RESUMO
Adult polyglucosan body disease (APBD) is a metabolic disorder usually caused by glycogen branching enzyme (GBE) deficiency. APBD associates progressive walking difficulties, bladder dysfunction and, in about 50% of the cases, cognitive decline. APBD is characterized by a recognizable leukodystrophy on brain MRI. We report here a novel presentation of this disease in a 35-year old woman who presented with an acute deterioration followed by an unexpected recovery. Enzymatic analysis displayed decreased GBE activity in leukocytes. Molecular analyses revealed that only one mutated allele was expressed, bearing a p.Arg515His mutation. This is the first observation reporting acute and reversible neurological symptoms in APBD. These findings emphasize the importance of searching GBE deficiency in patients presenting with a leukodystrophy and acute neurological symptoms mimicking a stroke, in the absence of cardiovascular risk factors.
Assuntos
Glucanos/metabolismo , Doença de Depósito de Glicogênio Tipo III/complicações , Doenças do Sistema Nervoso/etiologia , Adulto , Alelos , Biópsia , Encéfalo/patologia , DNA/genética , Feminino , Doença de Depósito de Glicogênio Tipo III/diagnóstico , Doença de Depósito de Glicogênio Tipo III/genética , Humanos , Processamento de Imagem Assistida por Computador , Leucócitos/química , Sintomas do Trato Urinário Inferior , Imageamento por Ressonância Magnética , Músculo Esquelético/patologia , Mutação , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Recuperação de Função FisiológicaRESUMO
Congenital mirror movements (CMM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the opposite side. CMM reflect dysfunctions and structural abnormalities of the motor network and are mainly inherited in an autosomal-dominant fashion. Recently, heterozygous mutations in DCC, the gene encoding the receptor for netrin 1 and involved in the guidance of developing axons toward the midline, have been identified but CMM are genetically heterogeneous. By combining genome-wide linkage analysis and exome sequencing, we identified heterozygous mutations introducing premature termination codons in RAD51 in two families with CMM. RAD51 mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by nonsense-mediated decay. RAD51 was specifically present in the developing mouse cortex and, more particularly, in a subpopulation of corticospinal axons at the pyramidal decussation. The identification of mutations in RAD51, known for its key role in the repair of DNA double-strand breaks through homologous recombination, in individuals with CMM reveals a totally unexpected role of RAD51 in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the molecular pathways underlying bimanual motor control in humans.
Assuntos
Anormalidades Congênitas/genética , Discinesias/genética , Transtornos dos Movimentos/genética , Rad51 Recombinase/genética , Axônios , Receptor DCC , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Regulação para Baixo , Exoma/genética , Saúde da Família , Heterogeneidade Genética , Estudo de Associação Genômica Ampla/métodos , Haploinsuficiência , Heterozigoto , Recombinação Homóloga/genética , Humanos , Córtex Motor/anormalidades , Mutação/genética , Fatores de Crescimento Neural/genética , Netrina-1 , Linhagem , RNA Mensageiro/genética , Receptores de Superfície Celular/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Approximately 10% of patients with non-small cell lung cancer (NSCLC) have brain metastases at the time of diagnosis. When surgical resection is not possible, whole brain radiotherapy is the standard of care, with a cerebral response rate of approximately 30%. We report our experience with an upfront association of carboplatin and pemetrexed (areas under the curve, 5 and 500 mg/m(2), respectively), every 3 weeks, in 30 patients presenting with newly diagnosed brain metastases and NSCLC. Cerebral MRIs were performed every 6-9 weeks. The radiologic response rates were assessed according to Response Evaluation Criteria in Solid Tumors. Overall survival was also determined. Twenty-six patients were evaluable for response, and the objective cerebral response rate (complete and partial response) in the intent-to-treat population was 40% (12 of 30 patients). Event-free survival was 31 weeks, and median overall survival was 39 weeks. The upfront association of carboplatin plus pemetrexed allows simultaneous treatment of cerebral and systemic disease in patients with NSCLC with newly diagnosed brain metastases and appears to be particularly interesting in terms of radiologic response and overall survival. Further clinical studies are warranted.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/secundário , Adenocarcinoma de Pulmão , Idoso , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carboplatina/administração & dosagem , Intervalo Livre de Doença , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pemetrexede , Resultado do TratamentoRESUMO
Patients with essential thrombocythemia often complain of various subjective neurological symptoms. This prospective study aims to assess their incidence and response to therapy. Among 37 consecutive patients with essential thrombocythemia, 11 presented with neurological symptoms. Among them 4 had thrombotic events, 7 complained of transient or fluctuating subjective symptoms, and one had both. Brain magnetic resonance imagery failed to detect any substratum in patients with subjective symptoms. JAK2V617F mutation was found in 9 of 11 patients with neurological symptoms versus 14 of 26 patients without symptoms. Ten patients received low-dose aspirin for these symptoms: complete resolution was observed in 3, improvement with persisting episodes in 2, and resistance to aspirin in 2 patients, in whom addition of cytoreductive therapy became necessary to resolve those disabling symptoms. In this prospective cohort, 30% of patients with essential thrombocythemia presented neurological symptoms. Aspirin was fully efficient in only 30% of cases. JAK2V617F mutation could be a risk factor for such symptoms.