Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
Freezing of gait (FOG) and postural instability are challenging motor symptoms that present a serious therapeutic dilemma in Parkinson’s disease. Appropriate distinction between FOG subtypes may be difficult during routine clinical visits, as shown in the case we present. The patient was examined in three different states in relation to levodopa (L-DOPA) and apomorphine subcutaneous (sc) tests with video documentation: (1) ‘overnight-off’, after 12 hours without medication; (2)‘on’, 60 min after intake of regular levodopa dose (200 mg) and 20 min after 2 mg of apomorphine sc; and (3) ‘supra-on’, after 350 mg of L-DOPA and 3 mg of apomorphine sc. The patient clearly showed a dose-dependent paradoxical response to L-DOPA treatment with the emergence of severe FOG and postural instability. The tendency to develop these axial symptoms was less pronounced with apomorphine at doses that achieved similar improvements of other Parkinsonian features.
Tuberous sclerosis complex (TSC) is a rare genetic disease of autosomal dominant transmission that, in most cases, results from the presence of pathogenic variants of the TSC1 or TSC2 genes, encoding hamartin and tuberin, respectively. It is a multisystemic disease, affecting most frequently the brain, skin, kidney, and heart. The wide variety of possible clinical manifestations, given this multisystem dimension, makes the follow-up of patients with TSC an exercise of multidisciplinarity. In fact, these patients may require the intervention of various medical specialties, which thus have to combine their efforts to practice a medicine that is truly holistic. The past few years have witnessed a dramatic leap not only in the diagnosis and management of TSC patients, with standard monitoring recommendations, but also in the therapeutic field, with the use of mTORC1 inhibitors. In this article, we review the clinical manifestations associated with TSC, as well as the treatment and follow-up strategies that should be implemented, from a multidisciplinary perspective.
Background and purpose Creutzfeldt–Jakob disease (CJD) is a rare form of rapidly progressive neurodegenerative disorder. Seizures are uncommon in the early stage of CJD, increasing diagnostic difficulty. Methods An autopsy‐proven case of CJD presenting initially as an epilepsia partialis continua is reported, in which the initial workup was unremarkable. Retrospectively, the presence of nystagmus, which proved to be non‐epileptic, pointed to a cerebellar lesion before a diagnosis of clinically probable CJD was made. Results A 70‐year‐old man presented with a 3‐week history of intermittent rhythmic jerking tremors in his left limbs, interfering with his gait. Examination showed left body clonic movements. Electroencephalography revealed an ictal right centroparietal pattern of focal status epilepticus. Video‐oculography revealed right‐beating nystagmus (mean slow phase velocity [SPV] 3.4º/s) in the dark and left‐beating nystagmus (SPV 2.6º/s) in the light, left‐beating nystagmus after head shaking (SPV 4º/s) and during mastoid vibration (SPV 11º/s) and mildly hypoactive horizontal head impulses. Search for occult malignancy, serologies, cerebrospinal fluid analyses, anti‐onconeural antigen, auto‐immune panel and brain magnetic resonance imaging were unrevealing. Rapid neurological decline was observed. Three weeks later, cerebrospinal fluid was positive for 14.3.3 protein, electroencephalography showed generalized periodic sharp wave complexes and brain magnetic resonance imaging revealed diffusion restriction and T2/fluid‐attenuated inversion recovery hyperintensities in the cerebellum, basal ganglia, thalamus and cortex. He died 1 month later. Neuropathological study confirmed the diagnosis of CJD. Conclusion This case highlights that CJD should be considered in the differential diagnosis of new onset epilepsia partialis continua and that neuro‐ophthalmological examination can be helpful in pointing to early asymmetric cerebellar involvement.
Introdução: A dermatoscopia é uma técnica in vivo não-invasiva, amplamente usada como ferramenta complementar no estudo de lesões pigmentadas da pele, permitindo um diagnóstico mais precoce do melanoma cutâneo. O objetivo deste estudo é avaliar a acuidade diagnóstica da dermatoscopia em lesões melanocíticas e alargar as correlações dermatoscopia-histopatologia já estabelecidas.Material e Métodos: Estudo retrospetivo utilizando a base de dados da Consulta de Dermatoscopia e Lesões Pigmentadas e a base de dados da Histologia de um Serviço de Dermatologia. Cada lesão melanocítica foi avaliada segundo parâmetros dermatoscópicos e histológicos. Determinou-se a concordância entre os diagnósticos e entre os parâmetros avaliados.Resultados: Verificou-se um ratio maligno/benigno de 1:9,2. Obteve-se uma concordância razoável entre os diagnósticos dermatoscópicos e histológicos. Para os melanomas obteve-se uma concordância excelente, tendo a dermatoscopia revelado uma sensibilidade de 92,9% e especificidade de 96,9%. Observou-se concordância entre padrão reticular e a presença de fusão de cristas e atipia citológica; padrão globular e presença de tecas; rede atípica e a presença de fibrose e atipia citológica; blotches e paraqueratose pigmentada; véu azul esbranquiçado e a presença de fibrose.Conclusão: Apesar de algumas limitações e achados não esperados, muitos dos resultados do presente estudo vêm na continuidade do que tem vindo a ser descrito na literatura, mostrando uma elevada sensibilidade e especificidade da dermatoscopia no diagnóstico de melanoma, o que se reflete numa otimização do diagnóstico precoce sem necessidade de aumento do número total de excisões de lesões pigmentadas.
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