Muscular dystrophies are a heterogeneous group of genetic disorders associated with an aberrant inflammatory response, that contributes to disease progression impairing regeneration and inducing fibrosis. Sarcoglycanopathies are recessively inherited limb-girdle muscular dystrophies (LGMDRs), in which the role of inflammation and its association with disease severity remains poorly understood, particularly in alpha-sarcoglycanopathy (LGMDR3). This study characterizes skeletal muscle and peripheral inflammatory signatures in 16 LGMDR3 patients and 8 unaffected individuals through bulk RNA sequencing with additional validation in Sgca-null mice. Patients were classified into mild and severe groups based on alpha sarcoglycan (SGCA) expression in muscle biopsy. Peripheral immunophenotype was assessed via flow cytometry analysis of peripheral blood mononuclear cells (PBMC). Principal component analysis showed a clear separation of severe LGMDR3 from mild LGMDR3 and unaffected individuals, with the latter two groups overlapping. Unsupervised hierarchical clustering analysis of the most variable genes identified distinct gene expression profiles between severe and mild LGMDR3 samples. Severe LGMD3 showed overexpression of innate immune system and T-cell activation pathways, with higher abundance of inflammatory infiltrate, mainly monocytes, cytotoxic T cells and dendritic cells. Notably, severe LGMDR3 were characterized by enrichment of M1-polarized macrophages and pro-inflammatory chemokines, whereas M2-polarized monocytes predominated in mild cases. Similar inflammatory profiles were observed in Sgca-null mice. PBMC analysis revealed significantly increased CD8+, TH1 CD4+ lymphocytes and activated monocytes in LGMDR3 patients compared with controls. Severe LGMDR3 patients additionally showed overexpression of genes governing fibrosis and muscle tissue regeneration and exhibited a clustering pattern similar to Duchenne muscular dystrophy patients. In conclusion, this study represents the first comprehensive characterization of LGMDR3 immunological profiles and demonstrated that inflammation plays a significant role in severe disease pathogenesis. The distinct immune signatures separating severe from mild cases provide a foundation for developing targeted anti-inflammatory therapies that may benefit severe LGMDR3 patients with severe phenotype.

Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disease leading to muscle weakness and impaired quality of life. Standard clinical methods for assessing motor-functional changes have limitations, such as poor sensitivity in detecting early alterations. This study proposes the use of wearable inertial sensors for the objective monitoring of trunk and pelvic biomechanics. Wearable inertial sensors were used to record accelerations and angular velocities during the Six-Minute Walk Test (6MWT) in a pediatric patient with DMD. Spatio-temporal gait parameters, trunk and pelvis harmonic ratios, and 3D angular range of motion were analyzed. Preliminary results demonstrate the feasibility of the proposed method. The objective quantification of spatio-temporal gait parameters and trunk and pelvic biomechanics was possible. The patient showed an increased range of motion of the trunk (total average sagittal ROM = 12.27°, total average frontal ROM = 10.80°, total average transverse ROM = 11.38°) and pelvis (total average sagittal ROM = 9.36°, total average frontal ROM = 18.17°, total average transverse ROM = 22.27°) compared to normative literature values. This preliminary study indicates that wearable inertial sensors offer objective insights into trunk and pelvic biomechanics in DMD patients during the 6MWT. This approach may enhance disease monitoring and aid in developing more effective therapies.

IntroductionThe availability of disease modifying therapies in Spinal Muscular Atrophy (SMA) has highlighted the need for more structured registries for collecting reliable information both in treated and untreated individuals. Regulators recommendations have recently become available suggesting how registries should be designed or adapted for different purposes. These include the study of disease epidemiology/natural history in untreated individuals or the assessment in a real world setting of post treatment long term efficacy and safety in much wider cohorts than those included in pivotal trials. We report the adaptation of an academic registry to a nationwide registry describing the different steps of the process.MethodsAll Italian centres were asked to participate. The initial electronic case report form was adapted to be more compliant with recent regulators recommendations, including a more structured coding of adverse events. Training sessions were performed to guarantee data reliability. The governance system was also reviewed and integrated to optimize transparency, accuracy, and collaboration among stakeholders.ResultsAll centres agreed to be part of this effort and completed training sessions. A critical analysis of the performance of the registry shows a high compliance of the centres.DiscussionOur experience suggests that it is possible to keep the reliable structure of an academic registry even when enlarging the registry at national level and adopting a more structured approach in compliance with regulators recommendations. Such a registry can be a valuable source for research purposes and to inform decisions both in a clinical setting and at regulatory level.

BACKGROUND:Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by survival motor neuron (SMN1) deletion. While loss of ambulation in SMA type III typically occurs at a median age of 13.4 years, outcomes in the treatment era remain unclear. This study aims to address that gap by investigating ambulation outcomes in individuals with type III receiving disease-modifying therapies. METHODS:This retrospective study analysed prospectively collected international data. Time-dependent Cox models assessed the association between treatment initiation and age at loss of ambulation, adjusting for age at onset, sex, SMN2 copies, birth year and country. Treatment was modelled as a time-dependent covariate to avoid immortal time bias. Descriptive analyses used Mann-Whitney U and χ² tests. RESULTS:Among 555 individuals with type III, treatment halved the risk of ambulation loss (HR=0.50), with median loss at 44 vs 32 years in treated and untreated groups. Later onset, ≥4 SMN2 copies and female sex were also protective. The treatment effect was significant in type IIIA (HR=0.34) but not IIIB, with no significant interactions by sex, country or SMN2, though effects remained directionally protective. CONCLUSIONS:Treatment in type III reduced the risk of ambulation loss by 50%, extending median ambulation by 12 years, with the greatest benefit in type IIIA. Later onset, female sex and higher SMN2 copy number were also protective but did not modify treatment effect. These findings underscore the value of early treatment and support its broad use to preserve ambulation across clinical subgroups.

Inclusion body myositis (IBM) is an acquired myopathy of older adults, associated with progressive weakness and functional limitations. The inclusion body myositis functional rating score (IBM-FRS) is a reliable tool for the assessment of disease severity, but poor data are available on its correlation with clinical features. In this cross-sectional, retrospective multicenter study, we analyzed IBM-FRS total score (TS) and its items in a cohort of 147 IBM patients, considering 4 functional domains (FD) (dysphagia, upper limb function, daily living and independence, lower limb function). We analyzed TS and FD values’ correlations with demographic and clinical variables (onset, loss of walking ability, non-invasive ventilation, percutaneous gastrostomy—PEG) as well as between each FD and the remaining TS. Lower, hence worse, scores in the dysphagia domain (FD1) correlated with female gender (p < 0.01), dysphagia as presenting symptom (p < 0.01), and PEG use (p < 0.0001), but interestingly without correlation with time variables IBM-FRS total score or other domains. This may define a distinct phenotype with different onset and outcome. Worse scores in the upper and lower limb and daily living domains (FD2–FD4) were strongly associated with loss of ambulation, higher age at baseline, and longer disease duration (p < 0.001). We identified a cutoff value of 28/40, allowing to differentiate patients with less disease burden, potentially able to show better response in future clinical trials. Our study enriches the literature by correlating IBM-FRS total scores and its items with patient characteristics, offering important implications for clinical management, subgroup analysis, and future trials design.

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.

Historically defined as non-functional copies of coding genes, pseudogenes are an abundant yet underexplored element in the human genome, despite growing evidence linking them to human diseases. From a genome-wide screen, we identified 411 gene-pseudogene pairs located in opposite orientation, an arrangement which is permissive for the occurrence of inversions, including 46 genes already associated with human disease. Next, by analysing long read sequencing (LRS) data from the 1000 Genomes Project, we confirmed that at least 3.6% of healthy individuals carry an inversion involving one of these gene/pseudogene pairs, while they were previously undetected by short read sequencing. Most importantly, we identified novel and recurrent inversions between SORD and its pseudogene SORD2P in 13 out of 151 patients (9%) affected by SORD-related Charcot-Marie-Tooth (CMT) neuropathy, including 6 out of 8 (75%) of SORD-CMT cases where only one pathogenic variant was identified on short read sequencing, making it the third most common pathogenic allele causing SORD-CMT. Of interest, gene-pseudogene pairs displaying chromatin contact in Micro-C data, including SORD/SORD2P, were found to be more likely to undergo inversion events. Overall, our results highlight gene-pseudogene inversions as a previously underrecognized type of pathogenic structural variant. Wider use of LRS could reveal their true prevalence and contribution to the missing heritability in Mendelian diseases.

Case presentation:A 34-year-old male with congenital clubfoot, post-exertional rhabdomyolysis, and a family history of sudden cardiac death in mid-life was evaluated for a severe rhabdomyolysis requiring multiple hemodialyses. Clinical evaluation showed mild distal myopathy signs, with CK levels around 3000 IU/L and muscle biopsy revealing desmin- and dystrophin-positive cytosolic protein aggregates/fibre splitting. After a minor SARS-CoV-2 infection at 55, modest signs of cardiomyopathy were observed via cardiac MRI, without patterns indicative of myocarditis. Subsequently, NGS analysis identified a variant in the LDB3 gene, potentially correlated with the clinical-histological-radiological picture, thus broadening the phenotypic spectrum of LDB3-related distal myopathies. Additionally, a possible link was suggested between the viral infection and the exacerbation of the otherwise subtle cardiomyopathy. In the context of hyperCKemia and positive family history for unexplained cardiac abnormalities, broad-spectrum NGS testing, and cardiac MRI in selected cases, should be considered for timely diagnosis and interventions.

Facioscapulo-humeral muscular dystrophy is characterized by a distinctive phenotype, although a wide range of clinical expressions is observed, possibly reflecting different disease progression rates or complex genetic mechanisms. To date, the diagnostic criteria for FSHD rely on identifying the genetic signature of the disease (reduced D4Z4 allele, permissive 4q allele, hypomethylation, and in some cases variants in modifier genes). However, interpreting genetic data requires careful correlation with the phenotype, especially in atypical cases. The study included a cohort of 42 patients with a D4Z4 contraction or belonging to a pedigree in which DRAs segregated but who were selected due to presenting atypical clinical features or an unexpected disease severity according to the Comprehensive Clinical Evaluation Form (CCEF). The 42 underwent 4q subtype analysis, DNA methylation assessment, whole-exome sequencing (WES) and segregation analysis. In 24 cases, WES identified likely pathogenic or pathogenic variants in genes associated with different neuromuscular disorders, in some cases possibly compatible with the observed phenotype. Methylation analysis proved useful in distinguishing asymptomatic and atypical cases, prompting differential diagnosis. Our results emphasize the importance of a detailed phenotypic characterization of patients with a suspicion of FSHD and, in the case of atypical phenotypes, the combination of D4Z4 sizing with other procedures such as WES.

The Italian Duchenne muscular dystrophy expert clinicians, gathered in the Italian Association of Myology (AIM), intend to express a position against the suspension of the Marketing Authorization of ataluren (Translarna®) for the treatment of nonsense mutation Duchenne muscular dystrophy. The marketing authorization has been recently withdrawn by the European Commission following a recommendation from the Committee for Medicinal Products for Human Use of the European Medicines Agency. This negative recommendation was based on the fact that three randomized controlled trials of ataluren in nonsense mutation Duchenne muscular dystrophy (007, 020, and 041) have failed to show statistically significant differencs in favor of the treatment in the selected primary outcomes for each individual study, i.e., 6-min walk distance, in the intent-to-treat population for 007 and 020 and in a subgroup for 041. However, observed differences always favored treatment, and several clinically meaningful secondary outcomes were positive and statistically significant across studies. Importantly, the largest and longest phase III study (041) showed a statistically significant effect in favor of ataluren in the wider intent-to-treat population. Furthermore, a long-term registry of "real-world" ataluren treatment data (Strategic Targeting of Registries and Database of Excellence, STRIDE), in addition to confirming a reassuring safety profile, suggested a prolonged maintenance of ambulatory, upper limb, and respiratory function. We deem that a withdrawal of ataluren from the European market would harm not only patients with nonsense mutation Duchenne muscular dystrophy, but the whole neuromuscular field, in which clinical trials are challenging because of the heterogenous complex slow-progressing nature of the disorders.

BACKGROUND:The aim of this international retrospective study was to assess 4-year change using the Hammersmith Functional Motor Scale Expanded (HFMSE) in individuals with type II and III spinal muscular atrophy (SMA) treated with nusinersen and to establish predictors of HFMSE changes. METHODS:Individuals with type II or III SMA, and at least 4 years of nusinersen-only treatment were included. All were assessed using the HFMSE. Age at baseline, sex, motor function, SMN2 copy number, and age of onset were also retrospectively collected. Linear mixed effect models were used to calculate yearly changes and trajectory predictors. RESULTS:We included 73 individuals with SMA type II (mean age 8.58 years, SD 7.91, IQR 3.04-10.70) and 111 type III (mean age 7.91 years, SD 17.83, IQR 8.15-34.42). Over 4 years, mean changes were + 4.18 (95% CI: 2.85-5.50) for SMA II and + 1.08 (95% CI: 0.12-2.04) for SMA III. Age (SMA II: -0.34\[-0.51 to -0.17]; SMA III: -0.13\[-0.20 to -0.06], p < 0.001) and baseline HFMSE (SMA II: 1.02\[0.70-1.34]; SMA III: 0.79\[0.71-0.87], p < 0.001) were the strongest predictors of progression, with younger age and higher baseline scores associated with better outcomes. Functional status was only predictive for type III (6.96\[4.26-9.66]). CONCLUSION:Our results confirm that, given a follow up of 4 years, there is a persistent impact of nusinersen on clinical progression that is better observed in younger patients with higher HFMSE scores at baseline, especially during the first 2 years of treatment.

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite at human chromosome 4q35. These deletions cause local chromatin changes and anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4. We discovered that FRG2A is part of a family of long noncoding RNAs (lncRNAs) expressed in skeletal muscle cells, with levels varying among patients. FRG2A localizes in the nucleolus and associates with repetitive DNA at ribosomal DNA (rDNA) loci and centromeres. Elevated FRG2A expression in FSHD cells alters the three-dimensional architecture of heterochromatin at the nucleolar periphery and reduces rDNA transcription and translation rates, resulting in decreased synthesis of skeletal muscle proteins. We also show that myoblasts from FSHD patients display reduced synthesis of skeletal muscle proteins during differentiation. Our results support a disease model in which nucleolar accumulation of D4Z4-driven lncRNA impairs protein synthesis and contributes to muscle wasting.

Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease attributable to mutations in DMD, leading to a deficient and less functional dystrophin, mainly in skeletal and cardiac muscle. Understanding the natural history of BMD is crucial for optimizing patient care and developing targeted treatments. Retrospective data were collected from 943 patients diagnosed with BMD based on a combination of clinical, biochemical and genetic criteria followed by 17 Italian neuromuscular centres. Patients' demographics, main signs and symptoms at BMD onset, neuropsychiatric comorbidities, age at loss of ambulation, cardiac left ventricular ejection fraction, pulmonary forced vital capacity and DMD mutations were collected. Disease milestones were analysed in specific DMD mutational groups. The median age at the last assessment was 26.0 (16.6-41.9) years, with a median age at diagnosis of 7.5 (4.0-14.0) years. In 55% of patients, the diagnosis was prompted by the incidental finding of hyperCKaemia. At the last assessment, 13.5% of patients had lost the ability to walk at a median age estimated by Kaplan-Meier analysis of 69 years. Thirty per cent of patients exhibited left ventricular impairment and 2.7% respiratory involvement. Ten per cent of patients carried out-of-frame mutations, 4% nonsense mutations and 86% in-frame deletions/duplications. The subset of in-frame deletions was classified further based on the specific mutations. Patients carrying del45-49 compared with del45-47 were associated with an earlier loss of ambulation (P = 1 × 10-4), whereas patients with del45-55 (P = 0.005), del48 (P = 0.02) and del48-49 (P = 0.02) were correlated with a later loss of ambulation compared with del45-47. Both del45-55 (P = 0.002) and del48 (P = 0.003) were significantly associated with decreased odds of developing a pathological left ventricular ejection fraction compared with del45-47. Our results contribute to a better understanding of the natural history of BMD and capture precious data in the era of emerging therapies. The knowledge of the specific DMD mutation might help to define a prognosis in a subset of BMD patients and will serve as a model for the design of future therapies.

Spinal muscular atrophy (SMA) is a progressive disorder caused by SMN1 mutations. While therapies have changed its course, current motor scales often miss aspects. This study aimed to validate the Italian SMA Independence Scale (SMAIS-ULM) for reliability, applicability, and expansion across diverse SMA phenotypes. Patients with genetically confirmed 5qSMA were recruited from 12 Italian centers. Analyses included Intraclass Correlation Coefficients (ICCs) for test–retest reliability, the Kruskal–Wallis for group comparisons, and the Spearman correlations with functional measures. Ceiling/floor effects were defined as ≥ 85

(i) provide a snapshot from a large cohort of Italian patients with SMA on risdiplam in the real-world setting; (ii) identify any differences in the cohorts before and after commercial drug approval considering the different eligibility access criteria (iii) describe preliminary data on adherence to treatment and reasons for shifting from nusinersen to risdiplam. Charts from patients on risdiplam were retrospectively reviewed. Results were then compared between patients accessing the drug during an initial restricted compassionate use program (cohort 1) and those after commercial approval, with no restrictions (cohort 2). Side effects and adherence were recorded for both cohorts as well as data on shifters. 283 patients (median age: 22 years) were included. Only a minority were walkers. Respiratory and bulbar comorbidities were more severe in cohort 1 (58

Background and Objectives The diagnostic process for myofibrillar myopathies (MFM) and distal myopathies (DM) is particularly complex because of the large number of causative genes, the existence of still molecularly undefined disease entities, and the overlapping features between the 2 categories. This study aimed to characterize a large cohort of patients affected by MFM and DM and identify the most important diagnostic and prognostic aspects of these diseases. Methods Patients with either a myopathological diagnosis of MFM or a clinical diagnosis of DM were included in this retrospective multicentric national study. Demographic, genetic, clinical, and histopathologic data of anonymized patients were collected from the neuromuscular centers of the Italian Association of Myology network. Results Data regarding 132 patients with MFM (mean age 57.0 +/- 15.8 years, 49% female) and 298 patients with DM (mean age 50.7 +/- 15.9 years, 40% female) were gathered from 20 neuromuscular centers. 69 patients fulfilled the criteria for both groups (distal myopathies with myofibrillar pathology, DM-MP). Molecular confirmation was achieved in 63% of the patients. Fifty-two percent of the patients with MFM carried pathogenic variants in either DES (n = 30), MYOT (n = 20), or DNAJB6 (n = 18), which were also the most frequent disease-causing genes in DM-MP, while GNE (n = 44) and MYH7 (n = 23) were the genes most commonly carrying pathogenic variants in DM. The mean age at onset varied from <25 years in patients with causative variants in MYH7 and DYSF to 59 years in patients with myotilinopathies. Cardiac involvement was reported in 29% of patients with MFM and 16% of patients with DM, with DES and MYH7 variants significantly associated with the development of cardiomyopathy. Respiratory impairment was more prevalent in patients with TTN and DES variants and rare in other disorders such as GNE myopathy and dysferlinopathies, which were instead associated, together with DNAJB6-related and PLIN4-related myopathies, with the risk of losing ambulation during the disease course. Discussion The Italian cohort of patients with MFM and DM recapitulates the phenotypic heterogeneity and the partial overlap between the 2 groups. However, in relative contrast to the encountered phenotypic variability, only 5 genes accounted for most of the molecular diagnoses. Specific genetic entities are associated with significantly increased risk of developing cardiorespiratory complications or loss of ambulation, which has relevant prognostic implications.

Facioscapulohumeral dystrophy (FSHD) is a myopathy characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). The assessment of DNA methylation at two regions (DUX4-PAS and DR1) of D4Z4 locus proved to be an effective method to detect epigenetic signatures compatible with FSHD. The present study aims at validating the employment of this method into clinical practice and improving the protocol by refining the classification thresholds of 4qA/4qA patients. To this purpose, 218 subjects with clinical suspicion of FSHD collected in 2022–2023 were analyzed. Each participant underwent in parallel the traditional FSHD molecular testing (D4Z4 sizing) and the proposed methylation assay. The results provided by both analyses were compared to evaluate the concordance and calculate the performance metrics of the methylation test. Among the 218 subjects, the 4q variant type distribution was 54

The availability of care recommendations has improved survival and delayed the progression of clinical signs in Duchenne muscular dystrophy. The aim of the study was to perform a nationwide survey investigating the prevalence, age distribution, and functional status of Duchenne muscular dystrophyin Italy. The survey was performed by collecting data from all 31 reference centers for Duchenne muscular dystrophy in Italy using a structured form. We assessed age distribution, motor function, and the need for respiratory and nutritional support to evaluate their prevalence in different age and functional subgroups. The estimated prevalence was 1.65/100,000 (3.4/100,000 males). There were 972 boys and adults with a confirmed diagnosis of Duchenne, of age ranging between 6 months and 48 years (mean = 16.5). Over 59

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy linked to deletions of the tandemly arrayed D4Z4 macrosatellite repeats at human chromosome 4q35. These deletions accompany local chromatin changes and the anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4. We discovered that FRG2A is one member of a family of long non-coding RNAs (lncRNA) expressed at elevated levels in skeletal muscle cells in an individual-specific manner. We found that FRG2A lncRNA preferentially associates with rDNA sequences and centromeres, and also promotes the three-dimensional association of centromeres with the nucleolar periphery in FSHD samples. Furthermore, we demonstrate that the elevated FRG2A expression in cells from FSHD patients reduces rDNA transcription and protein synthesis.Our results frame a new disease model in which elevated lncRNAs expression mediated by deletions of D4Z4 macrosatellite repeats leads to a diminished protein synthesis capacity, thereby contributing to muscle wasting. ### Competing Interest Statement The authors have declared no competing interest.

Background In facioscapulohumeral muscular dystrophy (FSHD), it is not known whether physical activity (PA) practiced at young age is associated with the clinical presentation of disease. To assess this issue, we performed a retrospective cohort study concerning the previous practice of sports and, among them, those with medium-high cardiovascular commitment in clinically categorized carriers of a D4Z4 reduced allele (DRA). Methods People aged between 18 and 60 were recruited as being DRA carriers. Subcategory (classical phenotype, A; incomplete phenotype, B; asymptomatic carriers, C; complex phenotype, D) and FSHD score, which measures muscle functional impairment, were assessed for all participants. Information on PAs was retrieved by using an online survey dealing with the practice of sports at a young age. Results 368 participants were included in the study, average age 36.6 years (SD = 9.4), 47.6% male. The FSHD subcategory A was observed in 157 (42.7%) participants with average (± SD) FSHD score of 5.8 ± 3.0; the incomplete phenotype (category B) in 46 (12.5%) participants (average score 2.2 ± 1.7) and the D phenotype in 61 (16.6%, average score 6.5 ± 3.8). Asymptomatic carriers were 104 (subcategory C, 28.3%, score 0.0 ± 0.2). Time from symptoms onset was higher for patients with A (15.8 ± 11.1 years) and D phenotype (13.3 ± 11.9) than for patients with B phenotype (7.3 ± 9.0). The practice of sports was associated with lower FSHD score (-17%) in participants with A phenotype (MR = 0.83, 95% CI = 0.73–0.95, p = 0.007) and by 33% in participants with D phenotype (MR = 0.67, 95% CI = 0.51–0.89, p = 0.006). Conversely, no improvement was observed in participants with incomplete phenotype with mild severity (B). Conclusions PAs at a young age are associated with a lower clinical score in the adult A and D FSHD subcategories. These results corroborate the need to consider PAs at the young age as a fundamental indicator for the correct clinical stratification of the disease and its possible evolution.