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Gerstmann-Sträussler-Scheinker disease (GSS) is a rare neurodegenerative illness that belongs to the group of hereditary or familial Transmissible Spongiform Encephalopathies (TSE). Due to the presence of different pathogenic alterations in the prion protein (PrP) coding gene, it shows an enhanced proneness to misfolding into its pathogenic isoform, leading to prion formation and propagation. This aberrantly folded protein is able to induce its conformation to the native counterparts forming amyloid fibrils and plaques partially resistant to protease degradation and showing neurotoxic properties. PrP with A117V pathogenic variant is the second most common genetic alteration leading to GSS and despite common phenotypic and neuropathological traits can be defined for each specific variant, strikingly heterogeneous manifestations have been reported for inter-familial cases bearing the same pathogenic variant or even within the same family. Given the scarcity of cases and their clinical, neuropathological, and biochemical variability, it is important to characterize thoroughly each reported case to establish potential correlations between clinical, neuropathological and biochemical hallmarks that could help to define disease subtypes. With that purpose in mind, this manuscript aims to provide a detailed report of the first Spanish GSS case associated with A117V variant including clinical, genetic, neuropathological and biochemical data, which could help define in the future potential disease subtypes and thus, explain the high heterogeneity observed in patients suffering from these maladies.

Survivors to COVID-19 have described long-term symptoms after acute disease. These signs constitute a heterogeneous group named long COVID or persistent COVID. The aim of this study is to describe persisting symptoms 6 months after COVID-19 diagnosis in a prospective cohort in the Northwest Spain. This is a prospective cohort study performed in the COHVID-GS. This cohort includes patients in clinical follow-up in a health area of 569,534 inhabitants after SARS-CoV-2/COVID-19 diagnosis. Clinical and epidemiological characteristics were collected during the follow up. A total of 248 patients completed 6 months follow-up, 176 (69.4%) required hospitalization and 29 (10.2%) of them needed critical care. At 6 months, 119 (48.0%) patients described one or more persisting symptoms. The most prevalent were: extra-thoracic symptoms (39.1%), chest symptoms (27%), dyspnoea (20.6%), and fatigue (16.1%). These symptoms were more common in hospitalized patients (52.3% vs. 38.2%) and in women (59.0% vs. 40.5%). The multivariate analysis identified COPD, women gender and tobacco consumption as risk factors for long COVID. Persisting symptoms are common after COVID-19 especially in hospitalized patients compared to outpatients (52.3% vs. 38.2%). Based on these findings, special attention and clinical follow-up after acute SARS-CoV-2 infection should be provided for hospitalized patients with previous lung diseases, tobacco consumption, and women.

Fabry disease is a rare X-linked disorder affecting α-galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to test a novel adeno-associated viral vector, serotype 9 (AAV9), ubiquitously expressing human α-galactosidase A to treat Fabry disease (scAAV9-PGK-GLA). The vector was preliminary tested in newborns of a Fabry disease mouse model. 5 months after treatment, α-galactosidase A activity was detectable in the analyzed tissues, including the central nervous system. Moreover, we tested the vector in adult animals of both sexes at two doses and disease stages (presymptomatic and symptomatic) by single intravenous injection. We found that the exogenous α-galactosidase A was active in peripheral tissues as well as the central nervous system and prevented glycosphingolipid accumulation in treated animals up to 5 months following injection. Antibodies against α-galactosidase A were produced in 9 out of 32 treated animals, although enzyme activity in tissues was not significantly affected. These results demonstrate that scAAV9-PGK-GLA can drive widespread and sustained expression of α-galactosidase A, cross the blood brain barrier after systemic delivery, and reduce pathological signs of the Fabry disease mouse model., Graphical Abstract, This study focuses on the development of a novel gene therapy vector for Fabry disease (FD). The approach is based on the systemic delivery of an AAV9, which crosses the blood brain barrier and drives sustained expression of α-galactosidase A, reducing pathological signs in multiple organs of a FD mouse model, including the central nervous system.