Education needs in palliative care and advance care planning of Italian residents in neurology: an online survey.

BACKGROUND AND PURPOSE: Most neurological diseases have a chronic and progressive clinical course, with patients living for extended periods with complex healthcare needs. Evidence from other countries suggests that palliative care (PC) is insufficiently integrated in the care of these patients. This study aims to identify PC and advance care planning (ACP) knowledge and the perceived preparedness of Italian residents in neurology. METHODS: This is a cross-sectional online survey of physicians attending the 36 Italian neurology residency programmes. RESULTS: Of 854 residents, 188 (22%) participated. Their mean age was 28.4 ± 2.0 years; 49% were women; 45% were from the north, 23% from the centre and 32% from the south of Italy. Few residents (6%) reported that a teaching course in PC was part of the graduate programme, and 3% of the postgraduate programme. During their residency, 9% of participants received PC training, and 18% ACP training. Only 13% reported to have participated in the ACP process, half within their neurology residency programme. Residents considered PC support very/extremely important in all the pre-specified clinical situations, with values ranging between 78% and 96%. Over 70% of residents revealed education needs, particularly concerning ACP. CONCLUSIONS: Our data confirm the need for improving PC training in the graduate and postgraduate curriculum. This, together with collaboration and joint training of neurology and PC, is essential to improve the quality and continuity of care and respond to the complex needs of people with neurological disorders causing severe disability.

Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population.

CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of approximately 1:30 000 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74 277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% [95% confidence interval (CI) 90.8-100%], specificity of 99% (95% CI 94.2-99.7%), and a positive predictive value of 97.4% (95% CI 84.4-99.6%). We found the mutation frequency to be 1:3182 (95% CI 1:2309-1:4386, n = 117 734) X chromosomes-10 times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced penetrance, and/or pleomorphic clinical manifestations.

The future of neurology after the COVID-19 pandemic according to neurology residents.

BACKGROUND: The ongoing COVID-19 pandemic has resulted in significant changes in the delivery of neurological disease care and in neurology training in academic departments. OBJECTIVE: We aimed to investigate how neurology residents viewed the future of neurology after the COVID-19 pandemic with regard to three main aspects: (i) organization of neurological activity, (ii) patient care, and (iii) funding availability for neurological diseases. METHODS: We surveyed Italian neurology residents in order to investigate how they viewed the future of neurology after the COVID-19 pandemic. RESULTS: Responses were collected from 254 residents who reported: a high risk of reduction of hospital neurological beds, of worsening of the quality of neurological patient management, and of lack of funding for neurological care and research. CONCLUSION: The survey results demonstrate the views of future neurologists regarding the direction of neurology after the COVID-19 emergency. It is important to focus on these aspects in order to adapt neurology training to the societal changes introduced by the pandemic, and to safeguard the essential role of neurology in the management and prevention of chronic degenerative illnesses and emergencies.

Essential tremor and cognitive impairment: who, how, and why.

BACKGROUND AND AIMS: Recent years have witnessed the switch from considering essential tremor (ET) a monosymptomatic disorder to consider it as part of a spectrum, including other neurological signs, such as mild cognitive impairment and dementia, thus defining it as "ET plus." There are few data on cognitive impairment in ET patients. The aim of this review is to analyze the clinical characteristics of ET patients developing cognitive impairment, their neuropsychological profile, the underpinning mechanisms, and the possible biomarkers. METHODS: The authors performed a narrative review on cognitive decline in essential tremor, including articles written in English since the year 2000. DISCUSSION: The most recent pathogenetic theories of cognitive impairment in ET rely on the cerebellar dysfunction, being part of the Cerebellar Cognitive Affective Syndrome spectrum. Cognitive impairment in ET patients could be assessed through many tests that demonstrate the involvement of different domains, such as attention, executive functions, and language. There are some clinical characteristics of ET that may indicate a greater risk of developing cognitive impairment, namely, cerebellar symptoms, falls, age at onset, and family history. However, there are no established clinical, neurophysiological, neuropathological, and fluid biomarkers of cognitive impairment in ET. CONCLUSIONS: Increasing data are showing in ET the presence of cerebellar symptoms and cognitive impairment. Further studies are needed to better understand cognition in ET patients, and to define the boundary between ET and ET plus, since deeper phenotyping might have important clinical and therapeutic implications.

Stapedial Reflex: A Possible Novel Biomarker of Early Bulbar Involvement in Amyotrophic Lateral Sclerosis Patients.

BACKGROUND AND AIM: Amyotrophic lateral sclerosis (ALS) is a neuromuscular progressive disorder, characterized by limb and bulbar muscle wasting and weakness. 30% of patients present a bulbar onset, while 70% a spinal outbreak, although most of them develop bulbar impairment later on. Due to the lack of an early biomarker of bulbar involvement, we chose to evaluate the role of stapedial reflex (SR) in order to predict preclinical bulbar impairment in ALS. MATERIALS AND METHODS: We enrolled 36 ALS patients. We assessed revised-ALS functional-rating-scale and SR for a total of 4 visits. We established the presence of SR, acoustic reflex latency test (ARLT), and SRs Decay. Patients who had not develop bulbar signs at fourth visit continued follow-up up to 15 months. Data were analyzed by using Mann-Whitney U test, Friedman test, and Cox regression analysis. RESULTS: We observed that SRs Decay at 500 and 1,000 Hz is the first parameter of SR to get altered in all ALS patients before the development of bulbar impairment. Twenty-eight patients developed bulbar impairment during the study. We highlighted a correlation between the progression rate of disease and both time of SRs Decay alteration and time of bulbar impairment from disease onset. Four patients who did not develop bulbar impairment had a progression rate lower than the other ones (p < 0.05). DISCUSSION AND CONCLUSIONS: This study shows that SR Decay test could be a sensitive measure for detecting pre-symptomatic bulbar involvement in ALS and could represent a simple, noninvasive, and useful biomarker of disease progression.

Telemedicine for management of patients with amyotrophic lateral sclerosis through COVID-19 tail.

Over the last months, due to coronavirus disease (COVID-19) pandemic, containment measures have led to important social restriction. Healthcare systems have faced a complete rearrangement of resources and spaces, with the creation of wards devoted to COVID-19 patients. In this context, patients affected by chronic neurological diseases, such as amyotrophic lateral sclerosis (ALS), are at risk to be lost at follow-up, leading to a higher risk of morbidity and mortality. Telemedicine may allow meet the needs of these patients. In this commentary, we briefly discuss the digital tools to remotely monitor and manage ALS patients. Focusing on detecting disease progression and preventing life-threatening conditions, we propose a toolset able to improve ALS management during this unprecedented situation.

COVID-19 impact on neurology training program in Italy.

The ongoing COVID-19 pandemic is having a huge impact on clinical activity of all hospitals, including the ones involved in training of residents. In addition, neurology residents underwent substantial modifications of their training program. Aim of our investigation was to evaluate the impact of COVID-19 pandemic on the educational activities of Italian neurology residents through an online questionnaire delivered to neurology residents. The results obtained showed that almost 30% of the respondents were redistributed to COVID-19 units. Neurology departments underwent substantial modifications of their organization influencing clinical educational activities; lessons and seminars were rescheduled online and research protocols were stopped and transferred to remote working, when feasible. There was a relevant use of telemedicine approach even if most of the respondents had never been trained before. Some of the changes had a North-South gradient, following the epidemiology of the pandemic. The data obtained from our survey highlight those points to address to be prepared for possible future emergencies.

Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

BACKGROUND AND AIM: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. CONCLUSIONS: To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

Validation of the revised classification of cognitive and behavioural impairment in ALS.

OBJECTIVE: In 2017, the diagnostic criteria for cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (ALSFTD-1) have been modified (ALSFTD-2) with the inclusion of a novel category (ALS with combined cognitive and behavioural impairment, ALScbi) and with changes of operational criteria of the other categories (ALS with cognitive impairment (ALSci), ALS with behavioural impairment (ALSbi) and ALS with frontotemporal dementia (ALS-FTD)). We compared the two sets of criteria to assess the effect of the revised criteria on the cognitive classification of patients with ALS. METHODS: Two cohorts of patients with ALS were included in this study: a population-based cohort including patients identified through the Piemonte/Valle d'Aosta register for ALS in the 2014-2017 period (n=321), and a referral cohort recruited at the Turin ALS centre and at the ALS centre of the Maugeri Institute in Milan in the same period (n=205). Cognitive function was classified in blind by two neuropsychologists expert in ALS. RESULTS: ALSFTD-2 criteria determined a shift of about 15% of patients from their original category to a new one. In both cohorts, about 9% of patients were reclassified to the novel category ALScbi. Among patients previously classified as cognitively normal, 14 (4.3%, population-based cohort) and 19 (9.3%, referral cohort) were reclassified as ALSbi or ALSci. The median survival of the different categories was significantly different with both with sets of criteria. CONCLUSIONS: The new ALSFTD-2 criteria, compared with the old ones, have positive effects on the clinical practice being more sensitive to the early cognitive impairment and having a better prognostic yield.

Early weight loss in amyotrophic lateral sclerosis: outcome relevance and clinical correlates in a population-based cohort.

OBJECTIVES: To assess the role of body mass index (BMI) and of the rate of weight loss as prognostic factors in amyotrophic lateral sclerosis (ALS) and to explore the clinical correlates of weight loss in the early phases of the disease. METHODS: The study cohort included all ALS patients in Piemonte/Valle d'Aosta in the 2007-2011 period. Overall survival and the probability of death/tracheostomy at 18 months (logistic regression model) were calculated. RESULTS: Of the 712 patients, 620 (87.1%) were included in the study. Patients ' survival was related to the mean monthly percentage of weight loss at diagnosis (p<0.0001), but not to pre-morbid BMI or BMI at diagnosis. Spinal onset patients with dysphagia at diagnosis had a median survival similar to bulbar onset patients. About 20% of spinal onset patients without dysphagia at diagnosis had severe weight loss and initial respiratory impairment, and had a median survival time similar to bulbar onset patients. CONCLUSIONS: The rate of weight loss from onset to diagnosis was found to be a strong and independent prognostic factor in ALS. Weight loss was mainly due to the reduction of nutritional intake related to dysphagia, but a subgroup of spinal onset patients without dysphagia at diagnosis had a severe weight loss and an outcome similar to bulbar patients. According to our findings, we recommend that in clinical trials patients should be stratified according to the presence of dysphagia at the time of enrolment and not by site of onset of symptoms.

Chest Dynamic MRI as Early Biomarker of Respiratory Impairment in Amyotrophic Lateral Sclerosis Patients: A Pilot Study.

Background: Amyotrophic lateral sclerosis (ALS) is a neuromuscular progressive disorder characterized by limb and bulbar muscle wasting and weakness. A total of 30% of patients present a bulbar onset, while 70% have a spinal outbreak. Respiratory involvement represents one of the worst prognostic factors, and its early identification is fundamental for the early starting of non-invasive ventilation and for the stratification of patients. Due to the lack of biomarkers of early respiratory impairment, we aimed to evaluate the role of chest dynamic MRI in ALS patients. Methods: We enrolled 15 ALS patients and 11 healthy controls. We assessed the revised ALS functional rating scale, spirometry, and chest dynamic MRI. Data were analyzed by using the Mann-Whitney U test and Cox regression analysis. Results: We observed a statistically significant difference in both respiratory parameters and pulmonary measurements at MRI between ALS patients and healthy controls. Moreover, we found a close relationship between pulmonary measurements at MRI and respiratory parameters, which was statistically significant after multivariate analysis. A sub-group analysis including ALS patients without respiratory symptoms and with normal spirometry values revealed the superiority of chest dynamic MRI measurements in detecting signs of early respiratory impairment. Conclusions: Our data suggest the usefulness of chest dynamic MRI, a fast and economically affordable examination, in the evaluation of early respiratory impairment in ALS patients.

Calculated Maximal Volume Ventilation (cMVV) as a Marker of Early Respiratory Failure in Amyotrophic Lateral Sclerosis (ALS).

Respiratory failure assessment is among the most debatable research topics in amyotrophic lateral sclerosis (ALS) clinical research due to the wide heterogeneity of its presentation. Among the different pulmonary function tests (PFTs), maximal voluntary ventilation (MVV) has shown potential utility as a diagnostic and monitoring marker, able to capture early respiratory modification in neuromuscular disorders. In the present study, we explored calculated MVV (cMVV) as a prognostic biomarker in a center-based, retrospective ALS population belonging to the Piemonte and Valle d'Aosta registry for ALS (PARALS). A Spearman's correlation analysis with clinical data and PFTs showed a good correlation of cMVV with forced vital capacity (FVC) and a moderate correlation with some other features such as bulbar involvement, ALSFRS-R total score, blood oxygen (pO2), carbonate (HCO3-), and base excess (BE), measured with arterial blood gas analysis. Both the Cox proportional hazard models for survival and the time to non-invasive ventilation (NIV) measurement highlighted that cMVV at diagnosis (considering cMVV(40) ≥ 80) is able to stratify patients across different risk levels for death/tracheostomy and NIV indication, especially considering patients with FVC% ≥ 80. In conclusion, cMVV is a useful marker of early respiratory failure in ALS, and is easily derivable from standard PFTs, especially in asymptomatic ALS patients with normal FVC measures.

Sensory neuropathy in amyotrophic lateral sclerosis: a systematic review.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of both upper and lower motoneurons, leading to motor and non-motor symptoms. Recent evidence suggests that ALS is indeed a multisystem disorder, associated with cognitive impairment, dysautonomia, pain and fatigue, excess of secretions, and sensory symptoms. To evaluate whether sensory neuropathy could broaden its spectrum, we systematically reviewed its presence and characteristics in ALS, extracting data on epidemiological, clinical, neurophysiological, neuropathological, and genetic features. Sensory neuropathy can be found in up to 20% of ALS patients, affecting both large and small fibers, although there is a great heterogeneity related to different techniques used for its detection (electromyography vs skin biopsy vs nerve biopsy). Moreover, the association between CIDP-like neuropathy and ALS needs to be better explored, although it could be interpreted as part of the neuroinflammatory process in the latter disease. Sensory neuropathy in ALS may be associated with a spinal onset and might be more frequent in SOD1 patients. Moreover, it seems mutually exclusive with cognitive impairment. No associations with sex and other genetic mutation were observed. All these data in the literature reveal the importance of actively looking for sensory neuropathy in ALS patients, and suggest including sensory neuropathy among ALS non-motor features, as it may explain sensory symptoms frequently reported throughout the course of the disease. Its early identification could help avoid diagnostic delays and improve patients' treatment and quality of life.

Neurological Consequences of COVID-19: A Systematic Review of the Pandemic's Impact on Neurology Training.

The COVID-19 pandemic had a significant impact on neurology training programs, leading to disruptions and changes that may have long-term implications for neurological education. The objective of this study was to investigate the impact of COVID-19 on neurological training programs, collecting available data relating to residents' experience worldwide. We performed a systematic search of the literature published on PubMed from January 2020 to March 2023, including studies referring to quantitative analysis of residents'/trainees' perspectives. Specifically, we included studies that examined how the pandemic has affected clinical and research activities, the use of telemedicine, the delivery of education and the psychological status of residents. Of the 95460 studies identified through database searching, 12 studies met the full criteria and underwent data extraction. In conclusion, the COVID-19 pandemic has had significant impacts on neurology training programs, highlighting the need for resilience and flexibility in medical education. Future research should focus on the long-term outcomes of these adaptations in the quality of neurology education and patient care.

The role of peripheral immunity in ALS: a population-based study.

BACKGROUND: Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population-based ALS cohort using readily available hematological indexes. METHODS: We collected clinical data and the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d'Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic-immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. RESULTS: Neutrophils (P = 0.001) and markers of increased innate immunity (NLR, P = 0.008 and SII, P = 0.006) were associated with a faster disease progression. Similarly, elevated innate immunity correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415). CONCLUSIONS AND RELEVANCE: The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.

Serum chloride as a respiratory failure marker in amyotrophic lateral sclerosis.

Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS) and occurs with great variability among patients according to different phenotypic features. Early predictors of respiratory failure in ALS are important to start non-invasive ventilation (NIV). Venous serum chloride values correlate with carbonate (HCO3-) blood levels and reflect metabolic compensation of respiratory acidosis. Despite its wide availability and low cost, few data on serum chloride as a prognostic marker exist in ALS literature. In the present study, we evaluated serum chloride values at diagnosis as prognostic biomarkers for overall survival and NIV adaptation in a retrospective center-based cohort of ALS patients. We collected all ALS patients with serum chloride assessment at diagnosis, identified through the Piemonte and Valle d'Aosta Register for ALS, evaluating the correlations among serum chloride, clinical features, and other serum biomarkers. Thereafter, time-to-event analysis was modeled to predict overall survival and NIV start. We found a significant correlation between serum chloride and inflammatory status markers, serum sodium, forced vital capacity (FVC), ALS functional rating scale-revised (ALSFRS-R) item 10 and 11, age at diagnosis, and weight loss. Time-to-event analysis confirmed both in univariate analysis and after multiple confounders' adjustment that serum chloride value at diagnosis significantly influenced survival and time to NIV start. According to our analysis, based on a large ALS cohort, we found that serum chloride analyzed at diagnosis is a low-cost marker of impending respiratory decompensation. In our opinion, it should be added among the serum prognostic biomarkers that are able to stratify patients into different prognostic categories even when performed in the early phases of the disease.

Plasma CHI3L1 in Amyotrophic Lateral Sclerosis: A Potential Differential Diagnostic Biomarker.

(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.

Validation of the Italian version of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) administered to patients and their caregivers.

Introduction: The Amyotrophic Lateral Sclerosis (ALS) functional rating scale - revised (ALSFRS-R) is the most widely used tool for the clinical monitoring in ALS patients. Despite his usefulness as a multidimensional scale, the combined score derived from different domains is not linearly related to symptoms severity. The Rasch-Built Overall ALS Disability Scale (ROADS) has recently been developed to overcome some of these limitations. Objectives: To validate the Italian version of the ROADS scale and assess the reliability of its administration to patients versus their respective caregivers and the correlation to the corresponding ALSFRS-R. Methods: In the Turin ALS Center, the ROADS Scale questionnaire was administered together with ALSFRS-R to 55 ALS patients and their caregivers during regular follow-up assessments. Correlation analysis was performed using Spearman's rho, Bland-Altman difference plots, Cronbach's alpha coefficient and Intraclass correlation coefficient (ICC), one-way random effects were used for proper comparison. Results: Their correlation coefficient between patients and caregivers ROADS was found to be very high (ICC 0.95, p < 0.001). Stratifying for age, sex, site of onset, type of caregiver, disease duration, and progression rate, ICC values that did not change significantly among the considered categories. We also found a high correlation between ROADS and ALSFRS-R total score (patients' correlation coefficient: 0.88). Conclusions: The Italian version of the ROADS scale is a valid and reliable tool to monitor disease burden, showing a high level of agreement between the responses given by patients and caregivers.

Phenotype Analysis of Fused in Sarcoma Mutations in Amyotrophic Lateral Sclerosis.

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.