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.

This study aims to characterize pain in patients with facioscapulohumeral muscular dystrophy (FSHD) and determine the interactions between pain and quality of life, mental health, and physical function. We analyzed data from the prospective, international, observational ReSolve study, with primary analyses focused on baseline assessments. Of 219 patients, 83% reported having pain at baseline, most commonly located in the lower back and shoulders. Most baseline characteristics did not differ significantly between patients with and without pain or between those with higher versus lower pain severity. However, patients experiencing more pain had more self-reported psychological problems and reduced performance of resistance exercise. Multivariable linear regression models revealed that both continuous pain intensity (range 0-10) and binary pain status (yes vs. no) were associated with Patient-Reported Outcome Measures Information System (PROMIS) 57 domains: Pain intensity was associated with all domains, including physical function, anxiety, depression, fatigue, sleep disturbance, and pain interference (all p-values <0.05), whereas binary pain status was associated with worse physical function, fatigue, sleep disturbance, and pain interference. Models were adjusted for age, sex, and Clinical Severity Score. These data highlight the significance of pain and the importance of optimizing therapies to treat pain in patients with FSHD.

Riboflavin transporter deficiency (RTD) is a rare but treatable autosomal recessive neurodegenerative disorder caused by biallelic variants in SLC52A2 (RTD2) or SLC52A3 (RTD3). It typically presents with motor neuronopathy and sensorineural hearing loss. High-dose riboflavin is beneficial but does not halt disease progression, and the determinants of treatment response remain unclear. To describe the phenotype and longitudinal riboflavin response in a Turkish kindred with homozygous SLC52A2 p.Pro134Leu, and to relate reversibility to the timing of treatment. All four patients underwent clinical, neurophysiological, audiological, ophthalmological, and neuroimaging evaluations; the variant was identified by whole-exome sequencing and confirmed by Sanger sequencing and family segregation. Patients received high-dose riboflavin and were followed for five years. The response to riboflavin was related to the interval between symptom onset and treatment. Case 1, treated eight months after onset, achieved complete clinical recovery, with improved nerve conduction and resolution of neurogenic changes within a year. Case 2, treated approximately thirteen years after onset, showed clinical stabilization but no electrophysiological improvement after two years; she also had optic atrophy and severe hearing loss. Cases 3 and 4 were identified by cascade screening and treated presymptomatically; both had subtle signs on examination and normal baseline electrophysiology, and they remain asymptomatic with normal nerve conduction studies and needle EMG after approximately four years. Once age at assessment was taken into account, phenotypic variability within the family was limited, confined to the initial presentation and to early audiological involvement. In Case 2, the earliest hearing loss was confined to 8000 Hz and later extended to the speech frequencies. This is the second independent Turkish family with p.Pro134Leu, consistent with either a regional founder allele or a recurrent mutation. In this family, the outcome of riboflavin therapy tracked how early it was started. Cascade screening revealed affected relatives at a subclinical, electrophysiologically intact stage, and high-frequency audiometry detected hearing loss before it affected speech frequencies.

Myofibrillar myopathies (MFMs) are genetically and clinically heterogeneous muscle disorders characterised by sarcoplasmic protein aggregation and myofibrillar disorganisation arising at the Z-disc. Although pathogenic variants are identifiable in ∼50% of cases, and mutations in 16 genes are now recognised to cause MFM, most reported cases follow an autosomal dominant pattern, with autosomal recessive forms considered rare. We describe the clinical, genetic, and pathological features of ten individuals harbouring homozygous variants in DES (desmin). The cohort shows marked clinical variability, with disease onset ranging from infancy to mid-adulthood, with occasional contractures and facial myopathy, whilst cardiac manifestations were surprisingly rare. Muscle pathology was similarly heterogeneous, with most cases lacking hallmark MFM features. These findings demonstrate that autosomal recessive DES mutations generate a broad, distinct clinical spectrum compared with dominant MFM, and that classical MFM histopathology may be absent, potentially contributing to diagnostic delay.

Type 2 myofiber atrophy is a clinically significant manifestation of muscle wasting. Its detection at autopsy depends on recognition of fiber size variation on routine hematoxylin and eosin (H&E) staining - a potentially subtle finding that may be missed without neuropathological training. Its prevalence is therefore likely to be under-reported, particularly in autopsy populations which are enriched for chronic illness, malignancy, and therapeutic high dose steroids. We conducted a prospective diagnostic accuracy study using a hospital autopsy cohort signed out by a board-certified neuropathologist, in which myosin fast immunohistochemistry was ordered prospectively as a reference standard. A non-neuropathology-trained pathologist's retrospective autopsy cohort, in which IHC was not ordered, served as a comparison. Diagnostic accuracy measures were calculated for fiber size variation as a predictor of type 2 atrophy. Logistic regression was performed to identify clinical predictors of type 2 atrophy. Diagnostic histopathological findings were present in 58.0% of prospective cases and included type 2 atrophy, necrosis and metastatic calcification. Type 2 fiber atrophy was identified in 52.2%. Fiber size variation as a predictor of type 2 atrophy had a sensitivity of 90.2%, specificity of 89.3%, positive predictive value of 92.5%, and negative predictive value of 86.2%. The non-neuropathology-trained pathologist identified type 2 atrophy in 10.5% of cases. Longer hospital stay was significantly associated with type 2 atrophy (median 19.0 vs. 4.0 days; p=0.0004; OR=6.37). In a hospitalized autopsy population, fiber size variation on H&E is a highly accurate proxy for clinically significant type 2 fiber atrophy. Type 2 atrophy may be substantially underdiagnosed at routine hospital autopsy, with a five-fold detection gap between neuropathology-trained and autopsy pathologists. Universal muscle sampling and targeted H&E evaluation for fiber size variation can achieve efficient and cost-effective detection of important diagnoses in the autopsy setting.

Charcot-Marie-Tooth disease is an inherited peripheral neuropathy marked by progressive loss of motor and sensory function. GDAP1 mutations are implicated in Charcot-Marie-Tooth disease, but the precise mechanism is not fully understood. This study aims to decipher the underlying genetic variant and its functional consequences in a consanguineous Indian family with two children (an 8-year-old boy and 3-years old girl) who presented with progressive motor and sensory limb involvement secondary to severe distal axonal neuropathy. Whole-exome sequencing identified a novel homozygous frameshift variant (c.503_504delAG) in GDAP1 in proband that was segregated among the family members. Patient-derived fibroblasts demonstrated complete loss of protein expression and swollen mitochondria with disrupted cristae in the cultured fibroblasts of affected individuals. Altered mitochondrial membrane potential with elevated reactive oxygen species levels, and significantly reduced ATP production and oxygen consumption rate in affected individuals compared to unaffected parents and controls, indicated impaired mitochondrial bioenergetics. We report a novel GDAP1 frameshift variant that disrupts mitochondrial structure and bioenergetics, underscoring GDAP1's role in mitochondrial quality control. However, the other downstream mechanisms implicated in axonal degeneration remains to be elucidated.