Browsing by Author "Melo-Pires, M."
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- Acute ischemic stroke secondary to glioblastoma. A case reportPublication . Pina, S.; Carneiro, A.; Rodrigues, T.; Samões, R.; Taipa, R.; Melo-Pires, M.; Pereira, C.Glioblastoma is a malignant infiltrative glial tumor occurring most often over 50 years of age, with diverse clinical presentations. We describe a case of temporal lobe glioblastoma with a rare presentation as an acute ischemic stroke, discussing the imaging and histopathological findings, and reviewing the literature. A 77-year-old woman had sudden onset of left hemiparesis and hemihypoesthesia. The neuroradiological studies revealed an acute ischemic lesion in the right lenticulostriate arteries territory and a right anterior temporal lobe tumor, enhancing heterogeneously after contrast with enhancement of the right middle cerebral artery wall. Histopathological analysis of the resected temporal lesion revealed a glioblastoma multiforme with tumoral infiltration of the vascular wall. Glioblastoma should be considered in the etiology of acute ischemic stroke, where neuroimaging plays an important diagnostic role, enabling a more immediate therapeutic approach, with a consequent impact on survival.
- Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin GenePublication . Gonçalves, A.; Oliveira, J.; Coelho, T.; Taipa, R.; Melo-Pires, M.; Sousa, M.; Santos, R.A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD.
- Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific databasePublication . Oliveira, J.; Oliveira, M.; Kress, W.; Taipa, R.; Melo-Pires, M.; Hilbert, P.; Baxter, P.; Santos, M.; Buermans, H.; den Dunnen, J.; Santos, R.Myotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin - a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2-15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligation-dependent probe amplification (MLPA) analysis. A large duplication spanning exons 1-5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343_444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved.
- Hansen Neuropathy: Still a Possible Diagnosis in the Investigation of a Peripheral NeuropathyPublication . Veiga, A.; Costa, A.; Taipa, Ri.; Guimarães, A.; Melo-Pires, M.INTRODUCTION: Leprosy is still one of the most frequent causes of peripheral neuropathy. Although regarded as eradicated in Portugal, is still documented in neuropathological study of patients with clinical peripheral neuropathy without proper diagnosis.
- Hereditary neuropathy with liability to pressure palsy: a recurrent and bilateral foot drop case report.Publication . Flor-de-Lima, F.; Macedo, L.; Taipa, R.; Melo-Pires, M.; Rodrigues, M.Hereditary neuropathy with liability to pressure palsy is characterized by acute, painless, recurrent mononeuropathies secondary to minor trauma or compression. A 16-year-old boy had the first episode of right foot drop after minor motorcycle accident. Electromyography revealed conduction block and slowing velocity conduction of the right deep peroneal nerve at the fibular head. After motor rehabilitation, he fully recovered. Six months later he had the second episode of foot drop in the opposite site after prolonged squatting position. Electromyography revealed sensorimotor polyneuropathy of left peroneal, sural, posterior tibial, and deep peroneal nerves and also of ulnar, radial, and median nerves of both upper limbs. Histological examination revealed sensory nerve demyelination and focal thickenings of myelin fibers. The diagnosis of hereditary neuropathy with liability to pressure palsy was confirmed by PMP22 deletion of chromosome 17p11.2. He started motor rehabilitation and avoidance of stressing factors with progressive recovery. After one-year followup, he was completely asymptomatic. Recurrent bilateral foot drop history, "sausage-like" swellings of myelin in histological examination, and the results of electromyography led the authors to consider the diagnosis despite negative family history. The authors highlight this rare disease in pediatric population and the importance of high index of clinical suspicion for its diagnosis
- Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomasPublication . Miranda-Gonçalves, V.; Granja, S.; Martinho, O.; Honavar, M.; Pojo, M.; Costa, B.; Melo-Pires, M.; Pinheiro, C.; Cordeiro, M.; Bebiano, G.; Costa, P.; Reis, R.; Baltazar, F.BACKGROUND: Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular. METHODS: Expression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions. RESULTS: Hypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX. CONCLUSION: Hypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM.
- Leucoencefalitis aguda hemorrágica de Weston Hurst. Estudio neuropatológico de un casoPublication . Fontoura, P.; Mendes, A.; Correia, M.; Melo-Pires, M.Summary. Introduction. Acute hemorrhagic leukoencephalitis (AHL), or Hurst disease is a rare, usually fatal, disease, probably due to an autoimmune cross reaction against myelin antigens present in the central nervous system, and which forms a spectrum of postinfeccious demyelinating diseases with acute disseminated encephalomyelitis. Case report. The patient was a 21 year old female who presented with an acute encephalopathy and generalized seizures following a 15 day febrile syndrome attributed to amygdalitis; a laboratory work-up, including CSF, was non-diagnostic, and a brain CT scan revealed diffuse cerebral edema. After 12 days the patient died from nosocomial pneumonia and multi-organ failure; neuropathological examination of the brain confirmed the diagnosis of Hurst acute hemorrhagic leukoencephalitis, with a weak perilesional inflammatory reaction, unlike the usual picture in AHL. Discussion. AHL should be a part of the differential diagnosis of acute encephalopathic diseases, particularly if preceded by systemic infections. The atypical laboratory findings, and the impossibilty of performing a brain MRI were obstacles to the diagnosis in this case. The relative paucity of the perivascular infiltrate is an atypical finding, and could be due to apoptotic clearance of the inflammatory cells, as has been described in other autoimmune demyelinating diseases.
- Recurrent focal myositis: a rare inflammatory myopathyPublication . Teixeira, F.; Peixoto, D.; Costa, J.; Bogas, M.; Taipas, R.; Melo-Pires, M.; Afonso, C.; Araújo, D.Focal myositis is an acute and localized muscle inflammation of unknown aetiology. The clinical diagnosis is often difficult to obtain, since it can be confused with infections, vascular thrombosis or muscle tumours such as sarcomas. This leads to a significant delay in the diagnosis, resulting in the administration of inappropriate and potentially harmful treatments. We report here a case of recurrent focal myositis in a woman where the diagnosis was only obtained after 6 years, despite multiple hospital admissions. This case reinforces the importance of clinical knowledge and experience to tackle challenging medical scenarios