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Abnormal cytoplasmic accumulation of fused in sarcoma (FUS) protein is the pathological hallmark of some cases of amyotrophic lateral sclerosis (ALS) with transactive response DNA‐binding protein of 43KDa (TDP‐43)‐negative pathology that lack SOD1 mutations. FUS is an RNA‐binding protein located predominantly in the nucleus and is involved in regulation of transcription, alternative splicing, RNA stability, microRNA biogenesis, apoptosis and cell division. FUS, Ewing's sarcoma (EWS) and TATA‐binding protein‐associated factor 15 (TAF15) proteins constitute the FET (FUS/EWS/TAF15) family, highly conserved and ubiquitously expressed RNA‐binding proteins that shuttle between nucleus and cytoplasm assisted by the nuclear import protein Transportin 1 (Trn1), This study was partially funded by Fundació Marató de TV3 (grant no. 20143810 to RSV, no. 20141610 to EG and no. 201437.10 to RRG) and Fondo Europeo de Desarrollo Regional (FEDER) (PI16/01673 to JG and PI15/01618 to RRG).

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded number of CAG repeats in the huntingtin gene. A hallmark of HD is unintended weight loss, the cause of which is unknown. In order to elucidate the underlying mechanisms of weight loss in HD, we studied its relation to other disease characteristics including motor, cognitive, and behavioral disturbances and CAG repeat number.In 517 patients with early stage HD, we applied mixed-effects model analyses to correlate weight changes over 3 years to CAG repeat number and various components of the Unified Huntington's Disease Rating Scale (UHDRS). We also assessed the relation between CAG repeat number and body weight and caloric intake in the R6/2 mouse model of HD.In patients with HD, mean body mass index decreased with -0.15 units per year (p < 0.001). However, no single UHDRS component, including motor, cognitive, and behavioral scores, was independently associated with the rate of weight loss. Patients with HD with a higher CAG repeat number had a faster rate of weight loss. Similarly, R6/2 mice with a larger CAG repeat length had a lower body weight, whereas caloric intake increased with larger CAG repeat length.Weight loss in Huntington disease (HD) is directly linked to CAG repeat length and is likely to result from a hypermetabolic state. Other signs and symptoms of HD are unlikely to contribute to weight loss in early disease stages. Elucidation of the responsible mechanisms could lead to effective energy-based therapeutics.

This is a study of the early identification of a new case of tropical spastic paraparesis/HLTV-1-associated myelopathy in a Spanish patient not previously reported on. The patient is 48 years of age, and he has been living in Sierra Leone for the past seventeen years, where he has worked as a surgeon. On first examination, he had been suffering from symptoms of a spastic paraparesis for the previous five months. This diagnosis was confirmed using serological tests (EIA and Western-blot) on the blood and cerebrospinal fluid (CSF). We have studied the cases outlined in medical literature, paying special attention to the time elapsed between the onset of symptoms and the date on which the diagnosis was made.

Proteïna TDP-43; Esclerosi lateral amiotròfica; Demència frontotemporal Proteína TDP-43; Esclerosis lateral amiotrófica; Demencia frontotemporal TDP-43 protein; Amyotrophic lateral sclerosis; Frontotemporal dementia Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer’s disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3 (grant no. 20141610 to EG and no. 20143710 to RRG) and Fondo Europeo de Desarrollo Regional (FEDER) (PI15/01618 to RRG). AA is funded by Departament de Salut de la Generalitat de Catalunya, Pla estratègic de recerca i innovació en salut (PERIS) 2016–2020 (SLT002/16/00329). JG is recipient of the Instituto de Salud Carlos III-FEDER grants (PI16/01673 and PI19/00593)

Background: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. Methods: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). Results: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. Conclusions: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations., This work was supported by grants from Spanish Fondo de Investigaciones Sanitarias PI08/0915 (European FEDER founds) to V. A. E. S-F. was a fellowship from FICYT-Principado de Asturias. The authors thank the patients and family members for their participation in this study. Authors wish to thank Fundacion Parkinson Asturias and Obra Social CAJASTUR for their support.