Background and Objectives Pathogenic variations in fused in sarcoma (FUS) are among the most common genetic causes of amyotrophic lateral sclerosis (ALS) worldwide. They are supposedly characterized by a homogeneous pure motor phenotype with early-onset and short disease duration. However, a few FUS-mutated cases with a very late disease onset and slow progression have been reported. To analyze genotype-phenotype correlations and identify the prognostic factors in FUS-ALS cases. Methods We identified and cross-sectionally analyzed 22 FUS-ALS patient histories from a single-center cohort of 2,615 genetically tested patients and reviewed 289 previously published FUS-ALS cases. Survival analysis was performed by Kaplan-Meier survival curves, followed by the log-rank test and multivariate Cox analysis. Results Survival of FUS-ALS is age-dependent: In our cohort, early-onset cases had a rapid disease progression and short survival (p = 0.000003) while the outcome of FUS-mutated patients with mid-to-late onset did not differ from non–FUS-ALS patients (p = 0.437). Meta-analysis of literature data confirmed this trend (p = 0.00003). This survival pattern is not observed in other ALS-related genes in our series. We clustered FUS-ALS patients in 3 phenotypes: (1) axial ALS, with upper cervical and dropped-head onset in mid-to-late adulthood; (2) benign ALS, usually with a late-onset and slow disease progression; and (3) juvenile ALS, often with bulbar onset and preceded by learning disability or mild mental retardation. Those phenotypes arise from different mutations. Discussion We observed specific genotype-phenotype correlations of FUS-ALS and identified age at onset as the most critical prognostic factor. Our results demonstrated that FUS mutations underlie a specific subtype of ALS and enable a careful stratification of newly diagnosed FUS-ALS cases for clinical course and potential therapeutic windows. This will be crucial in the light of incoming gene-specific therapy.

Background Social cognition (SC) deficits are included in the amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTDS) revised diagnostic criteria. However, the impact of SC assessment on cognitive classification and the cognitive–behavioural correlates of SC remain unclear. This cross-sectional study aimed to assess the impact of SC assessment on ALS-FTDS categorisation and explore the relationship of SC with executive functions (EF) and behaviour changes in a cohort of ALS patients. Methods 121 patients and 56 healthy controls from the Turin ALS Centre underwent cognitive/behavioural testing, including the SC subdomains of facial emotion recognition, and cognitive and affective theory of mind (ToM). Results Patients performed significantly worse than controls in all SC explored domains, and 45% of patients exhibited a deficit in at least one SC test, dissociated from the presence of EF deficits. In 13% of cases, the SC deficit was isolated and subclinical. SC assessment contributed to the attribution of cognitive impairment in 10% of patients. Through a statistical clustering approach, we found that ToM only partially overlaps with EF while behaviour changes are associated with emotional disorders (anxiety and depression). Conclusions SC is overall independent of EF in ALS, with ToM only partially associated with specific EF measures, and behaviour changes associated with emotional disorders. The influence of SC on cognitive categorisation and the frequent identification of a subclinical SC impairment have implications in a clinical setting, considering the substantial impact of cognitive impairment on disease burden and therapeutic choices.

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo. Methods and analysis: STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34 ⁺ cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment. Ethics and dissemination: The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria ‘Città della Salute e della Scienza’, Torino, Italy. Results will be presented during scientific symposia or published in scientific journals. Trial registration number: Eudract 2014-002228-28.

(1) Background: Motor neuron diseases (MNDs) are fatal neurodegenerative diseases. Biomarkers could help with defining patients’ prognoses and stratifications. Besides neurofilaments, chitinases are a promising family of possible biomarkers which correlate with neuroinflammatory status. We evaluated the plasmatic levels of CHI3L1 in MNDs, MND mimics, and healthy controls (HCs). (2) Methods: We used a sandwich ELISA to quantify the CHI3L1 in plasma samples from 44 MND patients, 7 hereditary spastic paraplegia (HSP) patients, 9 MND mimics, and 19 HCs. We also collected a ALSFRSr scale, MRC scale, spirometry, mutational status, progression rate (PR), blood sampling, and neuropsychological evaluation. (3) Results: The plasma levels of the CHI3L1 were different among groups (p = 0.005). Particularly, the MND mimics showed higher CHI3L1 levels compared with the MND patients and HCs. The CHI3L1 levels did not differ among PMA, PLS, and ALS, and we did not find a correlation among the CHI3L1 levels and clinical scores, spirometry parameters, PR, and neuropsychological features. Of note, the red blood cell count and haemoglobin was correlated with the CHI3L1 levels (respectively, p < 0.001, r = 0.63; p = 0.022, and r = 0.52). (4) Conclusions: The CHI3L1 plasma levels were increased in the MND mimics cohort compared with MNDs group. The increase of CHI3L1 in neuroinflammatory processes could explain our findings. We confirmed that the CHI3L1 plasma levels did not allow for differentiation between ALS and HCs, nor were they correlated with neuropsychological impairment.

The genetic contribution to clinical heterogeneity in amyotrophic lateral sclerosis (ALS) remains poorly understood, particularly regarding the role of genes associated with other neurodegenerative disorders. This study aimed to determine whether rare variants in neurodegeneration-associated genes influence ALS risk and clinical phenotype. This case-control study included patients with ALS without pathogenic variants in major ALS genes from the population-based Piemonte and Valle d'Aosta Register for ALS and matched controls. High-impact rare variants (minor allele frequency <0.01% or novel) in 151 genes associated with neurodegenerative disorders were identified through whole-genome sequencing. Main outcomes included ALS risk, motor phenotype, cognitive status, and survival. Findings were replicated in the Project MinE dataset (6,596 ALS cases, 2,454 controls). The study population consisted of 791 ALS patients (median age 67.9 years; 46.3% women) and 747 matched controls. One hundred twenty-seven ALS cases (16.1%) carried at least one rare variant in neurodegeneration-associated genes compared with 91 (12.2%) controls (odds ratio [OR] 1.37; 95% CI 1.04-1.80; p = 0.027). In particular, novel variants in Parkinson disease-associated genes (OR 3.62; 95% CI 1.33-9.80; p = 0.01) and hereditary neuropathy genes (OR 3.30; 95% CI 1.55-7.03; p = 0.002) conferred a 3-fold increased risk. These findings were independently replicated in the Project MinE dataset (OR 1.43; 95% CI 1.30-1.57; p < 0.001). Stratified analysis also confirmed the enrichment of rare variants in Parkinson disease and hereditary neuropathy-associated genes. Variant carriers were more likely to present with the flail arm phenotype (OR 2.05; 95% CI 1.05-3.98; p = 0.03) and showed increased risk of frontotemporal dementia (OR 1.85; 95% CI 1.04-3.21; p = 0.03) and shorter survival (hazard ratio 1.99; 95% CI 1.26-3.14; p = 0.003). Rare variants in genes associated with other neurodegenerative disorders influence both ALS susceptibility and clinical features, highlighting genetic pleiotropy across neurodegenerative diseases. Our findings support a model in which ALS arises from a complex and heterogeneous genetic landscape involving multiple variants, often shared with other neurodegenerative conditions, that shape disease expression. Although these findings suggest potential future expansion of genetic screening beyond classical ALS genes, such variants should be interpreted cautiously in clinical practice pending further functional validation.

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