pachygyria) from the neonatal period, and diffuse changes of the white matter, which remained with few changes during the first two years. They then began reducing in size in the form of high signal areas in T2, restricted to certain areas, and were evident for a few years more with little change. CONCLUSION: Intrauterine infection due to cytomegalovirus causes changes in the cortical grey matter, which consists of MDC, and in the subcortical white matter. The latter show a changing aspect as they appear as diffuse and wide areas of high signal intensity, which is usually due to delay in myelinisation, but could also be caused directly by the cytomegalovirus. These changes in the white matter are subjected to morphological changes throughout the first years of life, leading to brain atrophy. The neurological sequelae of these lesions left by these alterations are severe and chronic.
Assuntos
Encéfalo/anormalidades , Córtex Cerebral/anormalidades , Infecções por Citomegalovirus/congênito , Malformações do Desenvolvimento Cortical/patologia , Encéfalo/patologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Ventrículos Cerebrais/patologia , Infecções por Citomegalovirus/patologia , Eletroencefalografia , Feminino , Cabeça/patologia , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Convulsões/etiologia , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: The term focal cortical dysplasia (FCD) describes a particular migration disorder with a symptomatology mainly characterised by drug-resistant epileptic seizures, typical neuroradiological images, and histological characteristics, as well as a very positive response to surgical treatment in the majority of cases. MATERIAL AND METHODS: A total of 7 patients were studied, comprising 6 children with a mean age of 34.3 months and one 25-year-old male with very persistent focal seizures and MRI images that showed FCD. RESULTS: Three of the patients (all girls) were operated on while very young, with extirpation of the FCD and the surrounding area; with the histopathology study showed agreement between the MRI images and the macroscopic study of the slices. The histology study showed findings typical of a Taylor-type FCD (poor differentiation between the cortical grey matter and the subcortical white matter, and balloon cells). Three years after the FCD extirpation, the same 3 patients remained seizure-free with no anti-epilepsy medication. Two others have seizure control with medication, another (the adult) is on the surgical waiting list, and the remaining patient refused the operation. CONCLUSION: Taylor-type FCD is associated with a high percentage of all drug-resistant focal seizures, and it needs to be identified and extirpated as soon as possible. Well planned and well-performed surgery that leaves no remains of dysplasia can cure the disease it in many cases.
Assuntos
Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/psicologia , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/cirurgia , Procedimentos Neurocirúrgicos , Tomografia por Emissão de Pósitrons , Radiografia , Convulsões/etiologia , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To present 16 patients with schizencephaly and neurological involvement, and analyse their characteristics and neuroimages. MATERIAL AND METHODS: The study included 16 patients, 8 males and 8 females, all of whom were diagnosed with schizencephaly at less than 3 years of age; 2 patients were diagnosed prenatally. Schizencephaly was identified by computerized tomography (CT) in 1 patient and by MR or three-dimensional MR (3DMR) with a 1.5tesla apparatus in the others. Most patients were referred for evaluation because of psychomotor delay, motor disabilities and/or seizures. RESULTS: Five patients had bilateral schizencephaly with open lips (2 of them had suffered intrauterine cytomegalovirus infections); 2 showed unilateral schizencephaly with separated lips, 8 presented unilateral schizencephaly with fused lips, and 1 had schizencephaly with open lips on one side and fused lips on the other. Prenatal cytomegalovirus infection was diagnosed in 2 patients. A cerebral malformation that affected the midline was diagnosed by routine ultrasound studies in 2 patients. Eight patients (50%) presented with seizures that were focal, except for one patient who showed secondary generalisation. The latter was the only patient whose disease was refractory to complete seizure control with antiepileptic medication. All patients had some degree of motor deficit, which was either unilateral (hemiparesis) or bilateral (tetraparesis). CONCLUSION: 3D MR imaging was very important in diagnosing of schizencephaly in our patients because it showed the polymicrogyria that covered the area of the cleft and permitted us to rule out porencephaly. Neuronal migration disorders such as heterotopias and, more frequently, cortical dysplasias, were observed in several patients. Half of the patients had epilepsy which was controlled with antiepileptic medication, except in 1 patient.
Assuntos
Malformações do Desenvolvimento Cortical/patologia , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Eletroencefalografia , Feminino , Cabeça/anatomia & histologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/psicologia , Tomografia Computadorizada por Raios XRESUMO
We present in this paper the case of a 12-year-old girl who had the clinical features of 2 different disorders: neurofibromatosis 1 (NF1) and 3 hemangiomas located in the skin, liver and mediastinum. The patient did not receive any specific treatment and showed a normal progressive evolution that lasted 1 / to 2 years and a very slow regression that lasted for a more prolonged time than expected (the 3 hemangiomas have not completely disappeared yet), although all 3 have been asymptomatic. MRI of the brain did not disclose a hemangioblastoma of the cerebellum or any other vascular lesion of the brain. Mental development of this girl was in the borderline range, as is commonly seen in Pascual-Castroviejo II syndrome (P-CIIS)/PHACE syndrome and in NF1, 2 syndromes which have not been reported to be associated in the same patient previously.
Assuntos
Hemangioma/complicações , Neoplasias Hepáticas/complicações , Mediastino/patologia , Neoplasias Cutâneas/complicações , Criança , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância MagnéticaRESUMO
INTRODUCTION: The ability to draw is a complex perception and cognition function, which is acquired in infancy and is not usually investigated in the neuropaediatric clinic. OBJECTIVE: To validate the Pascual graphomotor test (PGT) in 5 to 11 year-old Cuban school children. PATIENTS AND METHODS: The PGT was performed on a total of 172 children from the city of Havana Círculo Infantil del Municipio Plaza nursery school and from the 1st to 5th year of a primary school in the same area. The sample was systematic. The test was repeated the following day. All the drawings were scored blind by a neurologist and neurology resident. RESULTS: For the validation of the test the differentiation with age and school year was taken as a validation criterion. A high correlation was obtained between the ages of the children and the scores obtained. The Spearman coefficient was -0.78 (P=0.01), and a there was a similar inverse correlation between the school year and the test scores (Spearman coefficient=-0.79, P=0.01). The test was very reliable, with an intraclass correlation coefficient (ICC) of 0.99 for inter-observer agreement and 0.97 for the test-retest. CONCLUSIONS: The test was valid according to the criterion employed, differentiation with age and school year. The PGT demonstrated good temporal and inter-observer stability. We believe that it is a very useful tool in the neurological examination of Cuban school children.
Assuntos
Testes Neuropsicológicos/normas , Desempenho Psicomotor/fisiologia , Instituições Acadêmicas , Criança , Pré-Escolar , Cuba , Feminino , Humanos , Masculino , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
We report on a girl with a left facial hemangioma and absence of the right ear and canal who also showed absence of the left vertebral and anterior cerebral arteries (ipsilateral to the facial hemangioma), and absence of the external carotid artery and presence of stapedial artery on the right side (contralateral to the facial hemangioma and ipsilateral to the auditory organ malformation). Persistence of the stapedial artery may be related to the facial hemangioma or with the hemifacial hypoplasia with similar possibilities. This is the first case to the best of our knowledge of the association between P-CIIS and a persistent stapedial artery.