Andi Nuredini

Background: Hereditary neuromuscular disorders exhibit marked phenotypic and molecular heterogeneity, which weakens genotype–phenotype correlation and complicates timely diagnosis, prognosis, and patient stratification for clinical trials. The Horizon Europe project CoMPaSS‐NMD aims to develop artificial‐intelligence‐based stratification tools by integrating clinical, genetic, histopathological, and imaging data from clinical reference centers across Europe and the United Kingdom. Methods: We developed CoMPaSS‐NMD Atlas, a secure, modular web platform for pseudonymized data collection, multimodal data management, and controlled exploration. Clinical, technical, and data‐management experts defined requirements; contributing centers co‐designed electronic clinical and histopathology forms. Clinical phenotypes used the Human Phenotype Ontology (HPO), while imaging, histopathology, and sequencing data followed international standards. Results: The platform supports role‐ and attribute‐based access, pseudonymized patient registration, metadata management, structured clinical data entry, MRI and histopathological uploads, and a dedicated genetic‐sequencing workflow. Cohort‐level exploration is driven by structured metadata and HPO terms, enabling hierarchical phenotype navigation, ontology‐aware data navigation, and cross‐domain queries spanning clinical, genetic, imaging, and histopathological features. Users can download raw files in their original formats, along with structured metadata reports in CSV or PDF, according to the permissions defined for data protection. Conclusions: The Atlas provides a foundation for harmonized, standardized prospective data collection and for building large datasets for artificial intelligence‐ and machine learning‐based patient stratification. With secure governance, traceability, and multimodal integration, it is designed to support diagnostic and stratification research in hereditary neuromuscular disorders; clinical validation is ongoing.

Background: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most common adult‐onset myopathies and is causally associated with a contraction of the D4Z4 macrosatellite repeat array on chromosome 4. It presents with a variable pattern of progressive muscle weakness affecting the face, shoulder girdle and lower limbs. Pathophysiological mechanisms remain incompletely understood, and no effective treatments are available. Moreover, the lack of validated biomarkers limits the assessment of disease progression and therapeutic effects in clinical trials. Metabolic dysfunction has been hypothesized as a contributing factor, yet remains poorly explored. Methods: In this multicentre, observational, cross‐sectional case–control study, we performed quantitative plasma metabolomics by mass spectrometry in 57 patients (age: 41.8 ± 11.9; females/males ratio: 1.04) with mild to moderate facioscapulohumeral muscular dystrophy (FSHD clinical score 6.4 ± 2.6) and age‐ and sex‐comparable controls (age: 41.1 ± 11.2; females/males ratio: 1.13) recruited from three tertiary neuromuscular reference centres. We restricted inclusion to patients with preserved ambulatory capacity to better capture systemic metabolic alterations not primarily driven by advanced disability. We analysed the data using an integrative framework combining univariate and multivariate analyses with five machine‐learning classifiers. Results: We identified 57 circulating metabolites discriminating patients from controls, suggesting systemic perturbations in nitric oxide, mitochondrial and one‐carbon metabolism, as well as oxidative stress, muscle mass maintenance and lipid membrane remodelling. Notably, decreased creatinine (fold change in patients vs. controls: 0.754; FDR‐corrected p = 0.000003) and increased asymmetric dimethylarginine (ADMA; fold change in patients vs. controls: 1.168; FDR‐corrected p = 0.000704) emerged as the most significantly altered metabolites, both showing strong correlations with clinical neuromuscular functional scores, including muscle strength (creatinine ρ = 0.62, p = 0.0001; ADMA ρ = 0.34, p = 0.0124), facioscapulohumeral muscular dystrophy severity score (creatinine ρ = 0.53, p = 0.0001; ADMA ρ = 0.32, p = 0.0145) and the daily activity limitation ACTIVLIM scale (creatinine ρ = 0.38, p = 0.0035; ADMA ρ = 0.35, p = 0.008). Plasma levels of GDF15, a biomarker commonly used to support the diagnosis of mitochondrial diseases, were modestly but significantly elevated in patients versus controls (542.3 pg/mL ± 277.2 vs. 444.4 pg/mL ± 164.5, p = 0.043). Further analysis of a predefined mitochondria‐related metabolite panel showed coordinated alterations involving mitochondrial metabolic pathways and discriminated FSHD1 patients from controls (best AUC = 0.83). Conclusions: These findings highlight systemic metabolic disturbances already detectable in mild‐to‐moderate stages of facioscapulohumeral muscular dystrophy, identifying creatinine and ADMA as promising biomarkers of disease severity, and expand current knowledge of disease pathophysiology. Trial Registration: ClinicalTrials.gov identifier: NCT06086548

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy characterized by marked clinical variability and diagnostic complexity. It comprises two forms: FSHD1, associated with contraction of D4Z4 repeats on chromosome 4q35, and FSHD2, linked to variants in chromatin remodeling genes. The presence of FSHD‐associated molecular signatures in healthy individuals further complicates diagnosis. Methods: We evaluated 39 unrelated Serbian probands with suspected FSHD. Family investigations were conducted in 30 probands (76.9%), involving 54 relatives (total n = 93). Clinical assessment was performed using the Comprehensive Clinical Evaluation Form (CCEF), and molecular testing followed the standard workflow for FSHD1. Results: A D4Z4 reduced allele (DRA, 1–10 repeats) was identified in 31 probands (79.5%). Of these, 24 (77.4%) showed a classical phenotype, while 7 (22.6%) had facial‐sparing presentations. Among 39 relatives from 23 DRA‐positive families, 13 (33.3%) carried a DRA; among them, 5 had classical FSHD and 8 were asymptomatic or mildly affected. Eight probands (20.5%) were DRA‐negative. Among 15 relatives from these families who were all DRA‐negative, one showed a classical phenotype, and six were asymptomatic or mildly affected. Conclusion: These findings confirm the marked phenotypic heterogeneity of suspected FSHD and highlight the importance of standardized clinical assessment and family investigations to improve diagnosis, genetic counseling, and patient selection for clinical trials.

Introduction/Aims: To investigate its potential role as a marker of disease severity in facioscapulohumeral dystrophy (FSHD), this study examined the association between whole‐body phase angle (PhA) and clinically assessed severity in FSHD patients. Methods: Patients were evaluated for PhA using bioelectrical impedance analysis ( BIA ) and for disease severity using the FSHD clinical score. In a subgroup, physical activity level ( PAL ) was assessed using a questionnaire. Pearson correlations were performed in the total cohort and PAL ‐assessed subgroup, stratified by sex and clinical phenotype (category A and non‐A) according to the Comprehensive Clinical Evaluation Form. Multivariate regression analyses were conducted adjusting for age, body mass index, and PAL . Due to the small sample, correlation was not performed in PAL ‐assessed non‐A patients, while multivariate regression was not performed in non‐A patients and PAL ‐assessed stratified subgroups. Results: Seventy‐two patients (mean age 39.94 ± 17.52 years; 27 females and 45 males; 58 category A and 14 non‐A) were enrolled. The PAL ‐assessed subgroup comprised 38 patients (mean age 41.39 ± 14.98 years; 16 females and 22 males; 31 category A and 7 non‐A). Pearson analyses revealed that PhA was inversely associated with clinical score in all groups ( r –0.63 to –0.84, p 0.02 to < 0.001). Multivariate regression confirmed PhA as the sole independent predictor across all groups ( β = –0.64 to –0.93, all p < 0.001). Discussion: These results support the potential role of PhA as a marker of disease severity in FSHD . Longitudinal studies are warranted to determine its sensitivity for monitoring disease progression over time.

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive inherited myopathy characterized by muscle weakness, fatty infiltration, and consequent reduction in functional capacity. In this context, physical exercise (PE) has been proposed as a non-pharmacological strategy aimed at preserving physical efficiency. However, its prescription in FSHD has historically been approached with caution due to concerns regarding overwork weakness and potential exacerbation of muscle damage. As a result, clinical management has often remained conservative, with limited and non-standardized PE recommendations. Nevertheless, physical inactivity may further contribute to deconditioning, loss of autonomy, and deterioration in quality of life, highlighting a clear tension between perceived risk and potential benefit. In this framework, identifying safe and effective PE strategies represents a central unmet need in FSHD care. Possibly due to disease rarity and historical concerns, the available literature on PE in FSHD remains fragmented, limiting the strength of definitive conclusions. A structured synthesis of existing evidence may help clarify feasible and potentially effective exercise modalities, as well as guide the development of optimized intervention strategies. This review critically examines the current evidence on PE in FSHD, with specific reference to aerobic, anaerobic, and combined training interventions. The potential synergistic role of concomitant nutritional strategies is also considered. The critical analysis highlights exercise modalities that appear more consistently safe and potentially beneficial, while underscoring substantial methodological limitations across studies. Finally, emerging concepts in exercise tailoring are discussed, with the aim of addressing the clinical variability of FSHD and informing future prospective, controlled investigations.

Neuromuscular diseases (NMDs) include a heterogeneous group of progressive chronic conditions that frequently lead to substantial physical disability and loss of autonomy. Although motor and functional impairments of NMDs are well documented, the psychological burden remains underexplored. This narrative review synthesizes current literature regarding four psychological domains in individuals with NMDs: (i) anxiety, (ii) depression, (iii) coping strategies, and (iv) quality of life. Evidence indicates that anxiety and depressive symptoms are highly prevalent in the spectrum of NMDs, influenced by factors such as disease severity, onset age, and perceived social support. Maladaptive coping strategies, including avoidance and denial, are associated with poorer mental health outcomes and reduced involvement in rehabilitation. In contrast, adaptive strategies, such as acceptance and problem-focused coping, may help buffer psychological distress. Quality of life is consistently reported to be lower in people with NMDs compared to the general population, with psychosocial factors such as social support playing a role. Despite these findings, psychological care remains inconsistently integrated in NMD management.

Background Since 2005, the European Training Requirements in Neurology (ETRN) have defined the clinical, practical, and research competencies expected in European neurology residency programmes. However, significant variability in training quality persists among Italian programmes. This survey, conducted by the Italian Section of Young Neurologists, aimed to assess how closely Italian neurology residency programmes with ETRN standards and to evaluate residents’ and early-career neurologists' self-reported perceived knowledge, practical skills, and access to specialized training. Methods An anonymous, online survey was distributed in November 2023 to neurology residents and recently qualified neurologists across Italy. The 39-item questionnaire covered four sections: demographics, residency programme structure, learning objectives, and out-of-network internship opportunities. Responses were evaluated using descriptive statistics and comparative analyses across institution sizes and training years. Results Of 248 respondents (45.2% female, mean age 28.9 years), only 70.5% of ETRN’s basic training objectives were met, with lower compliance observed for advanced competencies. Practical skills like lumbar puncture and history-taking were widely acquired, but advanced diagnostic techniques (e.g., EMG, neuro-sonography) and subspecialty training (e.g., neuro-oncology, palliative care) showed limited availability. Out-of-network internship participation was low (21.7%), mainly due to institutional constraints and lack of financial support, limiting exposure to diverse clinical environments. Conclusions Residency programmes demonstrate moderate adherence to ETRN standards at the basic level, though significant gaps remain in advanced training, diagnostic techniques, and interdisciplinary skills. Enhanced standardization, improved funding for extra-network internships, and focused efforts on advanced training are essential to elevate Italian neurology residency programmes to meet European standards more fully.

Objective: Despite its clinical heterogeneity, amyotrophic lateral sclerosis is unified by early and prominent alterations in cortical excitability, increasingly recognized as contributors to disease progression. This study assessed whether the ratio between motor evoked potential (MEP) amplitude, reflecting upper motor neuron integrity, and compound muscle action potential (CMAP) amplitude, indexing lower motor neuron function, could provide an accessible marker of corticospinal excitability to stratify patients by phenotype, stage, and survival. Methods: In this multicenter retrospective study, 743 amyotrophic lateral sclerosis patients from 16 tertiary centers in Italy were analyzed. The MEP:CMAP ratio, recorded from upper limb muscles, was categorized as hyperexcitable, normal, or hypoexcitable. Phenotypes included progressive muscular atrophy (or lower motor neuron), flail arm/leg, classic, bulbar, patient with predominant upper motor neuron signs (or pyramidal), and primary lateral sclerosis. Disease stage was assessed using King's staging. Survival was analyzed using Kaplan–Meier curves and Cox regression models. Results: The MEP:CMAP ratio differed significantly across phenotypes ( p < 0.0001), with hyperexcitability predominating in lower motor neuron, flail, classic, and bulbar forms, and hypoexcitability in pyramidal and primary lateral sclerosis. Hypoexcitability increased in advanced King's stages ( p < 0.0001). Hyperexcitable patients had shorter survival ( p = 0.004), including when tested within 1 year of onset ( p = 0.006). Cox regression identified the MEP:CMAP ratio as an independent survival predictor (HR 1.84, 95% CI 1.12–3.03, p = 0.016). Interpretation: This real‐world study supports the clinical value of the MEP:CMAP ratio as a scalable biomarker of cortical excitability in amyotrophic lateral sclerosis, with prognostic relevance across phenotypes and disease stages. ANN NEUROL 2025;98:801–813

Background/Objectives: C9ORF72 expansion is associated with significant phenotypic heterogeneity. This study aimed to characterize the clinical features of C9ALS patients from the Emilia Romagna ALS registry (ERRALS) and compare them with non-mutated ALS (nmALS) patients matched for sex, age at onset, and diagnostic delay, sourced from the same register. Methods: In total, 67 C9ALS patients were compared to 201 nmALS. Clinical data, phenotype, and prognostic factors were analyzed in the two groups and within the C9ALS group after stratification by sex. Results: C9ALS patients displayed a higher disease progression rate and shorter times to gastrostomy and invasive ventilation, despite no differences in overall survival. Female C9ALS had a more severe bulbar and upper motor neuron involvement compared to males. Cognitive and behavioral symptoms were more common in the C9ALS group, and the former was an independent prognostic factor. Prevalences of, autoimmune diseases, and dyslipidemia were significantly higher among C9ALS patients. Conclusions: In our dataset, we show an overall increased disease progression rate in C9ALS patients and hint at sex-specific discrepancies in some phenotypical characteristics. We also suggest a possible clinically relevant involvement of C9ORF72 expansion in metabolism and autoimmunity.

Background Since 2005, the European Union of Medical Specialists – Section of Neurology and the European Board of Neurology have outlined a comprehensive curriculum, the European Training Requirements in Neurology (ETRN), which defines the essential clinical knowledge, practical skills, and research competencies that European neurology training programmes should encompass. Despite these standards, notable differences in training quality and resources persist among Italian residency programmes. This survey, conducted by the Italian Section of Young Neurologists, aimed to assess the alignment of Italian neurology residency programmes with ETRN standards and to evaluate residents’ and early-career neurologists’ self-reported knowledge, practical skills, and access to specialised training opportunities. Methods An anonymous, online survey was distributed to neurology residents and recently qualified neurologists across Italy in November 2023. The survey included 39 items across four sections: demographics, residency programme structure, learning objectives, and out-of-network internship opportunities. Responses were evaluated using descriptive statistics and comparative analyses across institution sizes and training years. Results Of 248 respondents (45.2% female, mean age 28.9 years), only 70.5% of ETRN’s basic training objectives were met, with lower compliance observed for advanced competencies. Practical skills like lumbar puncture and history-taking were widely acquired, but advanced diagnostic techniques (e.g., EMG, neuro-sonography) and subspecialty training (e.g., neuro-oncology, palliative care) showed limited availability. Out-of-network internship participation was low (21.7%), mainly due to institutional constraints and lack of financial support, limiting exposure to diverse clinical environments. Conclusions Italian neurology training programmes align reasonably well with ETRN standards at the basic level, though significant gaps remain in advanced training, diagnostic techniques, and interdisciplinary skills. Enhanced standardisation, improved funding for extra-network internships, and focused efforts on advanced training are essential to elevate Italian neurology residency programmes to meet European standards more fully.