The TOR1AIP1 gene encodes the nuclear envelope protein LAP1; pathogenic variants cause distinct phenotypes, from muscular dystrophy to multisystem involvement. This recessive disease presents from in utero to late adulthood. Survival depends on phenotype. A 63-year-old woman first presented at 48 years of age with progressive proximal lower limb weakness since age 28, recently involving the upper limbs. There was no consanguinity, but familial gait impairment was reported. She had lumbar hyperlordosis, proximal tetraparesis, and waddling gait. CK was normal and neurophysiological studies revealed myopathic changes and a 12% decremental response on repetitive nerve stimulation. Muscle biopsy showed muscular dystrophy. Weakness progressively worsened over 15 years of follow-up. Exome sequencing revealed a probably homozygous pathogenic TOR1AIP1 variant. This case contributes to characterizing the TOR1AIP1-related disease phenotypic heterogeneity. The association of myopathy with electrophysiological findings of myasthenic syndrome highlights the overlap between muscle and neuromuscular junction dysfunction.

Generalized edema is an uncommon manifestation of dermatomyositis (DM) and may lead clinicians to consider alternative systemic conditions. Anti-transcriptional intermediary factor 1 gamma (TIF1γ) antibodies are associated with an increased risk of malignancy and dysphagia in patients with DM. We report an 82-year-old woman with anti-TIF1γ-positive DM who initially presented with generalized edema, followed by progressive dysphagia and proximal muscle weakness. Skin manifestations, anti-TIF1γ antibody positivity, electromyography, muscle magnetic resonance imaging, and muscle biopsy established the diagnosis of DM. Subsequent malignancy screening identified ovarian cancer. Despite immunotherapy, severe dysphagia persisted and required prolonged nasogastric tube feeding. This case highlights generalized edema as an early manifestation of anti-TIF1γ-positive DM and suggests that it may precede more typical manifestations of the disease, potentially leading to diagnostic delay.

Centile curves may improve the interpretation of motor outcomes in specific populations. This study aimed to develop Italian age-specific centile curves for NSAA, rise-from-floor velocity (RFFV), and 10-meter walk/run velocity (10MWRV) in boys with Duchenne muscular dystrophy (DMD) and to assess their agreement with existing UK reference curves. Data from 627 patients (5080 assessments) with an age between 3-18 years were extracted from the Italian DMD Registry. GAMLSS models were used to estimate centile curves. Agreement with UK data (restricted to ages 5-16 years and who are actively on steroids) was evaluated using SDS deviation and percentile coverage analyses. NSAA scores peaked at approximately 6 years; RFFV and 10MWRV peaked at 5 years, then progressively declined. The Italian cohort showed small deviations from the UK centiles (all p<0.001): mean SDS values were significantly different across all outcomes, and age was significantly associated with SDS deviation through both linear and quadratic effects. The Italian centile curves extend reference data to wider age ranges. Available for both general and steroid-treated patients, they support clinical trials and real-world practice. The minor differences observed, especially in timed velocities, highlight the need for future international harmonisation.

FLNC-related myopathy (FLNC-RM) with actin-binding domain (ABD) variants is known to show heterogeneous muscle involvement; however, whether such variability exists within families sharing the same variant, and which muscles contribute to this heterogeneity, remain unclear. We investigated muscle involvement patterns in four members of a single family carrying the FLNC c.577G>A (p.A193T) variant who underwent serial longitudinal muscle imaging. A five-point semi-quantitative visual assessment of fatty replacement was performed across 43 muscles using whole-body CT and MRI, covering the shoulder, trunk, pelvis, thighs, and lower legs. Uniform manifold approximation and projection (UMAP) provided a visualization in which longitudinal observations tended to group by individual. In the original 43-dimensional mMS matrix, the mean within-patient distance was smaller than the mean between-patient distance among P1a-c (3.58 vs. 7.29; exact permutation P = 0.00017), supporting the persistence of individual-specific mMS distribution profiles over the observed period. Analysis across muscles identified a subset-gluteus medius, gluteus minimus, adductor magnus, semimembranosus, gastrocnemius (medial and lateral heads), and soleus-for which mMS showed a strong fit to age-based models, while many other muscles showed marked interindividual variability. Chronological data further illustrated common and variable patterns of muscle involvement while preserving individual differences. Notably, relative preservation of the tibialis anterior and extensor digitorum longus was observed even at advanced stages. Overall, these findings indicate that FLNC-RM with the ABD variant, particularly the c.577G>A, is characterized by marked interindividual variability in muscle involvement patterns, even among members of the same family.

Tibial muscular dystrophy (TMD) is a late-onset autosomal dominant distal myopathy initially described in the Finnish population and caused by monoallelic, mostly missense, TTN variants. More recently, earlier-onset limb girdle muscular dystrophy phenotypes have been reported in patients carrying biallelic TTN variants. We describe the first African patient homozygous for a previously described TMD related TTN variant presenting with a limb-girdle muscular dystrophy (LGMD) phenotype. The proband, an ambulant 11-year-old boy originally from Libya, presented with progressive lower limb weakness that was first noted at the age of 9 months. He displayed a phenotype characterised by proximal and distal lower-limb weakness that evolved over 10 years into a clear limb-girdle pattern. T1-weighted muscle MRI images revealed fatty replacement of the gluteus maximus, vasti, adductor magnus, soleus, and tibialis anterior muscles. Formal cardiac and pulmonary evaluations were unremarkable, and electromyography depicted a myopathic pattern. Muscle biopsy revealed mild dystrophic changes with fibre size variation, internal nuclei, rimmed vacuoles, with absent calpain-3 expression on western blot. Whole-genome sequencing revealed that the proband is homozygous for the c.107837A>C (p.His35946Pro) pathogenic TTN variant. His first-degree consanguineous parents are heterozygous for the variant, yet they remain asymptomatic. This case expands the genetic spectrum of biallelic TTN variants associated with LGMD R10.

Neuromuscular disorders (NMDs) represent a heterogeneous group of conditions with substantial effects on physical functioning, participation, and quality of life throughout the lifespan. Aligning research priorities with the needs of patients, clinicians, and society is essential to ensure relevance and impact. In the Netherlands, collaboration between patients, patient organizations, clinicians and basic researchers have played a pivotal role in shaping research agendas through structured engagement of adults with NMD, and children and parents. Nationwide surveys, filled in by patients, consistently identified the need for faster and less invasive diagnostics, effective symptomatic treatments, improved quality of life, and access to new therapies. Across age groups, fatigue, mobility limitations, pain, and social participation emerged as key challenges, while children specifically emphasized inclusion in school and sports. These patient-identified priorities have informed diagnosis-specific research agendas, guided national funding strategies, and stimulated targeted initiatives focusing on rehabilitation, lifestyle interventions, and participation in physical activity. By integrating patient perspectives into national research strategies, the Dutch collaborative model demonstrates that meaningful, patient-driven agenda-setting can accelerate scientific progress while ensuring outcomes of direct relevance to those affected, and illustrates how collaborative, field-wide approaches may serve as a valuable example for research agenda-setting for other patient organizations.

Newly discovered genetic subtypes of muscular dystrophy tend to be rarer than older ones, as occurs for other genetically heterogeneous classes of inherited disorders. Epidemiologically, there is a higher likelihood of ascertaining more prevalent genetic subtypes, but it is unclear why pathogenic variants are more abundant in certain genetic subtypes than others. We hypothesized that distributions of pathogenic variant types and molecular consequences of those variants for each genetic subtype vary based on the year of discovery of the muscular dystrophy gene. We compiled a list of genes associated with muscular dystrophy that had pathogenic or likely pathogenic variants listed in ClinVar, then extracted those variants for analysis. To explore the relationship between the year of gene discovery and distribution of variant types, we performed Kendall's τ-b test for each variant type. Sixty-four muscular dystrophy genes had pathogenic or likely pathogenic variants listed in ClinVar. We found a significant negative correlation with year of gene discovery in the proportion of frameshift, splice acceptor, and splice donor variants and a corresponding significant positive correlation in missense variants for muscular dystrophy genes. There was a decrease in the observed / expected missense score and an increase in missense z-score by year of discovery, indicating less tolerance to missense changes in more recently discovered genes. Other trends included fewer insertions and deletions, and increased single nucleotide variants (SNVs) by year of gene discovery. Our findings suggest that recently discovered muscular dystrophy genes are less tolerant of variation, potentially explaining why variants and cases are less abundant in these genes.

Regular exercise may improve health and reduce morbidity in people with neuromuscular diseases. This study examined the application of exercise, perceived barriers to it, perceived benefits from it, and the support needs of healthcare professionals and adults with neuromuscular diseases. Two international online surveys were distributed through professional networks, patient organizations, and social media. A survey for healthcare professionals was open, from August-November 2024. It was answered by 109 respondents from 19 countries across three continents covering respondent profile, prescription practice, perceived barriers, and need for support. A patient survey was open from July-September 2024. It had a response of 1909 adult respondents from 42 countries across six continents covering respondent profiles, engagement in exercise, perceived barriers, and benefits. Although 80% of people with neuromuscular diseases reported engaging in exercise and 94% of healthcare professionals reported prescribing exercise, these estimates are likely influenced by non-response bias. Despite this, 77% of healthcare professionals reported underuse (i.e., insufficient training dose), suggesting that exercise is perceived as not being fully implemented in clinical practice. Aerobic exercise was typically prescribed thrice weekly at moderate intensity for 21-30 minutes, while resistance training was commonly prescribed twice weekly at low-to-moderate intensity for 11-20 minutes. Reported exercise patterns in both surveys were broadly consistent with recent recommendations. Barriers were multifactorial. Healthcare professionals most frequently reported safety concerns, lack of guidelines, and insufficient staff, whereas people with neuromuscular diseases reported health-related concerns and low motivation. People not exercising reported barriers more frequently than people who exercised, and wheelchair use was associated with lower odds of exercise engagement and more barriers. Although exercise is commonly prescribed and widely perceived as beneficial, underuse and barriers remain. Development of personalized guidelines addressing safety, individual motivators, and barriers may support greater exercise participation in adults with neuromuscular diseases.

Lower urinary tract dysfunction is an underrecognized manifestation of myotonic dystrophy type 1 (DM1), despite the multisystem nature of the disease. This study aimed to characterize the prevalence and clinical profile of lower urinary tract symptoms (LUTS), urinary incontinence, and pelvic floor dysfunction in adults with DM1 and to explore their association with functional status. In this cross-sectional study, 36 adults with genetically confirmed DM1 (50% men; median age 43 years, IQR 33-52.8) completed validated questionnaires assessing LUTS, urinary incontinence, and overactive bladder (OAB). Functional independence was evaluated using the Modified Barthel Index and pelvic floor muscle strength using the Modified Oxford Scale. A control group of 20 healthy individuals (40% men; median age 30 years, IQR 25-43.5) completed the same urinary symptom assessment protocol. LUTS were present in 75.0% of patients, predominantly storage symptoms. OAB symptoms were identified in 44.5% and urinary incontinence in 58.3% of the cohort. Pelvic floor muscle contractions were weak or absent in most evaluated patients. Compared with controls, patients with DM1 had significantly higher prevalence of LUTS (75.0%vs 35.0%, p = 0.005), OAB symptoms (44.5%vs 10.0%, p = 0.009), and urinary incontinence (58.3%vs 15.0%, p = 0.002). Urinary incontinence was also more frequent among patients with greater functional dependence. Lower urinary tract dysfunction is common in DM1 and is mainly characterized by storage symptoms, OAB, and urinary incontinence. Routine screening for urinary dysfunction should therefore be considered in the clinical management of patients with DM1.

Nemaline myopathy (NM) is among the most common of the congenital myopathies, characterized by hypotonia and muscle weakness. Despite its prevalence and morbidity, NM remains underrepresented in studies of lived experience and the impact on patients and caregivers. To expand upon the current knowledge, we conducted an international cross-sectional survey to systematically characterize patient and caregiver perspectives, including daily challenges, medical complications across age groups, and priorities for future treatment development. All respondents reported facing daily challenges, regardless of disease severity. The most frequently cited challenges related to NM included mobility, fatigue, respiratory, and mental health. Our results indicated that children more frequently were reported as having severe phenotypes, and adults often present with milder forms, likely due to survival bias. While 7% of participants reported congenital-onset cardiac complications, 16% reported cardiac complications developing during childhood or adulthood. This study provides the first comprehensive assessment of NM patient and caregiver perspectives across age groups, severity levels, and 33 countries. By uncovering previously unreported insights, these findings establish a more complete understanding of NM that strengthens the patient-centered translational impact for future study and therapeutic development.

MYO18B is an unconventional class XVII myosin that is predominantly expressed in muscle and heart tissue. Recessive pathogenic MYO18B variants cause a rare myopathy associated with Klippel-Feil syndrome (KFS), facial dysmorphism, short stature and less frequently cardiomyopathy. Reported neuromuscular manifestations were variable, with nemaline bodies observed in one patient. We report six novel patients from four families with an early onset myopathy due to biallelic MYO18B variants. Facial, axial, proximal upper and lower limb weakness was prevalent. Three patients had congenital findings including hip dislocation, reduced fetal movements and arthrogryposis with generalized hypotonia. Marked intrafamilial variability of muscle involvement was noted in two siblings. Short stature was present in three patients, ptosis and facial dysmorphisms in two, respectively. KFS was radiologically noted in one patient. Cardiac involvement was absent. Lower limb MRI revealed selective involvement of semitendinosus and tibialis anterior muscles. The clinical myopathic findings were supported in two patients by myopathic histological features including fiber size variation, type I fiber predominance and core pathology, without any detectable nemaline bodies. Our cases highlight the variable presentation and intrafamilial variability and first report selective muscle MRI involvement in this condition, adding on the limited literature on patients with MYO18B gene myopathy.

Early institutions of enzyme replacement therapy (ERT) for infantile-onset Pompe disease (IOPD) greatly improved patients' outcome. However, the long-term prognosis of patients' muscular and respiratory systems has not been fully elucidated. We conducted a longitudinal study for a cohort of early-treated IOPD patients with continuous monitoring of motor and respiratory functions (spirometry and polysomnography). Statistical analyses were performed for the relationship between Gross Motor Function Measure (GMFM), forced vital capacity (FVC), apnea-hypopnea index (AHI), and oxygen desaturation index (ODI). Sixteen patients (13 classical and 3 nonclassical IOPD) were followed up to a median age of 16.0 years (range 7.5-19.6), providing approximately 244 patient-years of observation and 132 polysomnographic assessments. Eleven of the 16 patients developed an AHI greater than 5 events/hour (indicating moderate obstructive sleep apnea, with nearly all events being obstructive apneas or hypopneas) at a Kaplan-Meier-estimated median age of 7.8 years. Night-time respiratory support was prescribed for 7 patients at a median age of 17.5 years. Data analyses revealed that FVC and AHI deteriorated faster in patients who became non-ambulatory than in other patients with better motor outcome. However, although FVC and AHI correlated slightly (r = -0.48), cases with sleep apnea were observed in patients with relatively normal gross motor or FVC. Nocturnal sleep abnormalities can occur in early-treated IOPD patients before frank deterioration of motor and respiratory function. Polysomnography is recommended for all those patients, and night-time respiratory support may be necessary to prevent morbidity and mortality.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited muscular dystrophies and the focus of rapidly expanding therapeutic development. Yet several longstanding assumptions continue to shape discussions among researchers, clinicians, regulators, and industry stakeholders in ways that may not fully reflect the experiences of people living with FSHD. In this Patient Forum, FSHD Europe presents perspectives arising from extensive engagement with the patient community and participation in international initiatives. We address three commonly cited assumptions: that FSHD is a slowly progressive disease, that it can be divided into infantile and classic forms, and that no treatments are available. We argue that FSHD is better described as a progressive disease with a highly variable course, reflecting the heterogeneity of patient experiences and disease burden. We also highlight recent international consensus that childhood-onset FSHD represents part of a continuous disease spectrum rather than a distinct subtype. Finally, although disease-modifying therapies remain under development, evidence-based symptomatic and multidisciplinary care already provides meaningful treatment and should remain central to care alongside future molecular therapies. These perspectives emphasize the importance of integrating lived experience into research, drug development, health technology assessment, and healthcare decision-making, ensuring that future therapies address outcomes that matter most to people with FSHD.