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Abstract Objective Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results Fixed‐effects meta‐analysis found that rare (MAF

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.

Amyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. The pathophysiology of ALS is not well understood but TDP-43 proteinopathy (aggregation and mislocalization) is one of the major phenomena described. Several factors can influence TDP-43 behavior such as mild pH alterations that can induce conformational changes in recombinant TDP-43, increasing its propensity to aggregate. However to our knowledge, no studies have been conducted yet in a cellular setting, in the context of ALS. We therefore tested the effect of cellular pH alterations on the localization, aggregation, and phosphorylation of TDP-43. HEK293T cells overexpressing wildtype TDP-43 were incubated for 1 h with solutions of different pH (6.4, 7.2, and 8). Incubation of cells for 1 h in solutions of pH 6.4 and 8 led to an increase in TDP-43-positive puncta. This was accompanied by the mislocalization of TDP-43 from the nucleus to the cytoplasm. Our results suggest that small alterations in cellular pH affect TDP-43 and increase its mislocalization into cytoplasmic TDP-43-positive puncta, which might suggest a role of TDP-43 in the response of cells to pH alterations.

Philippe Corcia,1 Paul H Gordon21Centre SLA, CHRU de Tours, Tours, France; UMR INSERM U930, Université François Rabelais de Tours (PC), Tours, France; 2AP-HP, Hôpital de la Pitié-Salpêtrière, Département des Maladies du Système Nerveux (PHG), Paris, FranceAbstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to progressive weakness from loss of motor neurons and death on average in less than 3 years after symptom onset. No clear causes have been found and just one medication, riluzole, extends survival. Researchers have identified some of the cellular processes that occur after disease onset, including mitochondrial dysfunction, protein aggregation, oxidative stress, excitotoxicity, inflammation, and apoptosis. Mitochondrial disease may be a primary event in neurodegeneration or occur secondary to other cellular processes, and may itself contribute to oxidative stress, excitotoxicity, and apoptosis. Clinical trials currently aim to slow disease progression by testing drugs that impact one or more of these pathways. While every agent tested in the 18 years after the approval of riluzole has been ineffective, basic and clinical research methods in ALS have become dramatically more sophisticated. Dexpramipexole (RPPX), the R(+) enantiomer of pramiprexole, which is approved for symptomatic treatment of Parkinson disease, carries perhaps the currently largest body of pre- and early clinical data that support testing in ALS. The neuroprotective properties of RPPX in various models of neurodegeneration, including the ALS murine model, may be produced through protective actions on mitochondria. Early phase trials in human ALS suggest that the drug can be taken safely by patients in doses that provide neuroprotection in preclinical models. A Phase III trial to test the efficacy of RPPX in ALS is underway.Keywords: dexpramipexole, amyotrophic lateral sclerosis, survival, clinical trials, neurodegeneration

Abstract Background Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. Methods The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. Discussion This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. Trial registration ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.

Post-translational modifications (PTMs) affecting proteins during or after their synthesis play a crucial role in their localization and function. The modification of these PTMs under pathophysiological conditions, i.e., their appearance, disappearance, or variation in quantity caused by a pathological environment or a mutation, corresponds to post-translational variants (PTVs). These PTVs can be directly or indirectly involved in the pathophysiology of diseases. Here, we present the PTMs and PTVs of four major amyotrophic lateral sclerosis (ALS) proteins, SOD1, TDP-43, FUS, and TBK1. These modifications involve acetylation, phosphorylation, methylation, ubiquitination, SUMOylation, and enzymatic cleavage. We list the PTM positions known to be mutated in ALS patients and discuss the roles of PTVs in the pathophysiological processes of ALS. In-depth knowledge of the PTMs and PTVs of ALS proteins is needed to better understand their role in the disease. We believe it is also crucial for developing new therapies that may be more effective in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

IntroductionMicroplastic pollution has become a global issue, eliciting attention not just from the scientific community but also both from the public and governmental bodies. Drawing data-driven policies and interventions, however, remain difficult due to the severely lacking baseline information from different environments such as beaches. One of the challenges in doing baseline studies is the lack of harmonized methodologies that will allow for comparison of results, integration of data, and its effective translation to evidence-based policies. Emphasis on quality control measures among baselining efforts through the proper implementation of experimental controls is also lacking.MethodologyTo address these gaps, we compared methodologies for preparing the sediment matrix for experimental controls, as well as evaluated protocols for extracting microplastics from tropical beach sediments. Beach sediments were collected, dried, sieved, and spiked with known amounts of microplastics of different polymer types. The removal and extraction efficiencies of the protocols being compared were evaluated.Results and discussionOur results showed that subjecting beach sediments to a furnace at 550° C for 4 hours is the most efficient way to remove plastic contamination, implying its applicability for preparing experimental controls. Meanwhile, a modified version of Masura et al. (2015), one of the widely cited methodologies for microplastics extraction, exhibited the highest mean extraction efficiency (99.05 ± 0.82%) among the protocols being compared. Results of this work will be useful in identifying methods that can be adopted and utilized for research and baselining efforts not just in the Philippines but also in Southeast Asia. This will also be helpful in the harmonization of methods, data reporting, and even skills as implemented through the regional and national action plans to address marine plastic pollution.

Background: Psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are inflammatory diseases with shared genetic backgrounds and clinical comorbidities. Headache, a common global health issue, affects over 50% of adults and encompasses various types, including migraine, tension-type, and cluster headaches. Migraine, the most prevalent, recurrent, and disabling type, is often associated with other medical conditions such as depression, epilepsy, and psoriasis, but little is known about the relationship between autoimmune disease and the risk of migraine. Methods: A cross-sectional study was conducted from July to November 2022, enrolling 286 participants, including 216 with PsA, 70 with axSpA, and 87 healthy controls. Results: Headache prevalence was significantly higher in the PsA (39.81%) and axSpA (45.71%) patients compared to the healthy controls. The prevalence of migraine without aura was also significantly higher in both the PsA (18.52%) and axSpA (28.57%) groups compared to the healthy controls. Conclusions: These findings underscore the high burden of headache and migraine in PsA and axSpA participants, highlighting the need for improved management and treatment strategies for these patients.

Introduction Congenital heart disease (CHD) represents the most common birth defect, affecting from 0.4% to 1.2% of children born in developed countries. The survival of these patients has increased significantly, but CHD remains one of the major causes of neonatal and childhood death. The aetiology of CHD is complex, with some evidence of both genetic and environmental causes. However, there is still lack of knowledge regarding modifiable risk factors and molecular and genetic mechanisms underlying the development of CHD. This study aims to develop a prospective cohort of patients undergoing cardiac procedures that will bring together routinely collected clinical data and biological samples from patients and their biological mothers, in order to investigate risk factors and predictors of postoperative-outcomes, as well as better understanding the effect of the surgical intervention on the early and long-term outcomes.Methods and analysis Children OMACp (OMACp, outcome monitoring after cardiac procedure in congenital heart disease) is a multicentre, prospective cohort study recruiting children with CHD undergoing a cardiac procedure. The study aims to recruit 3000 participants over 5 years (2019–2024) across multiple UK sites. Routine clinical data will be collected, as well as participant questionnaires collecting sociodemographic, NHS resource use and quality of life data. Biological samples (blood, urine and surgical waste tissue from patients, and blood and urine samples from biological mothers) will be collected where consent has been obtained. Follow-up outcome and questionnaire data will be collected for 5 years.Ethics and dissemination The study was approved by the London–Brent Research Ethics Committee on 30 July 2019 (19/SW/0113). Participants (or their parent/guardian if under 16 years of age) must provide informed consent prior to being recruited into the study. Mothers who wish to take part must also provide informed consent prior to being recruited. The study is sponsored by University Hospitals Bristol and Weston Foundation Trust and is managed by the University of Bristol. Children OMACp is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated through peer-reviewed publications, presentation at conference, meetings and through patient organisations and newsletters.Trial registration number ISRCTN17650644.

Abstract Background Given the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. Methods A randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between −6.0 and −2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. Discussion Lithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup. Trial registration EudraCT number 2020-000579-19 . Registered on 29 March 2021.

Abstract Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability.

There is currently no diagnostic or prognostic biomarker available in clinical practice for Amyotrophic Lateral Sclerosis (ALS). The objective of this study was to monitor a combination of various inflammatory markers, lipids, and apolipoproteins alterations in ALS patients at the time of diagnosis, to assess their role as early diagnostic or prognostic biomarker candidates. C-reactive protein, orosomucoid, prealbumin, calprotectin, lipids and apoliproteins were determined in the blood of all subjects (25 ALS patients, 23 controls) as routinely performed in our laboratory. Inflammatory mediators were evaluated by a bead-based multiplex assay. A two-step approach was used for each analytical strategy: univariate analysis followed by multivariate analysis. Eight features were significantly different between ALS patients and controls, sometimes with important fold changes. The supervised Partial least Squares Discriminant Analysis separated ALS and controls with great accuracy (94 %) and the permutation test was significant (p < 0.01), ensuring the robustness of the model. The prediction model leads to a mean sensitivity and specificity of 90 (+/- 10) and 78 (+/- 10) %, respectively, with a mean predictive positive value and negative predictive value of 80 (+/- 8.9) and 89 (+/- 11.8) %, respectively. However, the models did not discriminate subgroups of ALS patients based on ALS characteristics. This study highlights the usefulness of evaluating a combination of multiple pathways rather than focusing on a single target. These promising results suggest the need for the longitudinal monitoring of these candidates to determine their role in disease evolution.

Abstract Background Cyclic Vomiting Syndrome (CVS) is a rare functional gastrointestinal disorder, which has a considerable burden on quality of life of both children and their family. Aim of the study was to evaluate the diagnostic modalities and therapeutic approach to CVS among Italian tertiary care centers and the differences according to subspecialties, as well as to explore whether potential predictive factors associated with either a poor outcome or a response to a specific treatment. Methods Cross-sectional multicenter web-based survey involving members of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP). Results A total of 67 responses were received and analyzed. Most of the respondent units cared for less than 20 patients. More than half of the patients were referred after 3 to 5 episodes, and a quarter after 5 attacks. We report different diagnostic approaches among Italian clinicians, which was particularly evident when comparing gastroenterologists and neurologists. Moreover, our survey demonstrated a predilection of certain drugs during emetic phase according to specific clinic, which reflects the cultural background of physicians. Conclusion In conclusion, our survey highlights poor consensus amongst clinicians in our country in the diagnosis and the management of children with CVS, raising the need for a national consensus guideline in order to standardize the practice.

Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions.We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease.We found no evidence for enrichment of positively-selected SNPs in the heritability of Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, suggesting that common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk.These findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with a difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocyte count as lymphocytes and neutrophils. The neutrophil-to-lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS. Thus, the aim of this study was to analyze the evolution of the NLR during disease evolution in a French cohort of ALS patients and its relation with survival. In this monocentric retrospective study, clinical parameters and NLR were collected in ALS patients followed at the University Hospital of Tours (France). ALS patients were subdivided into three groups regarding their NLR value at inclusion: group 1 (NLR < 2); group 2 (NLR: 2–3); group 3 (NLR > 3). A comparison of qualitative and quantitative clinical and biological variables between NLR groups was performed. Then, Cox regressions were carried out to determine the association of NLR with survival. We observed a significant correlation of NLR with ALSFRS-r score (p < 0.0001) and with vital forced capacity (p = 0.0004) at inclusion. We observed that increased NLR at diagnosis is associated with decreased ALS patients’ survival.

OBJECTIVE: To revise the 1999 Airlie House consensus guidelines for the design and implementation of preclinical therapeutic studies and clinical trials in amyotrophic lateral sclerosis (ALS). METHODS: A consensus committee comprising 140 key members of the international ALS community (ALS researchers, clinicians, patient representatives, research funding representatives, industry, and regulatory agencies) addressed 9 areas of need within ALS research: (1) preclinical studies; (2) biological and phenotypic heterogeneity; (3) outcome measures; (4) disease-modifying and symptomatic interventions; (5) recruitment and retention; (6) biomarkers; (7) clinical trial phases; (8) beyond traditional trial designs; and (9) statistical considerations. Assigned to 1 of 8 sections, committee members generated a draft set of guidelines based on a background of developing a (pre)clinical question and a rationale outlining the evidence and expert opinion. Following a 2-day, face-to-face workshop at the Airlie House Conference Center, a modified Delphi process was used to develop draft consensus research guidelines, which were subsequently reviewed and modified based on comments from the public. Statistical experts drafted a separate document of statistical considerations (section 9). RESULTS: In this report, we summarize 112 guidelines and their associated backgrounds and rationales. The full list of guidelines, the statistical considerations, and a glossary of terms can be found in data available from Dryad (appendices e-3-e-5, doi.org/10.5061/dryad.32q9q5d). The authors prioritized 15 guidelines with the greatest potential to improve ALS clinical research. CONCLUSION: The revised Airlie House ALS Clinical Trials Consensus Guidelines should serve to improve clinical trial design and accelerate the development of effective treatments for patients with ALS.

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts.Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype.Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days.Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2–4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.MethodsSamples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.ResultsThere were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10−12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10−7). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10−4).DiscussionAlthough telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.

Background Rome became the prosperous Capital of the Roman Empire through the political and military conquests of neighbouring areas. People were able to move Romeward modifying the Rome area’s demographic structure. However, the genomic evidence for the population of one of the broadest Empires in antiquity has been sparse until recently. Aim The genomic analysis of people buried in Quarto Cappello del Prete (QCP) necropolis was carried out to help elucidate the genomic structure of Imperial Rome inhabitants. Subjects and methods We recruited twenty-five individuals from QCP for ancient DNA analysis through whole-genome sequencing. Multiple investigations were carried out to unveil the genetic components featuring in the studied samples and the community’s putative demographic structure. Results We generated reliable whole-genome data for 7 samples surviving quality controls. The distribution of Imperial Romans from QCP partly overlaps with present-day Southern Mediterranean and Southern-Near Eastern populations. Conclusion The genomic legacy with the south-eastern shores of the Mediterranean Sea and the Central and Western Northern-African coast funerary influence pave the way for considering people buried in QCP as resembling a Punic-derived human group.

The ubiquitin pathway, one of the main actors regulating cell signaling processes and cellular protein homeostasis, is directly involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). We first analyzed, by a next-generation sequencing (NGS) strategy, a series of genes of the ubiquitin pathway in two cohorts of familial and sporadic ALS patients comprising 176 ALS patients. We identified several pathogenic variants in different genes of this ubiquitin pathway already described in ALS, such as FUS, CCNF and UBQLN2. Other variants of interest were discovered in new genes studied in this disease, in particular in the HECW1 gene. We have shown that the HECT E3 ligase called NEDL1, encoded by the HECW1 gene, is expressed in neurons, mainly in their somas. Its overexpression is associated with increased cell death in vitro and, very interestingly, with the cytoplasmic mislocalization of TDP-43, a major protein involved in ALS. These results give new support for the role of the ubiquitin pathway in ALS, and suggest further studies of the HECW1 gene and its protein NEDL1 in the pathophysiology of ALS.

Abstract Background Kennedy’s disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations. Results The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy. Conclusion The French national Kennedy’s disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines.