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Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43 Tg -ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy., (© 2024. The Author(s).)

Background and Objectives: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival., Methods: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate., Results: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (β = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (β = -4.79 [-8.39 to -2.49], p = 0.001, β = -10.14 [-15.88 to -4.39], p = 0.004, and β = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (β = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029)., Discussion: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.

Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Objectives: We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the C9orf72 repeat expansion., Methods: We included all patients with ALS carrying a C9orf72 repeat expansion in The Netherlands. Using structured questionnaires, we determined the number of first-degree relatives, their age at death due to ALS or another cause, or age at time of questionnaire. The cumulative incidence of ALS among first-degree relatives was estimated, while accounting for death from other causes. Variability in ALS risk between families was evaluated using a random effects hazards model. We used a second, distinct approach to estimate the risk of ALS and FTD in the general population, using previously published data., Results: In total, 214 of the 2,486 (9.2%) patients with ALS carried the C9orf72 repeat expansion. The mean risk of ALS at age 80 for first-degree relatives carrying the repeat expansion was 24.1%, but ranged between individual families from 16.0 to 60.6%. Using the second approach, we found the risk of ALS and FTD combined was 28.7% (95% CI 17.8%-54.3%) for carriers in the general population., Conclusions: On average, our estimated risk of ALS in the C9orf72 repeat expansion was lower compared to historical estimates. We showed, however, that the risk of ALS likely varies between families and one overall penetrance estimate may not be sufficient to describe ALS risk. This warrants a tailor-made, patient-specific approach in testing. Further studies are needed to assess the risk of FTD in the C9orf72 repeat expansion.

Objective: To report the frequency and characteristics of patients diagnosed with primary lateral sclerosis (PLS) with a positive family history for motor neuron diseases (MND) in the Netherlands and to compare our findings to the literature., Methods: Patients were identified through our ongoing, prospective population-based study on MND in The Netherlands, which also includes a standardized collection of patient characteristics, genetic testing, and family history. Only patients meeting the latest consensus criteria for definite PLS were included. The family history was considered positive for MND if any family members had been diagnosed with PLS, amyotrophic lateral sclerosis (ALS)(-FTD), or progressive muscular atrophy (PMA). Additionally, the literature was reviewed on PLS cases in which MND co-occurred within the same family., Results: We identified 392 definite PLS cases, resulting in 9 families with a PLS patient and a positive family history for MND (2.3%). In only one of these pedigrees, a pathogenic variant ( C9orf72 repeat expansion) was found. Our literature review revealed 23 families with a co-occurrence of PLS and MND, with 12 of them having a potentially pathogenic genetic variant., Conclusions: The consistent observation of PLS patients with a positive family history for MND, evident in both our study and the literature, implies the presence of shared underlying genetic factors between PLS and ALS. However, these factors are yet to be elucidated.

Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process., (Copyright © 2024. Published by Elsevier Inc.)

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Current scales used in amyotrophic lateral sclerosis (ALS) attempt to summarize different functional domains or "dimensions" into 1 overall score, which may not accurately characterize the individual patient's disease severity or prognosis. The use of composite score risks declaring treatments ineffective if not all dimensions of ALS disease progression are affected equally. We aimed to develop the ALS Impairment Multidomain Scale (AIMS) to comprehensively characterize disease progression and increase the likelihood of identifying effective treatments., Methods: The Revised ALS Functional Rating Scale (ALSFRS-R) and a preliminary questionnaire, based on literature review and patient input, were completed online by patients from the Netherlands ALS registry at bimonthly intervals over a period of 12 months. A 2-week test-retest, factor analysis, Rasch analysis, and a signal-to-noise optimization strategy were performed to create a multidomain scale. Reliability, longitudinal decline, and associations with survival were evaluated. The sample size required to detect a 35% reduction in progression rate over 6 or 12 months was assessed for a clinical trial that defines the ALSFRS-R or AIMS subscales as a primary endpoint family., Results: The preliminary questionnaire, consisting of 110 questions, was completed by 367 patients. Three unidimensional subscales were identified, and a multidomain scale was constructed with 7 bulbar, 11 motor, and 5 respiratory questions. Subscales fulfilled Rasch model requirements, with excellent test-retest reliability of 0.91-0.94 and a strong relationship with survival ( p < 0.001). Compared with the ALSFRS-R, signal-to-noise ratios were higher as patients declined more uniformly per subscale. Consequently, the estimated sample size reductions achieved with the AIMS compared with those achieved with the ALSFRS-R were 16.3% and 25.9% for 6-month and 12-month clinical trials, respectively., Discussion: We developed the AIMS, consisting of unidimensional bulbar, motor, and respiratory subscales, which may characterize disease severity better than a total score. AIMS subscales have high test-retest reliability, are optimized to measure disease progression, and are strongly related to survival time. The AIMS can be easily administered and may increase the likelihood of identifying effective treatments in ALS clinical trials., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data., Methods: We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association., Results: WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), "ALS-HSP-CMT overlap" (FIG4, NEFL, SPG11)., Discussion: In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS., (© 2023. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the UNC13A gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in UNC13A lead to the inclusion of a cryptic exon in UNC13A messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission. Recent discoveries have identified UNC13A as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in UNC13A cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering UNC13A is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of UNC13A as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials., Competing Interests: Competing interests: PVD has served in advisory boards for Biogen, CSL Behring, Alexion Pharmaceuticals, Ferrer, QurAlis, Cytokinetics, Argenx, UCB, Muna Therapeutics, Alector, Augustine Therapeutics, VectorY (paid to institution). LHvdB declares fees to his institution from Biogen, Wave, Amylyx, Ferrer, and Cytokinetics for being on a scientific advisory board; fees to his institution from Amylyx for a lecture; an unrestricted educational grant from Takeda; and is the Chair of ENCALS and TRICALS. MAvE has consulted for Biogen and has received travel grants from Shire (formerly Baxalta) and serves as medical monitor for Ferrer in the ADORE trial (NCT05178810)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by the degeneration of motor neurons. Large-scale genetic studies have now identified over 60 genes that are associated with ALS, which in large part have also been functionally characterized. The purpose of this review is to outline how these advances are being translated into novel therapeutic strategies., Recent Findings: The emergence of techniques that allow the specific therapeutic targeting of a (mutant) gene, in particular antisense oligonucleotide therapy (ASOs), have led to the first successful gene therapy for SOD1-ALS and multiple other gene-targeted trials are underway. This includes genetic variants that modify the disease phenotype as well as causal mutations., Summary: Technological and methodological advances are enabling researchers to unravel the genetics of ALS. Both causal mutations and genetic modifiers are viable therapeutic targets. By performing natural history studies, the phenotype-genotype correlations can be characterized. In conjunction with biomarkers for target engagement and international collaboration, this makes performing gene-targeted trials ALS feasible. The first effective treatment has now been developed for SOD1-ALS and, with multiple studies underway, it seems realistic that more therapies will follow., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: We investigated effects of C9orf72 repeat expansion and gene expression on longitudinal cerebral changes before symptom onset., Methods: We enrolled 79 asymptomatic family members (AFMs) from 9 families with C9orf72 repeat expansion. Twenty-eight AFMs carried the mutation (C9+). Participants had up to 3 magnetic resonance imaging (MRI) scans, after which we compared motor cortex and motor tracts between C9+ and C9- AFMs using mixed effects models, incorporating kinship to correct for familial relations and lessen effects of other genetic factors. We also compared cortical, subcortical, cerebellar, and connectome structural measurements in a hypothesis-free analysis. We correlated regional C9orf72 expression in donor brains with the pattern of cortical thinning in C9+ AFMs using meta-regression. For comparison, we included 42 C9+ and 439 C9- patients with amyotrophic lateral sclerosis (ALS) in this analysis., Results: C9+ AFM motor cortex had less gyrification and was thinner than in C9- AFMs, without differences in motor tracts. Whole brain analysis revealed thinner cortex and less gyrification in parietal, occipital, and temporal regions, smaller thalami and right hippocampus, and affected frontotemporal connections. Thinning of bilateral precentral, precuneus, and left superior parietal cortex was faster in C9+ than in C9- AFMs. Higher C9orf72 expression correlated with thinner cortex in both C9+ AFMs and C9+ ALS patients., Interpretation: In asymptomatic C9orf72 repeat expansion carriers, brain MRI reveals widespread features suggestive of impaired neurodevelopment, along with faster decline of motor and parietal cortex than found in normal aging. C9orf72 expression might play a role in cortical development, and consequently explain the specific brain abnormalities of mutation carriers. ANN NEUROL 2023;93:668-680., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objective: To explore the association between lipids, polygenic profile scores (PPS) for biomarkers of lipid metabolism, markers of disease severity, and survival in patients with amyotrophic lateral sclerosis (ALS)., Methods: We meta-analyzed the current literature on the prognostic value of lipids in patients with ALS. Subsequently, we evaluated the relationship between lipid levels at diagnosis, clinical disease stage, and survival in all consecutive patients diagnosed in the Netherlands. We determined the hazard ratio (HR) of each lipid for overall survival, defined as death from any cause. A subset of patients was matched to a previous genome-wide association study; data were used to calculate PPS for biomarkers of lipid metabolism and to determine the association between observed lipid levels at diagnosis and survival., Results: Meta-analysis of 4 studies indicated that none of the biomarkers of the lipid metabolism were statistically significantly associated with overall survival; there was, however, considerable heterogeneity between study results. Using individual patient data (N = 1,324), we found that increased high-density lipoprotein (HDL) cholesterol was associated with poorer survival (HR of 1.33 (95% CI 1.14-1.55, p < 0.001)). The correlation between BMI and HDL cholesterol (Pearson r -0.26, 95% CI -0.32 to -0.20) was negative and between BMI and triglycerides (TG) positive (Pearson r 0.18, 95% CI 0.12-0.24). Serum concentrations of total cholesterol and LDL cholesterol were lower in more advanced clinical stages (both p < 0.001). PPS for biomarkers of lipid metabolism explained 1.2%-13.1% of their variance at diagnosis. None of the PPS was significantly associated with survival (all p > 0.50)., Discussion: Lipids may contain valuable information about disease severity and prognosis, but their main value may be driven as a consequence of disease progression. Our results underscore that gaining further insight into lipid metabolism and longitudinal data on serum concentrations of the lipid profile could improve the monitoring of patients and potentially further disentangle ALS pathogenesis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)

Objective: The purpose of this study was to identify subtypes of amyotrophic lateral sclerosis (ALS) by comparing patterns of neurodegeneration using brain magnetic resonance imaging (MRI) and explore their phenotypes., Methods: We performed T1-weighted and diffusion tensor imaging in 488 clinically well-characterized patients with ALS and 338 control subjects. Measurements of whole-brain cortical thickness and white matter connectome fractional anisotropy were adjusted for disease-unrelated variation. A probabilistic network-based clustering algorithm was used to divide patients into subgroups of similar neurodegeneration patterns. Clinical characteristics and cognitive profiles were assessed for each subgroup. In total, 512 follow-up scans were used to validate clustering results longitudinally., Results: The clustering algorithm divided patients with ALS into 3 subgroups of 187, 163, and 138 patients. All subgroups displayed involvement of the precentral gyrus and are characterized, respectively, by (1) pure motor involvement (pure motor cluster [PM]), (2) orbitofrontal and temporal involvement (frontotemporal cluster [FT]), and (3) involvement of the posterior cingulate cortex, parietal white matter, temporal operculum, and cerebellum (cingulate-parietal-temporal cluster [CPT]). These subgroups had significantly distinct clinical profiles regarding male-to-female ratio, age at symptom onset, and frequency of bulbar symptom onset. FT and CPT revealed higher rates of cognitive impairment on the Edinburgh cognitive and behavioral ALS screen (ECAS). Longitudinally, clustering remained stable: at 90.4% of their follow-up visits, patients clustered in the same subgroup as their baseline visit., Interpretation: ALS can manifest itself in 3 main patterns of cerebral neurodegeneration, each associated with distinct clinical characteristics and cognitive profiles. Besides the pure motor and frontotemporal dementia (FTD)-like variants of ALS, a new neuroimaging phenotype has emerged, characterized by posterior cingulate, parietal, temporal, and cerebellar involvement. ANN NEUROL 2022;92:1030-1045., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Background: The Gold Coast criteria (GCC) have been proposed as a means of selecting patients for amyotrophic lateral sclerosis (ALS) clinical trials. We aimed to characterise disease progression according to the GCC., Methods: Data from population-based ALS registries from the Netherlands and Belgium were analysed. The GCC additionally define ALS as lower motor neuron (LMN) dysfunction in ≥2 body regions without upper motor neuron dysfunction. Therefore, the revised El Escorial criteria (rEEC) were supplemented with a 'Gold Coast ALS' category for patients with only LMN dysfunction in ≥2 body regions. We assessed survival time, ALS Functional Rating Scale (ALSFRS-R) progression rates and between-patient variability per diagnostic category., Results: We included 5957 ALS patients, of whom 600 (10.1%) fulfilled the GCC but not the rEEC, and 95 (1.6%) fulfilled only the rEEC. ALSFRS-R progression rates were similar for the rEEC (0.84 points/month) and GCC (0.81 points/month) with similar variability (standard deviation of 0.59 vs. 0.60) and median survival time (17.8 vs.18.7 months). Survival time and average progression rates varied (p<0.001) between categories. Per category, however, there was considerable between-patient variability with progression rates ranging from: -2.10 to -0.14 (definite), -1.94 to -0.06 (probable), -2.10 to -0.02 (probable laboratory supported), -1.79 to -0.02 (possible) and -1.31 to 0.08 (Gold Coast)., Conclusions: The GCC broaden the definition of ALS, allowing more patients to participate in trials, while minimally impacting population heterogeneity. Given the large variability per diagnostic category, selecting only specific categories for trials may not result in a more homogeneous study population., Competing Interests: Competing interests: ADdJ, MW, NB, MAvE, PM, JHV, LHvdB and RPAvE report no disclosures relevant to this study. PvD holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds 'Een Hart voor ALS', 'Laeversfonds voor ALS Onderzoek' and the 'Valéry Perrier Race against ALS Fund'. Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD)., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.

The objective of this study was to examine if patterns of resting-state brain activity and functional connectivity in cortical and subcortical regions in patients with early symptomatic amyotrophic lateral sclerosis (ALS) resemble those of behavioural variant frontotemporal dementia (bvFTD). In a cross-sectional design, eyes-closed resting-state magnetoencephalography (MEG) data of 34 ALS patients, 18 bvFTD patients and 18 age- and gender-matched healthy controls (HCs) were projected to source-space using an atlas-based beamformer. Group differences in peak frequency, band-specific oscillatory activity and functional connectivity (corrected amplitude envelope correlation) in 78 cortical regions and 12 subcortical regions were determined. False discovery rate was used to correct for multiple comparisons. BvFTD patients, as compared to ALS and HCs, showed lower relative beta power in parietal, occipital, temporal and nearly all subcortical regions. Compared to HCs, patients with ALS and patients with bvFTD had a higher delta (0.5-4 Hz) and gamma (30-48 Hz) band resting-state functional connectivity in a high number of overlapping regions in the frontal lobe and in limbic and subcortical regions. Higher delta band connectivity was widespread in the bvFTD patients compared to HCs. ALS showed a more widespread higher gamma band functional connectivity compared to bvFTD. In conclusion, MEG in early symptomatic ALS patients shows resting-state functional connectivity changes in frontal, limbic and subcortical regions that overlap considerably with bvFTD. The findings show the potential of MEG to detect brain changes in early symptomatic phases of ALS and contribute to our understanding of the disease spectrum, with ALS and bvFTD at the two extreme ends., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate sensitivity of brain MRI and neurological examination for detection of upper motor neuron (UMN) degeneration in patients with amyotrophic lateral sclerosis (ALS)., Methods: We studied 192 patients with ALS and 314 controls longitudinally. All patients visited our centre twice and underwent full neurological examination and brain MRI. At each visit, we assessed UMN degeneration by measuring motor cortex thickness (CT) and pyramidal tract fibre density (FD) corresponding to five body regions (bulbar region and limbs). For each body region, we measured degree of clinical UMN and lower motor neuron (LMN) symptom burden using a validated scoring system., Results: We found deterioration over time of CT of motor regions (p≤0.0081) and progression of UMN signs of bulbar region and left arm (p≤0.04). FD was discriminative between controls and patients with moderate/severe UMN signs (all regions, p≤0.034), but did not change longitudinally. Higher clinical UMN burden correlated with reduced CT, but not lower FD, for the bulbar region (p=2.2×10 -10 ) and legs (p≤0.025). In the arms, we found that severe LMN signs may reduce the detectability of UMN signs (p≤0.043). With MRI, UMN degeneration was detectable before UMN signs became clinically evident (CT: p=1.1×10 -10 , FD: p=6.3×10 -4 ). Motor CT, but not FD, deteriorated more than UMN signs during the study period., Conclusions: Motor CT is a more sensitive measure of UMN degeneration than UMN signs. Motor CT and pyramidal tract FD are discriminative between patients and controls. Brain MRI can monitor UMN degeneration before signs become clinically evident. These findings promote MRI as a potential biomarker for UMN progression in clinical trials in ALS., Competing Interests: Competing interests: LHvdB received travel grants and consultancy fees from Shire and serves on scientific advisory boards for Treeway, Cytokinetics, and Biogen, outside the submitted work. MAvE serves on the medical ethical review board of the UMC Utrecht and received travel grants from Shire and has consulted for Biogen, outside the submitted work. JHV reports having sponsored research agreements with Biogen, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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., (© 2021. The Author(s).)

The kinesin family member 5A ( KIF5A ) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 ( CMT2 ), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype.

Cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) negatively influences the quality of life and survival, and, therefore, screening for these impairments is recommended. We developed a cognitive screening tool, the amyotrophic lateral sclerosis-frontotemporal dementia-cognitive screen (ALS-FTD-Cog) and aimed to validate it in patients with ALS. During the current study, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was published and we, therefore, decided to compare these two cognitive screening methods. The ALS-FTD-Cog was administered to 72 patients with ALS, 21 patients with behavioural variant FTD (bvFTD) and 34 healthy controls. Twenty-nine patients with ALS underwent the ECAS. ROC curve analyses were performed and sensitivity and specificity of the ALS-FTD-Cog and ECAS were calculated, with a neuropsychological examination (NPE) as the gold standard. Cognitive impairment was present in 28% of patients with ALS. ROC curve analyses of the ALS-FTD-Cog and ECAS showed an area under the curve (AUC) of 0.72 (95% CI 0.58-0.86) and 0.95 (95% CI 0.86-1.03), respectively. Compared to a full NPE, sensitivity and specificity of the ALS-FTD-Cog were 65.0% and 63.5% and of the ECAS 83.3% and 91.3%, respectively. The sensitivity and specificity of the ALS-FTD-Cog in patients with bvFTD were 94.4% and 100%, respectively. Test characteristics of the ALS-FTD-Cog were moderate, suggesting restricted practical value, as compared to a comprehensive NPE. The ECAS had an excellent AUC and high sensitivity and specificity, indicating that it is a valid screening instrument for cognitive impairment in ALS.

Background: Personalized ENCALS survival prediction model reliably estimates the personalized prognosis of patients with amyotrophic lateral sclerosis. Concerns were raised on discussing personalized prognosis without causing anxiety and destroying hope. Tailoring communication to patient readiness and patient needs mediates the impact of prognostic disclosure. We developed a communication guide to support physicians in discussing personalized prognosis tailored to individual needs and preferences of people with ALS and their families., Methods: A multidisciplinary working group of neurologists, rehabilitation physicians, and healthcare researchers A) identified relevant topics for guidance, B) conducted a systematic review on needs of patients regarding prognostic discussion in life-limiting disease, C) drafted recommendations based on evidence and expert opinion, and refined and finalized these recommendations in consensus rounds, based on feedback of an expert advisory panel (patients, family member, ethicist, and spiritual counsellor)., Results: A) Topics identified for guidance were 1) filling in the ENCALS survival model, and interpreting outcomes and uncertainty, and 2) tailoring discussion to individual needs and preferences of patients (information needs, role and needs of family, severe cognitive impairment or frontotemporal dementia, and non-western patients). B) 17 studies were included in the systematic review. C) Consensus procedures on drafted recommendations focused on selection of outcomes, uncertainty about estimated survival, culturally sensitive communication, and lack of decisional capacity. Recommendations for discussing the prognosis include the following: discuss prognosis based on the prognostic groups and their median survival, or, if more precise information is desired, on the interquartile range of the survival probability. Investigate needs and preferences of the patients and their families for prognostic disclosure, regardless of cultural background. If the patient does not want to know their prognosis, with patient permission discuss the prognosis with their family. If the patient is judged to lack decisional capacity, ask the family if they want to discuss the prognosis. Tailor prognostic disclosure step by step, discuss it in terms of time range, and emphasize uncertainty of individual survival time., Conclusion: This communication guide supports physicians in tailoring discussion of personalized prognosis to the individual needs and preferences of people with ALS and their families.

A change in our current approach toward drug development is required to improve the likelihood of finding effective treatment for patients with amyotrophic lateral sclerosis (ALS). The aim of the Treatment Research Initiative to Cure ALS (TRICALS) is to extend the collective effort with industry and consolidate drug development paths. TRICALS has begun a series of meetings on how to best move the field forward collaboratively, thereby addressing five major topics in ALS clinical trials: (1) preclinical research, (2) biomarker development, (3) eligibility criteria, (4) efficacy endpoints and (5) innovative trial design. There is an appetite for ongoing discussions of these major topics in clinical trials between representatives from academia, patient advocacy groups, industry partners and funding bodies. Industry is open to fundamentally change drug development for ALS and shorten the time to effective therapy for patients by implementing promising innovations in biomarker development, trial design, and patient selection. There is however, a pressing need from all stakeholders for regulatory discussions and amendments of current guidelines to successfully adopt innovation in future clinical development lines.

Objective: A recent case-series described patients with ALS to improve and/or stabilize after treatment with intravenous high-dose Penicillin G/Hydrocortisone (PenGH). In this study, we determine the safety and efficacy of intravenous PenGH versus placebo in combination with riluzole in patients with ALS., Methods: Patients diagnosed with ALS according to the El Escorial criteria were randomized double-blind to four quarterly cycles of 21 d of intravenous PenGH or placebo in a 5:3 ratio. The primary outcome was change from baseline to week 48 in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Secondary outcomes were lung function, muscle strength, plasma creatinine, clinical stage, gastrostomy placement, quality of life and occurrence of adverse of events., Results: In total, 16 patients were randomized (10 PenGH and 6 placebo), of which 6 (40%) completed the study. Patients treated with PenGH progressed with 2.2 (95% CI 1.1-3.3) ALSFRS-R points per month and PenGH treatment did not halt disease progression ( p  = 0.002). No significant differences were found between PenGH or placebo (mean difference 0.5, 95% CI -1.01 to ∞, p  = 0.28). Although PenGH was well-tolerated, 6 patients (38%, 3 in each arm) had thrombotic complications due to the intravenous administration method., Conclusions: Treatment with PenGH does not halt disease or reverse progression in patients with ALS and showed no statistical difference with those who received placebo. Prolonged intravenous administration therapies may inflate thrombosis risk.

Objective: The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS., Methods: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model., Results: Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p < 0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, and C/C 43.1%; p < 0.001), higher incidences of ALS-FTD (A/A 4.3%, A/C 5.2%, and C/C 9.5%; p = 0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, and C/C 86.5; p < 0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, and C/C 26.6; p < 0.001). UNC13A was associated with lower scores on ALS-specific cognition tests (means A/A 79.5, A/C 78.1, and C/C 76.6; p = 0.037), and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4%, and C/C 27.7%; p = 0.045). Thinner left inferior temporal and right fusiform cortex were associated with the UNC13A single nucleotide polymorphism (SNP; p = 0.045 and p = 0.036)., Interpretation: Phenotypical distinctions associated with UNC13A make it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counseling. ANN NEUROL 2020;88:796-806., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of upper and lower motor neurons. ALS has traditionally been classified within the domain of neuromuscular diseases, which are a unique spectrum of disorders that predominantly affect the peripheral nervous system. However, over the past decades compounding evidence has emerged that there is extensive involvement of the central nervous system. Therefore, one can question whether it remains accurate to classify ALS as a neuromuscular disorder., Areas Covered: In this review, the authors sought to discuss current approaches toward disease classification and how we should classify ALS based on novel insights from clinical, imaging, pathophysiological, neuropathological and genetic studies., Expert Opinion: ALS exhibits the cardinal features of a neurodegenerative disease. Therefore, classifying ALS as a neuromuscular disease in the strict sense has become untenable. Diagnosing ALS however does require significant neuromuscular expertise and therefore neuromuscular specialists remain best equipped to evaluate this category of patients. Designating motor neuron diseases as a separate category in the ICD-11 is justified and adequately deals with this issue. However, to drive effective therapy development the fields of motor neuron disease and neurodegenerative disorders must come together.

Importance: During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant., Objectives: To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18-labeled fluorodeoxyglucose ([18F]FDG positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation's association with clinical and fluid biomarkers., Design, Setting, and Participants: A prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. The study was conducted at the neuromuscular reference center of the University Hospitals Leuven, Leuven, Belgium., Main Outcomes and Measures: Neuroimaging data were spatially normalized and analyzed at the voxel level at a height threshold of P < .001, cluster-level familywise error-corrected threshold of P < .05, and statistical significance was set at P < .05 for the volume-of-interest level analysis, using Benjamini-Hochberg correction for multiple correction. W-score maps were computed using the individuals serving as controls as a reference to quantify the degree of [18F]FDG PET abnormality. The threshold for abnormality on the W-score maps was designated as an absolute W-score greater than or equal to 1.96. Neurofilament levels and performance on cognitive and neurologic examinations were determined. All hypothesis tests were 1-sided., Results: Of the 42 included participants, there were 17 with the preSxC9 mutation (12 women [71%]; mean [SD] age, 51 [9] years) and 25 healthy controls (12 women [48%]; mean [SD] age, 47 [10] years). Compared with control participants, significant clusters of relative hypometabolism were found in frontotemporal regions, basal ganglia, and thalami of preSxC9 participants and relative hypermetabolism in the peri-Rolandic region, superior frontal gyrus, and precuneus cortex. W-score frequency maps revealed reduced glucose metabolism with local maxima in the insular cortices, central opercular cortex, and thalami in up to 82% of preSxC9 participants and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9 participants. Other findings in the preSxC9 group were upper motor neuron involvement in 10 participants (59%), cognitive abnormalities in 5 participants (29%), and elevated neurofilament levels in 3 of 16 individuals (19%) who underwent lumbar puncture., Conclusions and Relevance: The results suggest that [18F]FDG PET can identify glucose metabolic changes in preSxC9 at an individual level, preceding significantly elevated neurofilament levels and onset of symptoms.

Objective: To determine the prevalence and prognostic value of weight loss (WL) prior to diagnosis in patients with amyotrophic lateral sclerosis (ALS)., Methods: We enrolled patients diagnosed with ALS between 2010 and 2018 in a population-based setting. At diagnosis, detailed information was obtained regarding the patient's disease characteristics, anthropological changes, ALS-related genotypes and cognitive functioning. Complete survival data were obtained. Cox proportional hazard models were used to assess the association between WL and the risk of death during follow-up., Results: The data set comprised 2420 patients of whom 67.5% reported WL at diagnosis. WL occurred in 71.8% of the bulbar-onset and in 64.2% of the spinal-onset patients; the mean loss of body weight was 6.9% (95% CI 6.8 to 6.9) and 5.5% (95% CI 5.5 to 5.6), respectively (p<0.001). WL occurred in 35.1% of the patients without any symptom of dysphagia. WL is a strong independent predictor of survival, with a dose response relationship between the amount of WL and the risk of death: the risk of death during follow-up increased by 23% for every 10% increase in WL relative to body weight (HR 1.23, 95% CI 1.13 to 1.51, p<0.001)., Conclusions: This population-based study shows that two-thirds of the patients with ALS have WL at diagnosis, which also occurs independent of dysphagia, and is related to survival. Our results suggest that WL is a multifactorial process that may differ from patient to patient. Gaining further insight in its underlying factors could prove essential for future therapeutic measures., Competing Interests: Competing interests: MAvE reports grants from the Netherlands Organization for Health Research and Development (Veni scheme), Joint Program Neurodegeneration (JPND), The Thierry Latran foundation and the Netherlands ALS foundation (Stichting ALS Nederland). He received travel grants from Shire (formerly Baxalta) and has consulted for Biogen. LHvdB reports grants from Netherlands ALS Foundation (Stichting ALS Nederland), The Netherlands Organization for Health Research and Development (Vici schema; and funded through the EU Joint Program – Neurodegenerative Disease Research, JPND (SOPHIA, STRENGTH, ALS-CarE projects)), personal fees from Shire, Biogen, Cytokinetics and Treeway, outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Patients with amyotrophic lateral sclerosis (ALS) not only show motor deficits, but may also have cognitive and/or behavioral impairments. Recognizing these impairments is crucial as they are associated with lower quality of life, shorter survival, and increased caregiver burden. Therefore, ALS-specific neuropsychological screening instruments have been developed that can account for motor and speech difficulties. This study provides an overview and comparison of these screeners. Methods: A systematic review was conducted using Medline and Embase. Articles describing cognitive/behavioral screening instruments assessed in ALS patients were included. Screening instruments were compared on multiple factors, such as domains, adaptability, required time, and validation. Results: We included 99 articles, reporting on nine cognitive screeners (i.e. ACE-R, ALS-BCA, ALS-CBS, ECAS, FAB, MMSE, MoCA, PSSFTS, and UCSF-SB), of which five ALS-specific. Furthermore, eight behavioral screeners (i.e. ALS-FTD-Q, AES, BBI, DAS, FBI, FrSBe, MiND-B, and NPI) were reported on, of which three ALS-specific. Conclusion: Considering the broad range of cognitive domains, adaptability, and satisfying validity, the ALS-CBS and ECAS appear to be the most suitable screeners to detect cognitive and behavioral changes in ALS. The BBI appears to be the best option to screen for behavioral changes in ALS, since all relevant domains are assessed, motor-related problems are considered, and has a satisfactory validity. The MiND-B and ALS-FTD-Q are promising as well. In general, all screening instruments would benefit from additional validation research to gain greater insights into test characteristics and to aid clinicians in selecting screening tools for use in clinical practice.

Objective: To understand the progressive nature of amyotrophic lateral sclerosis (ALS) by investigating differential brain patterns of gray and white matter involvement in clinically or genetically defined subgroups of patients using cross-sectional, longitudinal, and multimodal MRI., Methods: We assessed cortical thickness, subcortical volumes, and white matter connectivity from T1-weighted and diffusion-weighted MRI in 292 patients with ALS (follow-up: n = 150) and 156 controls (follow-up: n = 72). Linear mixed-effects models were used to assess changes in structural brain measurements over time in patients compared to controls., Results: Patients with a C9orf72 mutation (n = 24) showed widespread gray and white matter involvement at baseline, and extensive loss of white matter integrity in the connectome over time. In C9orf72 -negative patients, we detected cortical thinning of motor and frontotemporal regions, and loss of white matter integrity of connections linked to the motor cortex. Patients with spinal onset displayed widespread white matter involvement at baseline and gray matter atrophy over time, whereas patients with bulbar onset started out with prominent gray matter involvement. Patients with unaffected cognition or behavior displayed predominantly motor system involvement, while widespread cerebral changes, including frontotemporal regions with progressive white matter involvement over time, were associated with impaired behavior or cognition. Progressive loss of gray and white matter integrity typically occurred in patients with shorter disease durations (<13 months), independent of progression rate., Conclusions: Heterogeneity of phenotype and C9orf72 genotype relates to distinct patterns of cerebral degeneration. We demonstrate that imaging studies have the potential to monitor disease progression and early intervention may be required to limit cerebral degeneration., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.

Objective: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is widely applied to assess disease severity and progression in patients with motor neuron disease (MND). The objective of the study is to assess the inter-rater and intra-rater reproducibility, i.e., the inter-rater and intra-rater reliability and agreement, of a self-administration version of the ALSFRS-R for use in apps, online platforms, clinical care and trials., Methods: The self-administration version of the ALSFRS-R was developed based on both patient and expert feedback. To assess the inter-rater reproducibility, 59 patients with MND filled out the ALSFRS-R online and were subsequently assessed on the ALSFRS-R by three raters. To assess the intra-rater reproducibility, patients were invited on two occasions to complete the ALSFRS-R online. Reliability was assessed with intraclass correlation coefficients, agreement was assessed with Bland-Altman plots and paired samples t -tests, and internal consistency was examined with Cronbach's coefficient alpha., Results: The self-administration version of the ALSFRS-R demonstrated excellent inter-rater and intra-rater reliability. The assessment of inter-rater agreement demonstrated small systematic differences between patients and raters and acceptable limits of agreement. The assessment of intra-rater agreement demonstrated no systematic changes between time points; limits of agreement were 4.3 points for the total score and ranged from 1.6 to 2.4 points for the domain scores. Coefficient alpha values were acceptable., Discussion: The self-administration version of the ALSFRS-R demonstrates high reproducibility and can be used in apps and online portals for both individual comparisons, facilitating the management of clinical care and group comparisons in clinical trials., Competing Interests: Competing interests: LAB, CDS, HHGT, SMAGV, RPAVE and JMAV-M have nothing to disclose. MAvE received grants from the Netherlands Organization for Health Research and Development (Veni scheme), The Thierry Latran Foundation, Joint Programme – Neurodegenerative Disease Research (JPND) and the Netherlands ALS Foundation (Stichting ALS Nederland). He received travel grants from Shire (previously Baxalta) and serves on the medical ethical review board of University Medical Centre Utrecht. LHvdB reports grants from ALS Foundation Netherlands, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project), funded through the EU JPND, personal fees from Shire (previously Baxalta), personal fees from Biogen, personal fees from Cytokinetics, other from Prinses Beatrix SpierFonds, other from Latran Foundation, outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective : Spirometry is commonly used as screening tool for respiratory insufficiency in neuromuscular diseases. Despite the well-known effects of reference standards on spirometric outcomes, its standardization is overlooked in current guidelines. We aim to illustrate the effect of spirometric reference values on prognostication, medical decision-making, and trial eligibility in the applied setting of amyotrophic lateral sclerosis (ALS). Methods : We selected 4,651 patients with 32,022 FVC measurements from the PRO-ACT dataset. The FVC estimates were standardized according to five reference standards: Knudson '76, Knudson '83, ECSC, NHANES III, and GLI-2012. (Generalized) linear mixed-effects and Cox proportional hazard models were used to evaluate longitudinal patterns and time-to-event outcomes. Results : The mean population %predicted FVC varied between 78.5% (95% CI 78.0-79.1) and 88.5% (95% CI 87.9-89.1). The unstandardized liters provided the worst fit on the survival data (AIC 20573, c-index 0.760), whereas the GLI provided the best fit (AIC 20374, c-index 0.780, p  < 0.001). The mean population rate of decline in %predicted FVC could vary as much as 11.4% between reference standards. The median time-to-50% predicted FVC differed by 2.9 months between recent (14.5 months, 95% CI 14.4-16.1) and early reference standards (17.4 months, 95% CI 16.1-18.2). Conclusion : Independent of technique, device, or evaluator, spirometric reference values affect the utility of spirometry in ALS. Standardization of reference values is of the utmost importance to optimize clinical decision-making, improve prognostication, enhance between-center comparison and unify patient selection for clinical trials.

Here, we provide a case-report of an amyotrophic lateral sclerosis (ALS) patient with cognitive deficits best defined as posterior cortical atrophy (PCA). This is an unusual finding as ALS forms a spectrum with frontotemporal dementia (FTD), whereas PCA is predominantly associated with Alzheimer's disease pathology. We hypothesize on whether ALS with PCA might be an under recognized phenotype considering multiple imaging studies in ALS have also reported (asymptomatic) parietal atrophy.

Objective: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies., Methods: We prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non-amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS., Results: The mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was -1.8 ± 1.7 for ALS Functional Rating Scale-Revised and -1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G 4 C 2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives., Conclusions: We present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data., (© 2019 American Academy of Neurology.)

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10 -5 ). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Edinburgh cognitive and behavioral ALS screen (ECAS) was developed specifically to detect cognitive and behavioral changes in patients with amyotrophic lateral sclerosis (ALS). Differences with regard to normative data of different (language) versions of neuropsychological tests such as the ECAS exist., Objective: To derive norms for the Dutch version of the ECAS., Methods: Normative data were derived from a large sample of 690 control subjects and cognitive profiles were compared between a matched sample of 428 patients with ALS and 428 control subjects., Results: Age, level of education, and sex were significantly associated with performance on the ECAS in the normative sample. ECAS data were not normally distributed and therefore normative data were expressed as percentile ranks. The comparison of ECAS scores between patients and control subjects demonstrated that patients obtained significantly lower scores for language, executive function, verbal fluency, and memory, which is in line with the established cognitive profile of ALS., Conclusion: For an accurate interpretation of ECAS results, it is important to derive normative data in large samples with nonparametric methods. The present normative data provide healthcare professionals with an accurate estimate of how common or uncommon patients' ECAS scores are and provide a useful supplement to existing cut-off scores.

Objectives: Cognitive and behavioural changes within the spectrum of frontotemporal dementia (FTD) are observed frequently in patients with amyotrophic lateral sclerosis (ALS). Whether these changes also occur in other forms of motor neuron disease (MND) is not well studied. We therefore systemically screened a large cohort of patients with primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) for cognitive and behavioural changes, and subsequently compared our findings with a cohort of patients with ALS., Methods: Using a set of screening instruments (Edinburgh Cognitive and Behavioural ALS Screen, ALS and Frontotemporal Dementia Questionnaire, Frontal Assessment Battery, and Hospital Anxiety and Depression Scale), the presence of cognitive and behavioural changes as well as anxiety and depression in 277 patients with ALS, 75 patients with PLS and 143 patients with PMA was evaluated retrospectively., Results: We found a high frequency of cognitive and behavioural abnormalities with similar profiles in all three groups. Subjects with behavioural variant FTD were identified in all groups., Conclusions: The percentage of patients with PLS and PMA with cognitive dysfunction was similar to patients with ALS, emphasising the importance for cognitive screening as part of routine clinical care in all three patient groups. With a similar cognitive profile, in line with genetic and clinical overlap between the MNDs, the view of PLS as an MND exclusively affecting upper motor neurons and PMA exclusively affecting lower motor neurons cannot be held. Therefore, our findings are in contrast to the recently revised El Escorial criteria of 2015, where PLS and PMA are described as restricted phenotypes. Our study favours a view of PLS and PMA as multidomain diseases similar to ALS., Competing Interests: Competing interests: MAvE serves on the UK Motor Neurone Disease Association Biomedical Research Advisory Panel, has consulted for Biogen and has received travel grants from Shire (formerly Baxalta). LHvdB reports grants from Netherlands ALS Foundation, grants from Prinses Beatrix Spierfonds, grants from Netherlands Organization for Health Research and Development (Vici scheme), and grants from European Community’s Health Seventh Framework Programme (FP7/2007-2013) (grant agreement no 259867), during the conduct of the study; and personal fees from Baxter for scientific advisory board and travel grant, and personal fees from Scientific Advisory Board, Biogen Idec, outside the submitted work. The other authors declare that they have no conflict of interest., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease characterized by both upper and lower motor neuron degeneration. While neuroimaging studies of the brain can detect upper motor neuron degeneration, these brain MRI scans also include the upper part of the cervical spinal cord, which offers the possibility to expand the focus also towards lower motor neuron degeneration. Here, we set out to investigate cross-sectional and longitudinal disease effects in the upper cervical spinal cord in patients with ALS, progressive muscular atrophy (PMA: primarily lower motor neuron involvement) and primary lateral sclerosis (PLS: primarily upper motor neuron involvement), and their relation to disease severity and grey and white matter brain measurements., Methods: We enrolled 108 ALS patients without C9orf72 repeat expansion (ALS C9-), 26 ALS patients with C9orf72 repeat expansion (ALS C9+), 28 PLS patients, 56 PMA patients and 114 controls. During up to five visits, longitudinal T1-weighted brain MRI data were acquired and used to segment the upper cervical spinal cord (UCSC, up to C3) and individual cervical segments (C1 to C4) to calculate cross-sectional areas (CSA). Using linear (mixed-effects) models, the CSA differences were assessed between groups and correlated with disease severity. Furthermore, a relationship between CSA and brain measurements was examined in terms of cortical thickness of the precentral gyrus and white matter integrity of the corticospinal tract., Results: Compared to controls, CSAs at baseline showed significantly thinner UCSC in all groups in the MND spectrum. Over time, ALS C9- patients demonstrated significant thinning of the UCSC and, more specifically, of segment C3 compared to controls. Progressive thinning over time was also observed in C1 of PMA patients, while ALS C9+ and PLS patients did not show any longitudinal changes. Longitudinal spinal cord measurements showed a significant relationship with disease severity and we found a significant correlation between spinal cord and motor cortex thickness or corticospinal tract integrity for PLS and PMA, but not for ALS patients., Discussion: Our findings demonstrate atrophy of the upper cervical spinal cord in the motor neuron disease spectrum, which was progressive over time for all but PLS patients. Cervical spinal cord imaging in ALS seems to capture different disease effects than brain neuroimaging. Atrophy of the cervical spinal cord is therefore a promising additional biomarker for both diagnosis and disease progression and could help in the monitoring of treatment effects in future clinical trials., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify differences in demographics, disease characteristics, treatments, and co-morbidities between patients with "amyotrophic lateral sclerosis (ALS) reversals" and those with typically progressive ALS., Methods: Cases of possible ALS reversals were found in prior publications, in the Duke ALS clinic, through self-referral or referral from other Neurologists, and on the internet. Of 89 possible reversals identified, 36 cases were included because chart or literature review confirmed their diagnosis and a robust, sustained improvement in at least one objective measure. Controls were participants in the Pooled Resource Open-Access ALS Clinical Trials database and the National ALS Registry. Cases and controls were compared using descriptive statistics., Results: ALS reversals were more likely to be male, have limb onset disease, and initially progress faster. The prevalences of myasthenia gravis (MG) and purely lower motor neuron disease in cases were higher than estimates of these prevalences in the general population. The odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were greater for cases than controls., Conclusions: When compared to patients with typically progressive ALS, patients with reversals differed in their demographics, disease characteristics, and treatments. While some of these patients may have had a rare antibody-mediated ALS mimicker, such as atypical myasthenia gravis, details of their exams, EMGs and family histories argue that this was unlikely. Instead, our data suggest that ALS reversals warrant evaluation for mechanisms of disease resistance and that treatments associated with multiple ALS reversals deserve further study.

Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-in gene targeting. Both approaches yielded SETX mutant mice that develop neuromuscular phenotypes and motor neuron degeneration. Neuropathological characterization of SETX mice revealed nuclear clearing of TDP-43, accompanied by TDP-43 cytosolic mislocalization, consistent with the hallmark pathology observed in human ALS patients. Postmortem material from ALS4 patients exhibited TDP-43 mislocalization in spinal cord motor neurons, and motor neurons from SETX ALS4 mice displayed enhanced stress granule formation. Immunostaining analysis for nucleocytoplasmic transport proteins Ran and RanGAP1 uncovered nuclear membrane abnormalities in the motor neurons of SETX ALS4 mice, and nuclear import was delayed in SETX ALS4 cortical neurons, indicative of impaired nucleocytoplasmic trafficking. SETX ALS4 mice thus recapitulated ALS disease phenotypes in association with TDP-43 mislocalization and provided insight into the basis for TDP-43 histopathology, linking SETX dysfunction to common pathways of ALS motor neuron degeneration.

The biological pathways involved in amyotrophic lateral sclerosis (ALS) remain elusive and diagnostic decision-making can be challenging. Gene expression studies are valuable in overcoming such challenges since they can shed light on differentially regulated pathways and may ultimately identify valuable biomarkers. This two-stage transcriptome-wide study, including 397 ALS patients and 645 control subjects, identified 2,943 differentially expressed transcripts predominantly involved in RNA binding and intracellular transport. When batch effects between the two stages were overcome, three different models (support vector machines, nearest shrunken centroids, and LASSO) discriminated ALS patients from control subjects in the validation stage with high accuracy. The models' accuracy reduced considerably when discriminating ALS from diseases that mimic ALS clinically (N = 75), nor could it predict survival. We here show that whole blood transcriptome profiles are able to reveal biological processes involved in ALS. Also, this study shows that using these profiles to differentiate between ALS and mimic syndromes will be challenging, even when taking batch effects in transcriptome data into account., Competing Interests: LHvdB received travel grants and consultancy fees from Baxter; serves on scientific advisory boards for Prinses Beatrix Spierfonds, Thierry Latran Foundation, Cytokinetics and Biogen Idec. MAvE has received travel grants from Baxter and has consulted for Biogen Idec. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS., Methods: We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy, or death) and applied backward elimination with bootstrapping in the largest population-based dataset for predictor selection. Data were gathered on the day of diagnosis or as soon as possible thereafter. Predictors that were selected in more than 70% of the bootstrap resamples were used to develop a multivariable Royston-Parmar model for predicting the composite survival outcome in individual patients. We assessed the generalisability of the model by estimating heterogeneity of predictive accuracy across external populations (ie, populations not used to develop the model) using internal-external cross-validation, and quantified the discrimination using the concordance (c) statistic (area under the receiver operator characteristic curve) and calibration using a calibration slope., Findings: Data were collected between Jan 1, 1992, and Sept 22, 2016 (the largest data-set included data from 1936 patients). The median follow-up time was 97·5 months (IQR 52·9-168·5). Eight candidate predictors entered the prediction model: bulbar versus non-bulbar onset (univariable hazard ratio [HR] 1·71, 95% CI 1·63-1·79), age at onset (1·03, 1·03-1·03), definite versus probable or possible ALS (1·47, 1·39-1·55), diagnostic delay (0·52, 0·51-0·53), forced vital capacity (HR 0·99, 0·99-0·99), progression rate (6·33, 5·92-6·76), frontotemporal dementia (1·34, 1·20-1·50), and presence of a C9orf72 repeat expansion (1·45, 1·31-1·61), all p<0·0001. The c statistic for external predictive accuracy of the model was 0·78 (95% CI 0·77-0·80; 95% prediction interval [PI] 0·74-0·82) and the calibration slope was 1·01 (95% CI 0·95-1·07; 95% PI 0·83-1·18). The model was used to define five groups with distinct median predicted (SE) and observed (SE) times in months from symptom onset to the composite survival outcome: very short 17·7 (0·20), 16·5 (0·23); short 25·3 (0·06), 25·2 (0·35); intermediate 32·2 (0·09), 32·8 (0·46); long 43·7 (0·21), 44·6 (0·74); and very long 91·0 (1·84), 85·6 (1·96)., Interpretation: We have developed an externally validated model to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS. This model could be applied to individualised patient management, counselling, and future trial design, but to maximise the benefit and prevent harm it is intended to be used by medical doctors only., Funding: Netherlands ALS Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis is characterised by the progressive loss of motor neurons in the brain and spinal cord. This neurodegenerative syndrome shares pathobiological features with frontotemporal dementia and, indeed, many patients show features of both diseases. Many different genes and pathophysiological processes contribute to the disease, and it will be necessary to understand this heterogeneity to find effective treatments. In this Seminar, we discuss clinical and diagnostic approaches as well as scientific advances in the research fields of genetics, disease modelling, biomarkers, and therapeutic strategies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)