Immune-mediated necrotizing myopathy (IMNM) is a distinct entity with limited large-cohort data. We aimed to characterize clinico-serological features and treatment outcomes of anti-SRP, anti-HMGCR, and seronegative IMNM in a large Italian cohort. Retrospective multicenter study of adults diagnosed with IMNM (224th ENMC criteria) across 14 Italian neuromuscular centers between 2019 and 2022 was performed. We included 159 subjects (57

Neuromuscular disorders (NMDs) are a heterogeneous group of conditions characterised by progressive muscle weakness, motor impairment, and risk of malnutrition, affecting the quality of life (QoL) of patients. While pharmacological treatments are essential for the management of symptoms, the role of diet, nutrition, and other lifestyle factors remains underexplored. This narrative systematic review, performed on PubMed, Web of Science, and Scopus following PRISMA guidelines, aimed to investigate the relationship between lifestyle, the progression of NMDs, and the QoL. A total of 30 studies (n = 5055 patients) met inclusion criteria. According to our search strategy, the most representative lifestyle factors were diet (70%), physical activity (53.3%), and emotional perception and care (36.7%); seven papers (23.3%) evaluated three or more lifestyle aspects. Overall, both quantitative and qualitative deficiencies emerged: calories, proteins, lipids, and fibres, as well as vitamin C, vitamin E, zinc, selenium, and calcium, were lower than recommended. A reduced consumption of fruits, vegetables, legumes, nuts, and seeds, replaced by ultra-processed foods, was detected. Diets optimised for calorie and nutrients intake, rich in anti-inflammatory foods, have shown benefits both in mitigating oxidative stress and muscle degeneration. Regarding other aspects of lifestyle, although physical activity was associated with improved motor performance and QoL, adherence was low, particularly among females. Negative emotional status emerged as a critical factor influencing patients’ overall well-being. Even in the most complex neuromuscular disease settings, addressing nutrition and dietary habits, in the context of lifestyle, could support patients and their families throughout the disease course and improve their QoL.

To evaluate the diagnostic accuracy of the Gold Coast criteria (GCC) and compare their performance with the revised El Escorial (rEEC) and Awaji criteria in patients with suspected amyotrophic lateral sclerosis (ALS). Embase, MEDLINE, and Scopus were searched for English-language studies published between January 1, 2020, and August 11, 2025. Eligible studies assessed the diagnostic accuracy of GCC compared with rEEC and Awaji criteria in suspected ALS. Authors were invited to contribute individual participant data. Data were checked, harmonised, and recoded. A one-stage individual-participant data meta-analysis, adjusted for age and sex, was performed. Diagnostic performance was assessed using pooled sensitivity, specificity, and area under the receiver operating characteristic curve. Risk of bias was assessed using QUADAS-2 and QUADAS-C, and certainty of evidence using GRADE for diagnostic test accuracy. The study was registered with PROSPERO, CRD420251123597. Individual participant data were available for 3007 participants from five international studies. GCC demonstrated higher sensitivity than rEEC and Awaji criteria: 0.96 (95

Early treatment in late-onset Pompe disease (LOPD) increasingly depends on detecting subclinical muscle involvement. Quantitative muscle MRI (qMRI) has emerged as a promising tool in this context. We conducted a multicenter prospective study in LOPD patients (≥ 10-years-old), stratified into early-stage (Walton 0-1, FVC ≥ 80%) and symptomatic (Walton 2-6). Thigh MRIs were acquired at 3 T using T1-weighted and STIR sequences. Fat fraction (FF) and water T2 (wT2) were calculated in 11 different regions using 6-point Dixon and 17-echo multi-echo spin-echo acquisitions, respectively. Functional, respiratory, and patient-reported outcomes were assessed. The adductor magnus (AM)/rectus femoris (RF) FF ratio was evaluated for its discriminative power. wT2 was analyzed as a binary score per muscle (0 or 1), depending on whether its value exceeded the control mean plus two SD, and summed across 11 muscles to compute an individual wT2 involvement score (WIS). Thirty-three LOPD patients (16 early-stage; 17 symptomatic) and 34 controls were recruited. Thigh FF strongly correlated with clinical scales (ρ up to 0.86). ROC analysis identified AM as the best discriminator (AUC: 0.96, cut off ≥ 7.93%), with similar performance for the AM/RF ratio (AUC: 0.94). wT2 showed weaker correlation with clinical scores compared to FF; symptomatic patients had higher WIS compared to early-stage and controls. Thigh FF is a robust biomarker of disease severity. AM FF and the age-independent AM/RF FF are sensitive to early structural changes. A WIS > 3 may reflect symptomatic disease. If validated longitudinally, these qMRI parameters could help guide optimal timing of therapy initiation.

BACKGROUND:Facioscapolohumeral muscular dystrophy is characterized by a wide clinical variability; the underlying reasons and the relation between them and the genetic markers are still not clear. In fact, the different phenotypes could show a different disease progression and/or imply distinct genetic mechanisms. As clinical trials are approaching also for FSHD, the correct description and stratification of patients becomes mandatory. To address these matters, in 2016 the Italian Clinical Group for FSHD developed the Comprehensive Clinical Evaluation Form (CCEF), aimed at describing the different observed phenotypes in FSHD. METHODS:A working group composed by the former developers of the CCEF and other expert clinicians re-evaluated the whole structure of the CCEF, to develop a simplified version for use in clinical practice; also, other expert clinicians not referring to the Italian Clinical Group for FSHD read and approved the CCEF revised version for its international use. RESULTS:We present the CCEF-R, a revised and simplified version of the CCEF, that while maintaining all the core structure and items of the previous validated version, has been modified with new friendlier graphics, focused on the key anamnestic and neurological examination findings, to facilitate its understanding and use in clinical practice. CONCLUSIONS:The phenotypical classification combined with the genetic signature should be considered during the diagnostic work out for guiding genetic analysis and for genotype-phenotype correlations and genetic counseling. The CCEF could have a significant role in the clinical stratification process of patients for clinical trials and in laying the groundwork for evidence-based medical decision making.

SELENON-related myopathy is a rare autosomal recessive congenital neuromuscular disorder linked to defects in the selenoprotein N. The clinical onset typically occurs in infancy and axial weakness, rigid spine, and respiratory involvement are almost invariably present at early stages. We report the case of a 44-year-old Italian woman who underwent intubation for acute respiratory failure, followed by weaning from invasive ventilation within 6 months. Her medical history was not significant, but a detailed medical history collection revealed slight motor limitations since childhood such as slow running, difficulty climbing high steps, early muscle exhaustion, and fatigue. The neurological examination showed a waddling gait and axial and proximal limb muscle weakness without rigid spine. The right quadriceps muscle biopsy showed nonspecific myopathic abnormalities. Clinical exome sequencing revealed the presence of the two heterozygous variants c.713DupA and c.803G > A in the SELENON gene. This report focused on the clinical heterogeneity of SELENON-related myopathy. While we highlight that the absence of spinal rigidity and core pathology on muscle biopsy should not exclude the diagnostic suspicion, overall we stress the importance of respiratory failure as a possible late manifestation of the disease, even in middle-aged individuals.

BACKGROUND:Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood and CSF mtDNA levels and variant burden in Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) was also included as a paradigm of chronic neuroinflammation-driven neurodegeneration. METHODS:Medline, Embase, Scopus and Web of Science were searched for articles published from inception until October 2023. Studies focused on mtDNA haplogroups or hereditary pathogenic variants were excluded. Critical appraisal was performed using the Quality Assessment for Diagnostic Accuracy Studies criteria. RESULTS:Fifty-nine original studies met our a priori-defined inclusion criteria. The majority of CSF-focused studies showed (i) decreased mtDNA levels in PD and AD; (ii) increased levels in MS compared to controls. No studies evaluated CSF mtDNA in ALS. Results focused on blood cell-free and intracellular mtDNA were contradictory, even within studies evaluating the same disease. This poor reproducibility is likely due to the lack of consideration of the many factors known to affect mtDNA levels. mtDNA damage and methylation levels were increased and reduced in patients compared to controls, respectively. A few studies investigated the correlation between mtDNA and disease severity, with conflicting results. CONCLUSIONS:Additional well-designed studies are needed to evaluate CSF and blood mtDNA profiles as putative biomarkers in neurodegenerative diseases. The identification of "mitochondrial subtypes" of disease may enable novel precision medicine strategies to counteract neurodegeneration.

Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with variable clinical progression. While median survival is 2–4 years, 5–15% of individuals survive for longer. Methods: We conducted a retrospective, observational study using a population-based ALS register in Lombardy, Italy, to identify the clinical characteristics of long-term ALS survivors (≥10 years). Incident cases included in two periods (1998–2002 and 2008–2012) were considered. Results: A total of 828 ALS cases were included. Median survival for the entire cohort was 2.2 years (IQR 1.1–4.4). However, long-term survival was observed in 7% of individuals at 10 years, and 3% at 15 years. Long-survivors had a median survival of 13.4 years, significantly longer than the 1.9 years of non-long-survivors (IQR 1.0–3.6). Long-survivors were younger at disease onset and diagnosis, had longer diagnostic delay, and were more likely to have had a spinal onset. The cohort also showed a higher proportion of males among long-term survivors (75% vs. 59%). No significant difference in survival was observed between the two examined periods. Conclusions: Our findings suggest that long-term ALS survival is likely influenced by a complex interplay of clinical, genetic, and environmental factors, along with the intrinsic rate of motor neuron degeneration.

KIF5A (Kinesin family member 5A) is a motor protein that functions as a key component of the axonal transport machinery. Variants in KIF5A are linked to several neurodegenerative diseases, mainly spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic lateral sclerosis (ALS). These diseases share motor neuron involvement but vary significantly in clinical presentation, severity, and progression. KIF5A variants are mainly categorized into N-terminal variants associated with SPG10/CMT2 and C-terminal variants linked to ALS. This study utilized a multiplex NULISA targeted platform to analyze plasma proteome from KIF5A-linked SPG10 and ALS individuals and compare them to healthy controls. Our results revealed distinct proteomic signatures, with significant alterations in proteins related to synaptic function and inflammation. Notably, neurofilament light polypeptide, a biomarker for neurodegenerative diseases, was elevated in KIF5A ALS but not in SPG10 individuals. Moreover, these findings can now be used to gain mechanistic understanding of axonopathies linking to N- versus C-terminal KIF5A variants affecting both central and peripheral nervous systems.

Myotonia, defined as impaired relaxation of skeletal muscles after voluntary contraction or electrical stimulation, is a core feature of myotonic dystrophy type 1 (DM1) and can be highly disabling. The most used anti-myotonic drug, mexiletine, has limited availability and is associated with several side effects. Lamotrigine (LTG), an anti-epileptic drug that reduces voltage-sensitive sodium channel activity, has shown efficacy in treating myotonia in both in vitro models and patients with non-dystrophic myotonias. We aimed to investigate in a cohort of patients with DM1 the use of LTG as an anti-myotonic treatment in a real-world setting. We enrolled 14 consecutive adult patients with genetically confirmed DM1 and clinically significant myotonia impacting daily living (Myotonia Behaviour Scale, MBS > 1). LTG was administered in escalating doses, starting from 50 mg/day up to 200 mg/day. Efficacy was assessed using a linear mixed-effects model. Two functional timed tests [the 9-Hole Peg Test (9HPT) and the preparation of a coffee pot, devised by us and called the "Coffee Task" test] were performed at baseline (pre-treatment) and at each dose level. Safety data was also collected. The mean age at enrollment was 40 years, and the mean disease duration was 12 years. LTG dosage had a significant positive effect on 9HPT performance at the maximum dose compared to baseline. Age and disease duration significantly influenced 9HPT results. No significant changes were observed in the other functional timed test. No serious adverse events were reported. This pilot, open-label study provides preliminary evidence for the efficacy and safety of LTG as an anti-myotonic treatment in patients with DM1. These findings support the need for larger, placebo-controlled trials to confirm its clinical utility.

Hereditary transthyretin amyloidosis (ATTRv) is a rare, multisystemic disorder often presenting with peripheral neuropathy and can be misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), especially in non-endemic areas. While clinical red flags have been proposed to aid diagnosis, their predictive value remains uncertain. This study prospectively assessed the prevalence of TTR variants in CIDP patients with red flags for ATTRv and retrospectively analyzed features of genetically confirmed ATTRv cases initially misdiagnosed as CIDP. Thirteen Italian tertiary neuromuscular centers consecutively screened CIDP patients with at least one red flag for TTR gene variants. A retrospective analysis was also conducted on ATTRv patients initially misdiagnosed as CIDP, comparing clinical, electrophysiological, and treatment response features to confirmed CIDP cases. No TTR variants were identified among 124 screened CIDP patients despite 65

BACKGROUND:Multifocal motor neuropathy (MMN) is a rare motor neuropathy diagnosed by identifying motor conduction block (CB), which may be absent or transient. This study aimed to evaluate nerve conduction abnormalities beyond CB and their diagnostic value. METHODS:A retrospective analysis included patients fulfilling the 2010 EFNS/PNS clinical criteria for MMN and controls with axonal polyneuropathy, lower motor neuron disease, or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Electrophysiological studies evaluated motor distal latency prolongation, reduced motor conduction velocity, prolonged F-wave latency, absence of F-waves, abnormal temporal dispersion, and distal CMAP duration prolongation. The 2010 EFNS/PNS criteria for MMN were compared to an 'extended' set incorporating additional electrophysiological parameters. RESULTS:A total of 70 MMN patients and 359 controls were included. At least one nerve conduction abnormality, excluding motor CB, was detected in one or more nerve segments unaffected by CB in 71% of MMN patients, significantly more frequently than in axonal polyneuropathy or lower motor neuron disease patients. These parameters included abnormal temporal dispersion (47%), distal CMAP duration prolongation (31%), reduced motor conduction velocity (26%), absence of F-waves (9%), prolonged F-wave latency (6%), and motor distal latency prolongation (3%). Incorporating these parameters increased sensitivity for diagnosing probable/definite MMN by 26% (p < 0.001; compared to EFNS/PNS criteria), with minimal impact on specificity, even when compared to CIDP patients. CONCLUSION:Including additional electrophysiological parameters into the diagnostic criteria for MMN may enhance diagnostic sensitivity while maintaining comparable specificity. The observation of nerve conduction abnormalities beyond CB indicates a broader electrophysiological profile for MMN.

The aim of this case-control study was to evaluate the ability of digital health technology (DHT) to detect and quantify mobility alterations in late-onset Pompe Disease. The study enrolled eight subjects with Pompe Disease, including three young mildly affected/asymptomatic subjects, who underwent an extensive DHT mobility assessment and were contrasted to 52 matched controls. DHT enabled the detection of subtle mobility alterations, indicating a lower speed in walking, and worse performances in postural transition and turning in patients compared to controls. Interestingly, in the three mildly affected/asymptomatic cases, step time variability and step length showed detectable alterations compared to controls, despite scores within the normal range on clinical scales and timed tests.

Background:Pompe disease is a lysosomal storage disorder that primarily affects muscles, and its natural history has been transformed over the past 20 years by therapies designed to restore the deficient enzyme function, from the first enzyme replacement therapies (ERTs) to the gene therapy currently in development. However, despite these ground-breaking innovations, the importance of a multi-system and rehabilitative approach remains critical, as it addresses the complex systems involved in the disease and optimizes the success of pharmacological treatments. Methods:We conducted a narrative review of the current pharmacological treatments approved for Pompe disease, as well as those undergoing clinical trials. We also reviewed international recommendations for managing respiratory, musculoskeletal, and cardiac function specially focusing on the late-onset form. Results:There are no universally agreed guidelines for the multidisciplinary management and many recommendations are based on expert consensus and small interventional studies. Nevertheless, combined approaches involving ERT therapy along with specific rehabilitation and nutritional programs appear to yield beneficial effects. Conclusions:Pompe disease, one of the first neuromuscular diseases to benefit from the approval of disease-modifying therapies, is a paradigm for the importance of an integrated therapeutic-rehabilitative approach.