Common forms of migraine are complex disorders characterized by significant clinical diversity. Their genetic basis has been extensively studied but remains unclear. This study represents the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility loci through a case-control study and unravel population-specific variants. Genotyping data was acquired with Applied Biosystems Axiom™ PMDA array, producing 12,035,248 single-nucleotide polymorphisms (SNPs) post-imputation, providing a comprehensive scope for GWAS analysis. PRS models were created and tested using a k-folds cross-validation framework and the optimal significance threshold was assessed. We detected 12 potential risk loci corresponding to 12 lead SNPs (RP11-204N11.2, CTA-481E9.4/CTA-481E9.3, RAP1A, TIGD4, CADPS2, RP11-46E17.6, RP4-569D19.5, RP11-398K14.1, PCBP1-AS1, TCF15, IL6R and UNC13A). The top three variants (RP11-204N11.2, CTA-481E9.4/CTA-481E9.3 and RAP1A) were also supported by the PRS model. We highlight that several variants present putative biological relevance to migraine pathophysiology, reinforcing the importance of neurotransmitter release, synaptic transmission and the involvement of vascular components in migraine pathophysiology.

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. 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. 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. 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.

Migraine is a complex neurological disorder, and the most common migraine categories are migraine with aura and without aura. The higher prevalence of migraine in related individuals compared to the general population indicates a potential genetic predisposition; however, gene expression, which is influenced by both genetic and environmental factors, can also be a major factor in the migraine susceptibility. Given the high number of Portuguese migraine patients whose diagnosis and treatment have not yet been well established, we decided to carry out a whole transcriptome analysis within a migraine Portuguese cohort. This study aims to identify potential biomarkers that could contribute to improved migraine therapy. We performed total RNA sequencing on whole blood samples from 15 migraine patients and 12 age-matched controls. Differential expression analysis and gene set enrichment analysis were performed in different migraine subgroups. Finally, we performed the protein-protein interaction networks of differentially expressed genes. Gene set enrichment analysis comparing migraine patients with controls highlighted upregulated pathways linked to metabolism, and downregulated immuno-inflammatory pathways. Moreover, the groups of female migraine patients and female migraine without aura patients emphasized significant upregulated pathways, including G protein-coupled receptors signalling pathways, when compared with female controls. Interestingly, we found two important differentially expressed genes related to parathyroid hormone: PTH1R and PTH2. PTH1R was upregulated in female migraine without aura versus female controls, while PTH2 was both upregulated between female migraine patients and female controls, as well as between female migraine without aura and controls. Here, we show, for the first time, the involvement of parathyroid hormone receptors and their associated gene expression patterns in female migraine patients. These molecules stand out as sturdy and promising biomarkers for innovative therapeutic in female migraine patients.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is characterized by the deposition of amyloidogenic transthyretin, particularly in dorsal root ganglia (DRG) and peripheral nerve axons, resulting in sensorimotor axonopathy. Here, we investigated cytoskeleton alterations in peripheral axons from an ATTRv-PN mouse model, the hTTRA97S knockin 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, impacting synaptic vesicle recycling. Microtubule dynamics and axonal transport abnormalities were also observed in mutant axons. Cytoskeletal defects in hTTRA97S neurons preceded axonal degeneration and were mediated by Rac1 hyperactivation. Importantly, Rac1 inhibition rescued cytoskeleton alterations, preventing degeneration. In late-onset ATTRv-PN patients, a variant in RACGAP1, encoding a Rac1 inactivator, supported the neuroprotective role of Rac1 inhibition. Our findings demonstrate that cytoskeletal defects precede axonopathy in ATTRv-PN and highlight Rac1 as a promising therapeutic target.

Background: Neuromuscular diseases (NMDs) are rare, predominantly hereditary, with progressive course disorders. Furthermore, diagnosis can be delayed by years after symptoms emerge, resulting in missed opportunities for modifying disease progression, specific therapeutic approaches, and counseling. Some NMDs have high levels of creatine phosphokinase (CK). Thus, its measurement can indicate an NMD associated with muscle involvement. Objectives: We aimed to identify myopathies and muscular dystrophies through elevated CK levels for early detection of these disorders. Methods: A prospective, observational, and analytical study of children and teenagers showing high levels of CK, showing mild symptoms, or who were asymptomatic with elevation of transaminases from all pediatric units in the north of Portugal was performed. All diagnosed patients were referred to our Center for Neuromuscular Diseases. Additionally, CK level confirmation, clinical examination, and investigation were performed according to best-practice clinical guidelines. Results: We found 33 patients from 8/12 pediatric units. A diagnosis with implications for care measures and treatment was performed in half of the patients. A total of 30% presented an NMD diagnosis. Dystrophinopathies represented the largest group (21%). Conclusions: Therefore, NMDs should be considered in children and teenagers with high CK levels, even those with mild symptoms. Screening for CK elevation should be used to promote an earlier diagnosis of many NMDs.

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.

Familial hemiplegic migraine (FHM) is a rare autosomal-dominant form of migraine with aura. Three disease-causing genes have been identified for FHM: CACNA1A, ATP1A2 and SCN1A. However, not all families are linked to one of these three genes.PRRT2 variants were also commonly associated with HM symptoms; therefore, PRRT2 is hypothesized as the fourth gene causing FHM. PRRT2 plays an important role in neuronal migration, spinogenesis, and synapse mechanisms during development and calcium-dependent neurotransmitter release. We performed exome sequencing to unravel the genetic cause of migraine in one family, and a novel PRRT2 variant (c.938C > T;p.Ala313Val) was identified with further functional studies to confirm its pathogenicity. PRRT2-A313V reduced protein stability, led to protein premature degradation by the proteasome and altered the subcellular localization of PRRT2 from the plasma membrane (PM) to the cytoplasm. We identified and characterized for the first time in a Portuguese patient, a novel heterozygous missense variant in PRRT2 associated with HM symptoms. We suggest that PRRT2 should be included in the diagnosis of HM.

Migraine is a common and complex neurological disease potentially caused by a polygenic interaction of multiple gene variants. Many genes associated with migraine are involved in pathways controlling the synaptic function and neurotransmitters release. However, the molecular mechanisms underpinning migraine need to be further explored.Recent studies raised the possibility that migraine may arise from the effect of regulatory non-coding variants. In this study, we explored the effect of candidate non-coding variants potentially associated with migraine and predicted to lie within regulatory elements: VAMP2_rs1150, SNAP25_rs2327264, and STX1A_rs6951030. The involvement of these genes, which are constituents of the SNARE complex involved in membrane fusion and neurotransmitter release, underscores their significance in migraine pathogenesis. Our reporter gene assays confirmed the impact of at least two of these non-coding variants. VAMP2 and SNAP25 risk alleles were associated with a decrease and increase in gene expression, respectively, while STX1A risk allele showed a tendency to reduce luciferase activity in neuronal-like cells. Therefore, the VAMP2_rs1150 and SNAP25_rs2327264 non-coding variants affect gene expression, which may have implications in migraine susceptibility. Based on previous in silico analysis, it is plausible that these variants influence the binding of regulators, such as transcription factors and micro-RNAs. Still, further studies exploring these mechanisms would be important to shed light on the association between SNAREs dysregulation and migraine susceptibility.

Acute fulminant cerebral edema (AFCE) is a recently identified encephalitis type associated with significant morbimortality. Described as rare, limited data exists on its early detection and treatment. This paper describes a case of AFCE that progressed to unresponsive intracranial hypertension. A previously healthy four-year-old boy presented with fever, myalgias, and neurological symptoms. Diagnostic assessments showed cerebrospinal fluid abnormalities, and despite medical interventions, his condition deteriorated rapidly and developed severe cerebral edema and herniation within 24 hours. A decompressive craniectomy was attempted to decrease intracranial pressure, without success. This case emphasizes the urgency of early AFCE recognition and effective management strategies given its severe prognosis, aiming to improve understanding and spur further research.

Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. Blood and spot urine were collected in “severe” (n = 26), “critically ill” (n = 17) and “critically ill on VV-ECMO” (n = 17) patients with COVID-19 at days 1–2 (admission), 3–4, 5–8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

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.