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Background and Objective: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing., Methods: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region., Results: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 ( ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes., Conclusions: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

The County of Baix Llobregat (Barcelona, Catalonia, Spain) presents a high prevalence of familial frontotemporal dementia (FTD) in the presence of P301L mutation in the MAPT gene. To evaluate a possible unique founder effect of P301L, and its age, the analysis of 20 single-nucleotide polymorphisms covering 50 kb and 12 single-nucleotide polymorphisms located along 30 Mb around the mutation was performed by developing 2 multiplex single-base extension reactions. In addition, families with affected and healthy individuals from France and Italy were analyzed. The FTD-affected individuals from Barcelona carried the same 50-kb haplotype linked to P301L mutation, suggesting a unique common ancestor, as opposed to French patients. Italian patients are also probably descendants of a unique ancestor, which would be different from that of Barcelona. Diversity of 30-Mb haplotypes found in Barcelona and the inference of the mutation age in these populations, among other reasons, suggest that prevalence of FTD linked to P301L MAPT mutation is the result of a locally originated mutation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

AβPP locus duplications have been recently identified in early-onset Alzheimer's disease. We describe a patient who initiated memory problems and behavioral disturbances at 57 years, with a progressive cognitive decline, who died at the age of 68 years with dementia. Neuropathological examination revealed a temporobasal hemorrhage, extensive Alzheimer-type pathology, and severe cerebral amyloid angiopathy. We observed a chromosomal 21 region duplication spanning 0.59 Mb, which comprised JAM2, ATP5J, GABPA, and AβPP genes. We propose a replication based mutational mechanism (single Fork-Stalling and Template-Switching) or a recombination based one (non-homologous end-joining repair) for the AβPP locus duplication in this case.