Hereditary transthyretin-related amyloidosis (ATTRv amyloidosis) is a rare and progressively debilitating disease characterized by the deposition of transthyretin (TTR) amyloid fibrils in various organs and tissues, most commonly in the heart and peripheral nerves. This pathological deposition can lead to significant organ dysfunction and, ultimately, organ failure. ATTRv amyloidosis exhibits a broad range of clinical presentations, from purely neurological symptoms to purely cardiac manifestations, as well as mixed phenotypes which result from both neurological and cardiac implications. This wide phenotypical spectrum realistically challenges disease diagnosis and prognosis, especially in individuals without or with an unknown family history. Multiple factors are thought to contribute to this variability, including genetic, epigenetic, and even environmental influences. Understanding these factors is crucial, as they can significantly affect disease expression and progression. This review aims to summarize each of these contributing factors, to help elucidate the current knowledge on the phenotypical variability of ATTRv amyloidosis.

Species ranges often change in relation to multiple environmental and demographic factors. Innovative behaviors may affect these changes by facilitating the use of novel habitats, although this idea has been little explored. Here, we investigate the importance of behavior during range change, using a 25‐year population expansion of Bonelli's eagle in southern Portugal. This unique population is almost exclusively tree nesting, while all other populations in western Europe are predominantly cliff nesting. During 1991–2014, we surveyed nest sites and estimated the year when each breeding territory was established. We approximated the boundaries of 84 territories using Dirichlet tessellation and mapped topography, land cover, and the density of human infrastructures in buffers (250, 500, and 1,000 m) around nest and random sites. We then compared environmental conditions at matching nest and random sites within territories using conditional logistic regression, and used quantile regression to estimate trends in nesting habitats in relation to the year of territory establishment. Most nests (>85%,n = 197) were in eucalypts, maritime pines, and cork oaks. Nest sites were farther from the nests of neighboring territories than random points, and they were in areas with higher terrain roughness, lower cover by agricultural and built‐up areas, and lower road and powerline densities. Nesting habitat selection varied little with year of territory establishment, although nesting in eucalypts increased, while cliff nesting and cork oak nesting, and terrain roughness declined. Our results suggest that the observed expansion of Bonelli's eagles was facilitated by the tree nesting behavior, which allowed the colonization of areas without cliffs. However, all but a very few breeding pairs settled in habitats comparable to those of the initial population nucleus, suggesting that after an initial trigger possibly facilitated by tree nesting, the habitat selection remained largely conservative. Overall, our study supports recent calls to incorporate information on behavior for understanding and predicting species range shifts.

Migraine is a complex neurovascular disorder affecting one billion people worldwide, mainly females. It is characterized by attacks of moderate to severe headache pain, with associated symptoms. Receptor activity modifying protein (RAMP1) is part of the Calcitonin Gene-Related Peptide (CGRP) receptor, a pharmacological target for migraine. Epigenetic processes, such as DNA methylation, play a role in clinical presentation of various diseases. DNA methylation occurs mostly in the gene promoter and can control gene expression. We investigated the methylation state of the RAMP1 promoter in 104 female blood DNA samples: 54 migraineurs and 50 controls. We treated DNA with sodium bisulfite and performed PCR, Sanger Sequencing, and Epigenetic Sequencing Methylation (ESME) software analysis. We identified 51 CpG dinucleotides, and 5 showed methylation variability. Migraineurs had a higher number of individuals with all five CpG methylated when compared to controls (26% vs. 16%), although non-significant (p = 0.216). We also found that CpG −284 bp, related to the transcription start site (TSS), showed higher methylation levels in cases (p = 0.011). This CpG may potentially play a role in migraine, affecting RAMP1 transcription or receptor malfunctioning and/or altered CGRP binding. We hope to confirm this finding in a larger cohort and establish an epigenetic biomarker to predict female migraine risk.

Temporomandibular disorders (TMD) and headache are complex. This study aims to assess the association between TMD, headache, and psychological dimensions such as psychological inflexibility and pain acceptance. The sample consisted of 120 participants following a non-probabilistic convenience sampling strategy through a direct invitation to the patients attending our facilities and their relatives (n = 61 diagnosed with headache, n = 34 diagnosed with TMD-headache, n = 25 control group). Diagnostic Criteria for Temporomandibular Disorders (DC-TMD), International Classification of Headache Disorders (ICHD-3 beta version), Chronic Pain Acceptance Questionnaire (CPAQ-8), and Psychological Inflexibility in Pain Scale (PIPS) were used as assessment tools. One-way ANOVA, multiple regression analysis (MRA), and the Johnson-Neyman approach were run by IBM SPSS, version 27 (IBM^® Company, Chicago, IL, USA). The significance level was 0.05. One third of our sample presented with headache with TMD. Females were predominant. Males with headache, no systemic disease, less pain severity but higher frequency, living longer with the disease and having sensitive changes, showed higher pain acceptance. When headache occurs with TMD, women with higher education, no headache family history, less pain, and no motor changes showed higher pain acceptance. Patients with both conditions are more liable to have chronic pain and pain inflexibility. Pain intensity and willingness explain 50% of the psychological inflexibility in the headache group. In our sample, individuals suffering from both conditions show greater pain inflexibility, implicating more vivid suffering experiences, leading to altered daily decisions and actions. However, further studies are needed to highlight this possible association.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is characterized by the deposition of amyloidogenic TTR, particularly in dorsal root ganglia (DRG) and peripheral nerve axons, resulting in sensorimotor axonopathy with autonomic dysfunction. Here, we investigated cytoskeleton alterations in peripheral axons from an ATTRv-PN mouse model, the hTTRA97S knock-in mice. Proteomics of hTTRA97S sural nerves revealed dysregulation of actin-related proteins. hTTRA97S DRG neurons presented a defective actin distribution in growth cones along with a reduction in axonal actin trails, and an associated impairment in the pool of pre-synaptic vesicles. Microtubule dynamics and axonal transport abnormalities were also observed in mutant axons. Importantly, cytoskeletal defects in hTTRA97S neurons preceded axonal degeneration and were mediated by Rac1 hyperactivation in DRG neurites and sciatic nerves of pre-symptomatic mice. Rac1 inhibition rescued cytoskeleton alterations, preventing degeneration. Remarkably, in ATTRv-PN patients with late-onset disease, a variant in RACGAP1, encoding a Rac1 inactivator, supported the neuroprotective role of Rac1 inhibition. Our findings demonstrate that cytoskeletal defects precede axonal degeneration in ATTRv-PN and highlight Rac1 as a promising therapeutic target.

Objective: The most common forms of migraine are complex disorders characterized by significant clinical diversity. The genetic basis of migraine has been the subject of many studies but remains largely unknown. We present the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility risk loci through a case-control study, in order to unravel population-specific variants. Methods: Genotyping was conducted on 380 individuals using the Applied Biosystems Axiom™ PMDA array. A vast dataset of 8,031,293 single-nucleotide polymorphisms (SNPs) was available, providing a comprehensive scope for GWAS analysis. PRS models were created and tested on subsets of the genotyping data, and the optimal statistical significance threshold was assessed. Results: We detected nine risk loci corresponding to nine lead SNPs ( ZNF385D , YTHDF3 , NPS , RAP1A/INKA2 , CTA-481E9.4/CTA-481E9.3 , AC092079.1 , PPHLN1 , SMYD3 and AL355597.1 (near ADARB2 )). Additionally, eleven variants, without any previous association to pathogenicity in migraine, were highlighted by the chosen PRS model. Among our results, a new locus within the NPS gene, representing a novel association with migraine, is a potential new target directly related to recent and effective migraine treatments. Conclusions: These findings reinforce the importance of neurotransmitter release and synaptic transmission, as well as the involvement of vascular components, in migraine pathophysiology. This work underscores that GWAS can provide novel, clinically valuable insights into populational and disease-associated genetic landscapes, enabling therapeutic developments and bolstering personalized medicine strategies.