Browsing by Author "Costa, MC"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
- Motor uncoordination and neuropathology in a transgenic mouse model of Machado-Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage productsPublication . Silva-Fernandes, A; Costa, MC; Duarte-Silva, S; Oliveira, P; Botelho, C; Martins, L; Mariz, J; Ferreira, T; Ribeiro, F; Correia-Neves, M; Costa, C; Maciel, PMachado-Joseph disease (MJD) is a late-onset neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the ataxin-3 protein. We generated two transgenic mouse lineages expressing the expanded human ataxin-3 under the control of the CMV promoter: CMVMJD83 and CMVMJD94, carrying Q83 and Q94 stretches, respectively. Behavioral analysis revealed that the CMVMJD94 transgenic mice developed motor uncoordination, intergenerational instability of the CAG repeat and a tissue-specific increase in the somatic mosaicism of the repeat with aging. Histopathological analysis of MJD mice at early and late stages of the disease revealed neuronal atrophy and astrogliosis in several brain regions; however, we found no signs of microglial activation or neuroinflammatory response prior to the appearance of an overt phenotype. In our model, the appearance of MJD-like symptoms was also not associated with the presence of ataxin-3 cleavage products or intranuclear aggregates. We propose the transgenic CMVMJD94 mice as a useful model to study the early stages in the pathogenesis of MJD and to explore the molecular mechanisms involved in CAG repeat instability.
- Nonsense mutation in TITF1 in a Portuguese family with benign hereditary choreaPublication . Costa, MC; Costa, C; Silva, A; Evangelista, P; Santos, L; Ferro, A; Sequeiros, J; Maciel, PBenign hereditary chorea (BHC) is an autosomaldominant disorder of early onset characterized by a slowly progressing or nonprogressing chorea, without cognitive decline or other progressive neurologic dysfunction, but also by the existence of heterogeneity of the clinical presentation within and among families. The genetic cause of BHC is the presence of either point mutations or deletions in the thyroid transcription factor 1 gene (TITF1). We studied a Portuguese BHC family composed of two probands: a mother and her only son. The patients were identified in a neurology out-patient clinic showing mainly involuntary choreiform movements since childhood, myoclonic jerks, falls, and dysarthria. We performed magnetic resonance imaging (MRI), electroencephalogram (EEG), nerve conduction studies, thyroid ultrasound scan, biochemical thyroid tests, and electrocardiogram (ECG). We excluded Huntington disease by appropriate genetic testing and sequenced the entire TITF1 gene for both patients. The patients showed MRI alterations: (1) in the mother, abnormal hyperintense pallida and cortical cerebral/cerebellar atrophy; and (2) in the son, small hyperintense foci in the cerebellum and subtle enlargement of the fourth ventricle. Sequence analysis of the TITF1 gene in these patients revealed the presence of a heterozygous C > T substitution at nucleotide 745, leading to the replacement of a glutamine at position 249 for a premature stop codon. A previously undescribed nonsense mutation in the TITF1 gene was identified as being the genetic cause of BHC in this family.
- Posterior reversible encephalopathy syndrome and anti-angiogenic agents: a case reportPublication . Silva, F; Pêgo, P; Vendrell, MC; Farias, MJ; Timóteo, A; Costa, MC; Cravo, I; Gomes, FPosterior reversible encephalopathy syndrome is an increasingly recognised clinico-radiological entity, associated with several medical conditions (such as systemic arterial hypertension) and characterised by seizures, altered mental status, headaches, and visual symptoms. Magnetic resonance imaging is a key component in this diagnosis, with hyperintense foci in T2-weighted images, corresponding to vasogenic oedema. The pathophysiology is not fully understood but probably involves loss of auto-regulation of cerebral vasculature or endothelial dysfunction or both. A 56-year-old male, suffering from a gastro-intestinal stromal tumour with hepatic metastasis resistant to imatinib, on therapy with sunitinib, came to the Emergency Department because of headaches, hallucinations, and loss of vision. There was no previous history of high blood pressure. A hypertensive crisis was diagnosed; ophthalmological examination on admission showed no light perception bilaterally. Brain imaging displayed bilateral parieto-occipital and frontal vasogenic oedema, consistent with the clinical diagnosis of posterior reversible encephalopathy syndrome. After treatment of hypertension and suspension of sunitinib, the patient recovered from his symptoms. Control imaging showed no oedema. Angiogenesis inhibitors, such as sunitinib and bevacizumab, can cause hypertension, one of the many medical conditions associated with the posterior reversible encephalopathy syndrome. This syndrome should be considered in cases of acute visual loss, particularly in view of its reversible nature when diagnosed and treated promptly.