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Introduction/aims: Fatigue (subjective perception) and fatigability (objective motor performance worsening) are relevant aspects of disability in individuals with spinal muscular atrophy (SMA). The effect of nusinersen on fatigability in SMA patients has been investigated with conflicting results. We aimed to evaluate this in adult with SMA3., Methods: We conducted a multicenter retrospective cohort study, including adult ambulant patients with SMA3, data available on 6-minute walk test (6MWT) and Hammersmith Functional Motor Scale-Expanded (HFMSE) at baseline and at least at 6 months of treatment with nusinersen. We investigated fatigability, estimated as 10% or higher decrease in walked distance between the first and sixth minute of the 6MWT, at baseline and over the 14-month follow-up., Results: Forty-eight patients (56% females) were included. The 6MWT improved after 6, 10, and 14 months of treatment (p < 0.05). Of the 27 patients who completed the entire follow-up, 37% improved (6MWT distance increase ≥30 m), 48.2% remained stable, and 14.8% worsened (6MWT distance decline ≥30 m). Fatigability was found at baseline in 26/38 (68%) patients and confirmed at subsequent time points (p < 0.05) without any significant change over the treatment period. There was no correlation between fatigability and SMN2 copy number, sex, age at disease onset, age at baseline, nor with 6MWT total distance and baseline HFMSE score., Discussion: Fatigability was detected at baseline in approximately 2/3 of SMA3 walker patients, without any correlation with clinical features, included motor performance. No effect on fatigability was observed during the 14-month treatment period with nusinersen., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Spinal muscular atrophy (SMA) is a rare degenerative disorder with loss of motor neurons caused by mutations in the SMN1 gene. Nusinersen, an antisense oligonucleotide, was approved for SMA treatment to compensate the deficit of the encoded protein SMN by modulating the pre-mRNA splicing of SMN2, the centromeric homologous of SMN1, thus inducing the production of a greater amount of biologically active protein. Here, we reported a 10-month transcriptomics investigation in 10 adult SMA who received nusinersen to search for early genetic markers for clinical monitoring. By comparing their profiles with age-matched healthy controls (HC), we also analyzed the changes in miRNA/mRNAs expression and miRNA-target gene interactions possibly associated with SMA. A multidisciplinary approach of HT-NGS followed by bioinformatics/biostatistics analysis was applied. Within the study interval, those SMA patients who showed some clinical improvements were characterized by having the SMN2/SMN1 ratio slightly increased over the time, while in the stable ones the ratio decreased, suggesting that the estimation of SMN2/SMN1 expression may be an early indicator of nusinersen efficacy. On the other hand, the expression of 38/147 genes/genetic regions DE at T0 between SMA and HC like TRADD and JUND resulted "restored" at T10. We also confirmed the dysregulation of miR-146a(-5p), miR-324-5p and miR-423-5p in SMA subjects. Of interest, miR-146a-5p targeted SMN1, in line with experimental evidence showing the key role of astrocyte-produced miR-146a in SMA motor neuron loss. Molecular pathways such as NOTCH, NF-kappa B, and Toll-like receptor signalings seem to be involved in the SMA pathogenesis., (© 2024. The Author(s).)

Due to poor data in literature, we aimed to investigate the respiratory function in a large cohort of naïve Italian adult (≥18 years) SMA patients in a multi-centric cross-sectional study. The following respiratory parameters were considered: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and need for non-invasive ventilation (NIV). We included 145 treatment-naïve adult patients (SMA2=18, SMA3=125; SMA4=2), 58 females (40 %), with median age at evaluation of 37 years (range 18-72). Fifty-six (37 %) and 41 (31 %) patients had abnormal (<80 %) values of FVC and FEV1, respectively. Fourteen (14 %) patients needed NIV, started at median age of 21 (range 4-68). Motor function, measured by Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module as well as SMA2, loss of walking ability, surgery for scoliosis, use of NIV, and cough assisting device (CAD) were all significantly associated to lower FVC and FEV1 values, while no association with age at baseline, disease duration, gender or 6 min walking test was observed, except for a correlation between FVC and age in SMA3 walkers (p < 0.05). In conclusion, respiratory function in adult SMA patients is relatively frequently impaired, substantially stable, and significantly correlated with motor function and disease severity., Competing Interests: Declaration of Competing Interest The authors do not declare any financial and personal relationships with other people or organizations that could inappropriately influence their work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Approximately 80-96% of people with amyotrophic lateral sclerosis (ALS) become unable to speak during the disease progression. Assessing upper and lower motor neuron impairment in bulbar regions of ALS patients remains challenging, particularly in distinguishing spastic and flaccid dysarthria. This study aimed to evaluate acoustic voice parameters as useful biomarkers to discriminate ALS clinical phenotypes. Triangular vowel space area (tVSA), alternating motion rates (AMRs), and sequential motion rates (SMRs) were analyzed in 36 ALS patients and 20 sex/age-matched healthy controls (HCs). tVSA, AMR, and SMR values significantly differed between ALS and HCs, and between ALS with prevalent upper (pUMN) and lower motor neuron (pLMN) impairment. tVSA showed higher accuracy in discriminating pUMN from pLMN patients. AMR and SMR were significantly lower in patients with bulbar onset than those with spinal onset, both with and without bulbar symptoms. Furthermore, these values were also lower in patients with spinal onset associated with bulbar symptoms than in those with spinal onset alone. Additionally, AMR and SMR values correlated with the degree of dysphagia. Acoustic voice analysis may be considered a useful prognostic tool to differentiate spastic and flaccid dysarthria and to assess the degree of bulbar involvement in ALS.

Background and Purpose: The previous studies described phenotype-associated imaging findings in amyotrophic lateral sclerosis (ALS) with a prior categorization of patients based on clinical characteristics. We investigated the natural segregation of patients through a radiologic cluster-based approach without a priori patient categorization using 3 well-known prognostic MR imaging biomarkers in ALS, namely bilateral precentral and paracentral gyrus cortical thickness and medulla oblongata volume. We aimed to identify clinical/prognostic features that are cluster-associated., Materials and Methods: Bilateral precentral and paracentral gyri and medulla oblongata volume were calculated using FreeSurfer in 90 patients with amyotrophic lateral sclerosis and 25 healthy controls. A 2-step cluster analysis was performed using precentral and paracentral gyri (averaged pair-wise) and medulla oblongata volume., Results: We identified 3 radiologic clusters: 28 (31%) patients belonged to "cluster-1"; 51 (57%), to "cluster 2"; and 11 (12%), to "cluster 3." Patients in cluster 1 showed statistically significant cortical thinning of the analyzed cortical areas and lower medulla oblongata volume compared with subjects in cluster 2 and cluster 3, respectively. Patients in cluster 3 exhibited significant cortical thinning of both paracentral and precentral gyri versus those in cluster 2, and this latter cluster showed lower medulla oblongata volume than cluster 3. Patients in cluster 1 were characterized by older age, higher female prevalence, greater disease severity, higher progression rate, and lower survival compared with patients in clusters 2 and 3., Conclusions: Patients with amyotrophic lateral sclerosis spontaneously segregate according to age and sex-specific patterns of neurodegeneration. Some patients with amyotrophic lateral sclerosis showed an early higher impairment of cortical motor neurons with relative sparing of bulbar motor neurons (cluster 3), while others expressed an opposite pattern (cluster 2). Moreover, 31% of patients showed an early simultaneous impairment of cortical and bulbar motor neurons (cluster 1), and they were characterized by higher disease severity and lower survival., (© 2023 by American Journal of Neuroradiology.)

Background : Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1 -mutated patients. Methods : We included 183 SOD1 -mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan-Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results : SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival ( p = 0.034 and p = 0.004). Conclusions : We found that SOD1 -mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1 -ALS., Competing Interests: Antonio Canosa serves on the Editorial Board of Biomedicines and serves as Guest Editor for the Special Issues &lsquo;Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology&rsquo; and &lsquo;Recent Advances in Amyotrophic Lateral Sclerosis Genetics and Pathophysiology 2.0&prime; of Biomedicines. Andrea Calvo received a research grant from Cytokinetics. Adriano Chi&ograve; serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Biogen, Cytokinetics, Denali, and AveXis, and received a research grant from Italfarmaco. Jessica Mandrioli received research support from Pfizer. The other authors have no conflict of interest relevant for the manuscript.

Background and Purpose: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials., Methods: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed., Results: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60., Conclusions: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Natural history of spinal muscular atrophy (SMA) in adult age has not been fully elucidated yet, including factors predicting disease progression and response to treatments. Aim of this retrospective, cross-sectional study, is to investigate motor function across different ages, disease patterns and gender in adult SMA untreated patients., Methods: Inclusion criteria were as follows: (1) clinical and molecular diagnosis of SMA2, SMA3 or SMA4 and (2) clinical assessments performed in adult age (>18 years)., Results: We included 64 (38.8%) females and 101 (61.2%) males (p=0.0025), among which 21 (12.7%) SMA2, 141 (85.5%) SMA3 and 3 (1.8%) SMA4. Ratio of sitters/walkers within the SMA3 subgroup was significantly (p=0.016) higher in males (46/38) than in females (19/38). Median age at onset was significantly (p=0.0071) earlier in females (3 years; range 0-16) than in males (4 years; range 0.3-28), especially in patients carrying 4 SMN2 copies. Median Hammersmith Functional Rating Scale Expanded scores were significantly (p=0.0040) lower in males (16, range 0-64) than in females (40, range 0-62); median revised upper limb module scores were not significantly (p=0.059) different between males (24, 0-38) and females (33, range 0-38), although a trend towards worse performance in males was observed. In SMA3 patients carrying three or four SMN2 copies, an effect of female sex in prolonging ambulation was statistically significant (p=0.034)., Conclusions: Our data showed a relevant gender effect on SMA motor function with higher disease severity in males especially in the young adult age and in SMA3 patients., Competing Interests: Competing interests: LM has received honoraria for speaking, advisory boards and compensation for congress participations from Sanofi Genzyme, Roche and Biogen, outside the submitted work. LB participated in advisory boards for PTC Therapeutics, Sarepta Therapeutics, Edgewise Therapeutics, Epirium Bio and has received speaker honoraria from PTC Therapeutics and participated in research sponsored by Santhera Pharmaceuticals. SB has received funds for travel and congress participation from Sanofi Genzyme and Biogen. MG has received honoraria for speaking from Pfizer, Alnylam, Biogen and Sanofi-Aventis and has received financial support for research, not related to the study described in this manuscript, from Sanofi-Aventis. SCP has been Scientific board member for Esperare and Sarepta and PI of clinical trials for Esperare, FibroGen, Wave, Mallinckrodt, Dyne, Adienne. MT has received compensation for congress participations from Roche and Biogen. MC has received honoraria for speaking, advisory boards and compensation for congress participations from Roche and Biogen. RM has received funding for travel, meeting attendance or Advisory Board participation from Alexion, Argenx, Biomarin, Catalyst, SANOFI, Regeneron and UCB. RL reports personal fees from Biogen, Sanofi- Genzyme, Argon Healthcare s.r.l., Amicus Therapeutics s.r.l. and Alfasigma for Advisory Board consultancy and Lecture fees from Dynamicom Education, SIMG Service, Adnkronos salute unipersonale s.r.l. and DOC Congress s.r.l. outside the submitted work. ILS has received compensation for congress and honoraria for speaking from Biogen, Sanofi Genzyme, Roche, and Celgene Bristol Myers Squibb. TM has received honoraria for speaking, advisory boards and compensation for congress participations from Sanofi Genzyme, Roche and Biogen, outside the submitted work. GC has received compensation for participation ad advisory board for Roche, Sarepta and Italfarmaco. EP reports personal fees from Sarepta, grants and non-financial support from Santhera, personal fees and nonfinancial support from PTC Pharmaceuticals, non-financial support from Genzyme, personal fees from Roche, outside the submitted work., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)