Neuromuscular diseases are a heterogeneous group of disorders affecting muscles and peripheral nerves, leading to progressive muscle weakness and functional impairment. Muscle MRI facilitates the assessment of muscle pathology, but current analysis relies on time-consuming manual segmentation or subjective visual scoring. Validation across diverse patient populations and imaging protocols is lacking in existing automated methods. Deep learning segmentation methods were developed to quantify intramuscular fat infiltration and muscle volume across all lower limb muscles using heterogeneous multi-site data. Three convolutional neural network architectures (U-Net, U-Net + + , and Attention U-Net + +) were evaluated on a multi-site dataset comprising 27,858 slices from 797 muscle MRI scans across 376 patients, spanning 12 neuromuscular diseases and 12 international sites. Thirty-two individual muscles across pelvis, thigh, and lower leg regions were segmented. High accuracy was achieved by all architectures (DSC = 0.97). Leave-One-Site-Out experiments revealed strong generalisability across sites (average DSC = 0.96). Automated fat quantification placed 90.9% of muscles within one point of ground truth on standard visual scales and correlated strongly with quantitative fat fraction measurements (r = 0.995, p < 0.001). High correlation with ground truth was demonstrated by cross-sectional area predictions (r = 0.94, p < 0.001). Diverse imaging protocols were handled with minimal preprocessing. Accuracy equivalent to observer variability was achieved by automated segmentation, potentially eliminating the need for manual correction in large-scale applications.

Myotonic dystrophy type 1 (DM1) is a progressive, multisystemic disorder in which gastrointestinal (GI) involvement is prevalent but frequently underestimated in routine clinical care. This study aimed to evaluate the GI manifestations and symptom burden in patients with adult-onset DM1.We performed a retrospective study in patients with genetically confirmed adult-onset DM1. GI symptom burden was assessed through three sources: (1) patient-reported outcome measures (PROMs), specifically the Gastrointestinal Symptom Rating Scale (GSRS) and the Sydney Swallow Questionnaire (SSQ), (2) an open-ended question asking patients to name their five most bothersome symptoms, and (3) GI symptoms and diagnoses documented in their medical records. Associations between GI symptoms and sex, age, disease duration, Body Mass Index (BMI), and CTG repeat size were analysed.Ninety-five patients with adult-onset DM1 were included (57% female; mean age 44.2±11.8 years). GI symptoms imposed a substantial burden, as 54% of patients exceeded the GSRS clinical threshold and 53% exceeded the SSQ threshold. In open-ended reporting, 31% of patients named a gastrointestinal problem among their most bothersome symptoms, ranking it fourth among all complaints, 13% named swallowing difficulties. In line with the PROM findings, medical record review demonstrated a high prevalence of GI manifestations, including dysphagia (59%), diarrhoea (35%), and constipation (33%). Female sex was strongly associated with higher odds of constipation (OR 9.25,p<0.01), diarrhoea (OR 3.45,p=0.02), and abdominal pain (OR 7.40,p<0.01). Increasing age and longer disease duration were associated with higher odds of constipation, dysphagia, cholelithiasis, and non-alcoholic liver steatosis (p<0.05). No associations were observed for CTG repeat size or BMI.GI symptoms are highly prevalent and burdensome in adult-onset DM1. Female sex, longer disease duration, and older age were associated with a higher symptom prevalence. Structured screening using PROMs should be integrated into multidisciplinary care to ensure that these symptoms are detected promptly and addressed adequately.

BACKGROUND:Differentiating myogenic from neurogenic neuromuscular diseases (NMDs) can be clinically challenging. While quantitative muscle MRI (qMRI) with proton density fat fraction (PDFF,%) quantifies fat replacement, it misses micro-spatial patterns linked to underlying pathology. This study investigates whether qMRI with 3D radiomic texture analysis (TA) might improve differentiation between myogenic and neurogenic diseases, using myotonic dystrophy type 1 (DM1) and Charcot-Marie-Tooth neuropathy type 1A (CMT1A) as proof-of-concept models. METHODS:Thirty-three adults with DM1, 33 with CMT1A, and 33 matched healthy controls were included. qMRI on a 3T Philips Achieva system using a 6-point Dixon sequence generated PDFF(%) maps of the lower limbs, and a convolutional neural network performed 3D segmentation of 28 lower limb muscles. We extracted macroscopic features, including muscle volume, asymmetry, and disto-proximal gradients, alongside micro-spatial radiomic features (entropy, contrast, homogeneity) to quantify tissue heterogeneity. RESULTS:Both patient cohorts exhibited higher PDFF(%) in all lower limb muscles compared to controls (p < 0.001). DM1 predominantly involved the posterior compartment, while CMT1A targeted the anterolateral compartment with significantly steeper disto-proximal fat gradients (p < 0.05). TA revealed higher entropy and contrast, and lower homogeneity in CMT1A compared to DM1, reflecting a more reticular pattern of fat infiltration vs. the confluent pattern in DM1. CONCLUSION:In this proof-of-concept study, 3D radiomic texture analysis of PDFF(%) maps revealed distinct spatial patterns of fat replacement in DM1 and CMT1A. Integrating radiomic and conventional qMRI features may enhance the non-invasive distinction between DM1 and CMT1A and warrants further investigation in a broader range of NMDs.

Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder with significant morbidity and mortality. This study aimed to quantify the socioeconomic burden of DMD in Belgium, assessing direct medical and non-medical costs, indirect costs and health-related quality of life (HRQoL) using the University of Leicester's 8-stage model for DMD. A descriptive, retrospective, cross-sectional burden-of-illness study was conducted at an expert DMD center in Belgium between 02-11-2023 and 16-06-2024. One pediatric and one adult neuromuscular specialist from the University Hospitals Leuven completed an electronic Case Report Form using patient electronic medical records capturing demographics, clinical data, and data on healthcare resource utilization over the prior 12 months. Patients under medical follow-up were invited to participate and provided written informed consent (N = 40). Costs were sourced through the Belgian National Institute for Health and Disability Insurance and the Belgian Center for Pharmacotherapeutic Information. A questionnaire was given to the participants and their parents to collect additional costs, HRQoL, and caregiver burden. The estimated mean annual societal cost per Belgian DMD patient was €134,337, with costs ranging from €115,336 in early disease stages to €153,339 in late disease stages. Direct non-medical costs were the largest contributor, followed by indirect costs, primarily due to loss of productivity. HRQoL declined with disease progression. Caregiver burden remained high across all disease stages. DMD imposes a significant socioeconomic burden on patients, caregivers, and society in Belgium. The findings underscore the importance of improving access to supportive therapies and interventions.

Background Heterozygous variants in SLC12A6 have recently been shown to cause dominant Charcot-Marie-Tooth disease (CMT). We aim to characterise the phenotype of patients with previously reported and novel heterozygous variants in the gene and understand any genotype-phenotype correlation.Methods Patients were clinically and genetically assessed in sites from Europe, Australia, Brazil and the USA. All patients underwent whole exome or whole genome sequencing. Variants were classified using American College of Medical Genetics and Genomics criteria.Results Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants. Forty-eight percent (11/23) were male with a mean age of disease onset of 15.7 years (range 1-45 years). Clinical phenotype varied dramatically with genotype; Arg207His and Ser647Pro caused a severe childhood-onset, sensory and motor, conduction-slowing neuropathy, whereas Gly552Asp caused a mild, adult-onset, sensory-predominant neuropathy, Thr991Ala an infantile-onset motor neuropathy, and the Met282Lys/Gly286Cys locus a complex, axonal neuropathy.Conclusions Heterozygous variants in SLC12A6 can cause CMT of all clinical phenotypes, severity and age of onset, depending on the genotype. Such phenotypic diversity has not been described for any other CMT gene, and more work is needed to understand disease mechanisms to guide future therapeutic options.

ABSTRACT Objective Sarcoglycanopathies are among the most severe limb‐girdle muscular dystrophies (LGMD), though milder presentations have been described. These diseases are primarily caused by missense variants, but the limited predictability of their effect on protein maturation, complex formation, and transport has hindered reliable genotype–phenotype correlations. This study aimed to establish accurate genotype–phenotype correlations for LGMDR3, LGMDR4, and LGMDR5. Methods We analyzed the largest sarcoglycanopathy cohort to date (n = 541). Clinical data, including age at symptom onset and loss of ambulation, were collected and used to define phenotype severity. Predictive models were developed considering the impact of non‐truncating variants on secondary structure, functional domains, evolutionary conservation, and intra‐complex protein–protein interactions. Patients carrying two variants predicted to disrupt membrane trafficking were expected to present with severe phenotypes. Results For LGMDR3, the best‐performing model classified variants affecting β‐sheets, cadherin‐like, and ATP‐binding domains as disruptive to membrane translocation, achieving 89% predictive power, 0.867 balanced accuracy, and 2.4% false‐negative rate (clinically severe patients who were wrongly classified by the model as mild). For LGMDR4 and LGMDR5, the best‐performing model involved conserved residues, β‐sheets, EGF‐like domain, and protein–protein interactions—reaching 80% predictive power, 0.689 balanced accuracy, and 3.1% false‐negative rate (LGMDR4), and 90% predictive power, 0.536 balanced accuracy, with no false negatives (LGMDR5). Additionally, we developed an open‐access predictive tool for clinical and research application. Interpretation This study provides a robust genotype–phenotype correlation for sarcoglycanopathies, improving prognosis, patient management, and clinical trial recruitment.

BACKGROUND AND OBJECTIVES:Adult-onset myotonic dystrophy type 1 (DM1) is a progressive, multisystemic disorder, characterized by distal muscle weakness and myotonia. As disease-modifying therapies emerge, robust and sensitive outcome measures are urgently needed. This study characterized the natural history of adult-onset DM1 over 2 years and evaluated quantitative MRI (qMRI) and clinical outcome measures for clinical trials. METHODS:This prospective, monocentric study assessed patients with genetically confirmed adult-onset DM1 and age-matched and sex-matched healthy controls at baseline and 12, 18, and 24 months. qMRI measured proton density fat fraction (PDFF, %) and T2H2O (ms) of 18 proximal and 10 distal leg muscles using 3D segmentation. Clinical outcomes included 32-item motor function measure (MFM32), 6-minute walk distance (6MWD), 10-meter walk test, 30-second sit-to-stand, 9-hole peg test, hand opening time, MRC sum score, hand grip and pinch dynamometry, and peak cough flow. Patient-reported outcome measures included DM1-ActivC, Individualized Neuromuscular Quality of Life (INQoL), Brief Pain Inventory, and Fatigue and Daytime Sleepiness Scale. RESULTS:Thirty patients (median 38 years, 60% female, Muscular Impairment Rating Scale 3-4) and 30 matched controls were included. Baseline PDFF (%) was significantly higher in patients with distal (31.8% vs 5.9%, p < 0.001) and proximal (13.0% vs 7.6%, p < 0.001) leg muscles. T2H2O was significantly elevated in the distal leg muscles (+3.3, p < 0.001). Over 24 months, PDFF (%) increased significantly in 9 of 10 distal and 15 of 18 proximal muscles. Distal leg PDFF (%) showed the largest progression (+3.5%, 95% CI 2.9-4.1, standardized response mean [SRM] = 1.6), with significant changes detectable within 6-month intervals (+1.0%, 95% CI 0.4-1.6, SRM = 1.1). T2H2O remained stable. MFM32 (-3.2, -6.7, -7.3; SRM = 0.8, 1.9, 1.8) and MRC sum score (-5.0, -7.6, -9.6; SRM = 1.1, 1.4, 1.6) declined at 12, 18, and 24 months (p < 0.001). DM1-ActivC declined significantly at 12, 18, and 24 months (24 months: -10.3, 95% CI -14.0 to -6.7; SRM = 0.8). INQoL overall quality of life deteriorated significantly at 12 months (+5.4, 95% CI 0.8-10.0) and 18 months (+6.9, 95% CI 2.0-11.8), but not at 24 months. Distal leg PDFF (%) correlated strongly with 6MWD (ρ = -0.81) and MFM32 D1 (ρ = -0.75). DISCUSSION:PDFF (%) is a sensitive, objective outcome measure for adult-onset DM1, detecting change within 6-month intervals. MFM32, MRC sum score, DM1-ActivC, and INQoL demonstrate meaningful deterioration over 12-24 months, supporting their combined use with qMRI as outcomes in future trials for adult-onset DM1.

One of the main obstacles to deploying deep learning (DL) based segmentation models for analysis of MR images in clinical routine practice is their limited ability to generalize across different scanners and imaging protocols. Variability in MRI hardware and acquisition settings, such as field strength, gradient performance, and sequence parameters, can significantly affect image characteristics, making DL models trained under controlled conditions less robust in real-world clinical environments. In the diagnosis of neuromuscular diseases (NMD), Dixon MRI is a widely used imaging protocol for the assessment of muscular fattening due to its ability to separate fat and water signals by exploiting the slight frequency difference between fat and water protons.1 Dixon MRI yields several images with different contrast: in-phase (IP), out-of-phase (OP), fat-only (F), and water-only (W), from which the proton density fat fraction (PDFF) image is calculated as F/F+W. Per muscle 3D fat fraction (%FF) can then be quantified from the PDFF image provided that a 3D segmentation of each muscle in the Dixon MRI images is available.2 In our center, a variety of Dixon MRI protocols and scanners are used depending on the clinical context. Diagnostic scans, where speed is essential, typically use 2-point or 3-point Dixon sequences. In contrast, clinical studies prioritize accurate fat quantification and therefore employ 6-point Dixon imaging.3 The use of both 1.5T and 3T scanners further increases protocol diversity, underscoring the need for segmentation models that can generalize across these variations. In existing literature, a range of combinations of Dixon image types have been used as input to convolutional neural networks (CNNs) for 3D muscle segmentation. Some studies use the F and W images,4-6 while others include the IP and OP images,7 or rely solely on the IP8 or F9 images. This diversity in input strategies reflects the lack of consensus on the optimal image type combination for robust segmentation performance. This study investigates the generalizability of muscle segmentation models trained on Dixon MRI images of the proximal leg and examines the impact of the choice of different input image types on the robustness of model performance across different datasets acquired with different acquisition setups.

Conventional therapies for acetylcholine receptor antibody-positive (AChR-Ab+) generalized Myasthenia Gravis (gMG) often provide inadequate disease control. Although neonatal Fc receptor (FcRn) inhibitors have proven effective in clinical trials, real-world evidence on their use and effectiveness in heterogeneous patient populations is still limited. This study evaluates clinical outcomes, steroid-sparing effects, and treatment utilization of efgartigimod in patients with refractory AChR-Ab+ gMG. We conducted a retrospective analysis of 27 adult patients with AChR-Ab+ gMG treated with efgartigimod. Effectiveness, treatment utilization and long-term outcomes were evaluated over seven treatment cycles using longitudinal Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, inter-cycle interval duration, daily corticosteroid dosing, need for rescue therapies, and transition to other advanced therapies. In total, 130 treatment cycles were analyzed. Overall, the patients showed rapid and sustained clinical improvement. Baseline MG-ADL scores (EMM = 8.48) significantly decreased by 2.96 points by cycle-2 (p < 0.001), reaching maximum reduction of 3.95 points by cycle-6. Severe impairment (MG-ADL ≥ 10) decreased from 41% at baseline to 0% by cycle-5, while 66% of patients achieved mild symptoms (MG-ADL 2-4) or Minimal Symptom Expression by cycle-7. Significant corticosteroid-sparing effect occurred by cycle-3 (p = 0.023), with mean daily methylprednisolone doses decreasing from 5.8 mg at baseline to 2.3 mg by cycle-5. Four patients (15%) were non-responders and transitioned to complement inhibition therapy. Real-world efgartigimod use provides rapid symptomatic relief and significant corticosteroid reduction in patients with refractory AChR-Ab+ gMG. While most achieve sustained improvement, non-responders and patients with history of myasthenic crises require close monitoring and potential transition to alternative advanced therapies.

We determined the proportion of adults with late-onset Pompe disease (LOPD) with clinically important changes in 6-minute walk distance (6MWD) and/or forced vital capacity (FVC) after switching from alglucosidase alfa (alg) to cipaglucosidase alfa plus miglustat (cipa+mig) in PROPEL (NCT03729362). This post hoc analysis (95 patients) used published anchor- and distribution-based minimal clinically important differences for 6MWD (in meters for anchor-based; % predicted for distribution-based) and a 3 % threshold for FVC (% predicted). For 6MWD, a higher percentage of patients improved after switching to cipa+mig versus alg plus placebo (alg+pbo) (anchor-based: 29.2 % versus 13.3 %; distribution-based: 33.8 % versus 13.3 %), fewer patients worsened (anchor-based: 12.3 % versus 26.7 %; distribution-based: 7.7 % versus 13.3 %). For FVC, 27.7 % versus 0.0 % improved for cipa+mig versus alg+pbo, 27.7 % versus 53.3 % worsened. Overall, 50.8 % versus 13.3 % of patients experienced improvements in 6MWD (% predicted) and/or FVC with cipa+mig versus alg+pbo, 30.8 % versus 56.7 % worsened. For combined responses from 6MWD (% predicted) and FVC (% predicted), the odds of a better versus a lower response category (improvement > stability > worsening) were 4.05 (95 % confidence interval 1.73-9.51) times higher for cipa+mig than alg+pbo (P = 0.0013). Adults with LOPD switching from alg to cipa+mig have greater chances of clinically relevant motor and lung function improvements than those remaining on alg.

BACKGROUND:In the global Vivacity-MG3 study, nipocalimab (30-mg/kg loading dose; 15-mg/kg every-2-weeks) demonstrated sustained disease control versus placebo plus standard-of-care for generalized myasthenia gravis (gMG); this post-hoc analysis evaluated nipocalimab efficacy for participants with moderate-to-severe ocular symptoms (baseline score of ≥2 points on either ocular-domain item of MG-activities-of-daily-living [MG-ADL]). RESEARCH DESIGN AND METHODS:Mean MG-ADL and Quantitative Myasthenia Gravis total scores change-from-baseline (CFB) through Week (W)24 were assessed using ANCOVA. W24 percentages of participants with ≥2-point improvement in MG-ADL total (meaningful-within-person-improvement) or ocular-domain scores were compared using odds ratios (OR). Longitudinal odds of ≥2-point ocular-domain improvement were evaluated using generalized-estimating-equations logistic models. RESULTS:Nipocalimab (n = 54/77) and placebo-treated (n = 51/76) participants with moderate-to-severe ocular symptoms had similar baseline (mean [SD]) MG-ADL total (10.1 [2.8]; 9.4 [1.9]); ocular-domain scores were 4.1 (1.2); 3.5 (1.0). At W24, LS-mean (SE) CFB for nipocalimab versus placebo were -4.71 (0.50) versus -3.24 (0.50), p = 0.042 (MG-ADL total) and median (IQR) -2.00 (-3.0 to -0.5) versus -1.00 (-1.5 to 0.0), p = 0.024 (ocular-domain). W24 ≥ 2-point ocular-domain improvements were observed with nipocalimab (40.7%) versus placebo (19.6%; OR = 3.47 [95% CI = 1.34-8.97]; p = 0.010). Adverse events: 77.8% (nipocalimab) and 76.5% (placebo). CONCLUSION:These hypothesis-generating results suggest that nipocalimab may provide sustained disease control, reduce ocular symptoms, and improve activities-of-daily-living versus placebo in participants with gMG and moderate-to-severe ocular symptoms. CLINICAL TRIAL REGISTRATION:www.clinicaltrials.govidentifier is NCT04951622; www.clinicaltrialsregister.euidentifier is 2020-005732-29.

Given the intimate link between muscle function and the skeleton's ability to adapt to mechanical loads, it is no surprise that individuals with neuromuscular disorders (NMDs) are at risk for low-trauma (i.e., osteoporotic) fragility fractures. In this review, we highlight the interdependent relationship between muscle and bone strength and the need to assess individuals with NMD who demonstrate muscle weakness that interferes with weight bearing and typical activities of daily living. This review also emphasizes the importance of the clinical context when evaluating the risk of bone fragility, as well as the potential to reclaim bone strength in the absence of bone-targeted therapy. Indeed, longitudinal skeletal phenotyping is key to understanding the individual's bone health trajectory and the need for progressive intensification (or de-escalation) of osteoporosis prevention and treatment. Overall, osteoporosis management has moved away from a bone mineral density (BMD)-centric approach to a fracture-focused approach, with vertebral fractures a clear indicator for bone-strengthening therapy (recognizing that they are frequently asymptomatic, necessitating periodic spine imaging for their timely identification). BMD assessments help guide the frequency of spine imaging and response to bone-targeted therapy and are best undertaken at multiple skeletal sites given the potential for "regional osteoporosis." Multidisciplinary osteoporosis prevention and treatment, including an expert in skeletal health, is the cornerstone of effective osteoporosis management. Looking forward, the field is shifting from secondary osteoporosis prevention to a more proactive, anticipatory approach in those with persistent risk factors, one that involves initiation of bone-targeted therapy prior to first-ever fractures.

BACKGROUND AND OBJECTIVES:Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a slowly progressive demyelinating neuropathy with distal muscle weakness and atrophy. Sensitive, objective outcome measures are needed for future clinical trials. We aimed to identify responsive imaging and clinical biomarkers in CMT1A over 24 months. METHODS:In this prospective, monocentric natural history study, ambulatory adults with genetically confirmed CMT1A and healthy controls were enrolled for 3 visits (baseline, 12, and 24 months). Quantitative muscle MRI quantified proton density fat fraction (PDFF, %) and disease activity with water T2 (T2H2O, ms), using automated 3D whole-muscle segmentation of 18 proximal and 10 distal leg muscles. Clinical outcomes comprised the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), Overall Neuropathy Limitations Score, 32-item Motor Function Measure (MFM32), 6-Minute Walk Distance (6MWD), 10-Meter Walk Test (10MWT), 30-Second Sit-to-Stand, 9-Hole Peg Test (9HPT), MRC sum score, and isometric strength testing. Patient-reported measures included the Individualized Neuromuscular Quality of Life (INQoL), ActivLim, Fatigue Severity Scale, and Brief Pain Inventory. RESULTS:Thirty-three patients with CMT1A (43.8 years, 64% female) and 33 controls (42.2 years, 61% female) were included. At baseline, PDFF (%) was elevated in CMT1A across all leg muscles (p < 0.001). Distal leg PDFF (%) increased at 12 months (+1.1%, 95% CI 0.7-1.4, p < 0.001) and 24 months (+2.1%, 95% CI 1.4-2.8, p < 0.001). T2H2O in the anterolateral distal compartment increased at 12 months (+1.2 ms, 95% CI 0.3-2.1, p < 0.001) and 24 months (+1.5 ms, 95% CI 0.4-2.6, p < 0.001). Proximal leg PDFF (%) and T2H2O remained largely stable. The MFM32 total score declined at 12 months (-3.4%, 95% CI -4.1 to -2.6, p < 0.001) and 24 months (-5.8%, 95% CI -6.9 to -4.7, p < 0.001). INQoL scores worsened at 12 months (+15.1, 95% CI 10.0-20.2, p < 0.001) and 24 months (+23.6, 95% CI 18.8-28.7, p < 0.001). The 9HPT (+2.0s, 95% CI 0.5-3.4, p < 0.05) and CMTNSv2 (+3.3, 95% CI 2.2-4.5, p < 0.001) worsened at 24 months. Baseline distal leg PDFF (%) correlated with age, disease duration, 6MWD, 10MWT, MFM32, and MRC sum score. DISCUSSION:Distal leg PDFF (%) from 3D whole-muscle segmentation detects CMT1A progression within 12 months. Combined with the MFM32 and INQoL, these measures enable sensitive 12-month endpoints for future clinical trials in adults with CMT1A.

IntroductionHereditary transthyretin amyloidosis (hATTRv) is a rare, genetic, adult-onset, multisystemic disorder which can affect diverse organs, including peripheral nerves, heart, kidneys, gastrointestinal tract, liver, skin and eyes. Currently, several disease-modifying treatments for hATTRv are available in Belgium including the TTR stabilizer tafamidis and TTR mRNA silencers patisiran and vutrisiran. Patisiran contains a small interfering RNA encapsulated into a lipid nanoparticle to deliver to hepatocytes, the main source of TTR protein production, thereby reducing TTR production.MethodsWe report and discuss five cases of hATTRv in different clinical scenarios that were successfully managed with patisiran, highlighting our real-world clinical practice.ResultsThese cases illustrate that patisiran is effective to improve mild symptoms and stabilize the moderate ones. The cases also highlight the importance of red flags recognition to allow early diagnosis and treatment to prevent further disease progression.ConclusionDue to the multisystemic nature of the disease and its heterogeneous clinical presentation, close collaboration between neurologists and cardiologists is highly recommended, ideally within a multidisciplinary amyloidosis team, to provide holistic care in hATTRv patients.

Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicentre phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available. In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C>A (p.Ala153Asp), while other variants were identified, mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy. Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score <= 1). One-fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in a quarter of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion). In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.

ABSTRACT Objective This phase 3b, open‐label, randomized ADAPT NXT study investigated the efficacy, safety, and tolerability of efgartigimod administered in either a fixed cycles dosing regimen (3 cycles of 4 once‐weekly infusions, with 4 weeks between cycles) or a cycle followed by every‐other‐week (Q2W) dosing. Methods Adult participants with anti‐acetylcholine receptor antibody‐positive generalized myasthenia gravis (gMG) were randomized 3:1 to Q2W or fixed cycles dosing of efgartigimod (10 mg/kg intravenously) for 21 weeks. The primary endpoint was the mean change from baseline in total Myasthenia Gravis Activities of Daily Living (MG‐ADL) score averaged across 21 weeks. Results Sixty‐nine participants were treated (fixed cycles, n = 17; Q2W, n = 52). Least squares (LS) mean (95% CI) of the change from baseline in MG‐ADL total score from Weeks 1 to 21 was −5.1 (−6.5 to −3.8) in the fixed cycles arm and −4.6 (−5.4 to −3.8) in the Q2W arm. Clinical improvements were observed in MG‐ADL total scores as early as Week 1 and were maintained throughout the study. Achievement of minimal symptom expression (MG‐ADL: 0–1) from Weeks 1 to 21 occurred in 47.1% (n = 8/17) and 44.2% (n = 23/52) of participants in the fixed cycles and Q2W arms, respectively. Efgartigimod was well tolerated; COVID‐19, headache, and upper respiratory tract infection were the most common treatment‐emergent adverse events. Interpretation Efgartigimod administered as either fixed cycles or Q2W dosing results in rapid, robust, and sustained clinically meaningful improvement. These results build upon previous studies and provide additional efgartigimod dosing approaches to achieve and sustain clinical efficacy in patients with gMG.

Background and Objectives:Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression. Methods:Muscle biopsy images and data were collected retrospectively from adults (≥18 years) with pathogenic or likely pathogenic VCP variants enrolled in the VCP Multicentre International Study. Biopsy data were standardized using the "Common Data Elements for Muscle Biopsy Reporting." Variations in biopsy findings were analysed by biopsy site, time from disease onset, the four most common VCP variants, and clinical phenotypes. Result:A total of 112 muscle biopsies were included. Most individuals were male (66.0%). The mean age at biopsy was 53.3 years (SD 10.0), with a mean disease duration of 6.5 years (SD 4.5). The most frequent VCP variant was c.464G>A (p.Arg155His) (18.8%). The top clinical phenotypes were isolated myopathy (37.5%), myopathy with Paget disease of bone (17.9%), and myopathy with motor neuron involvement (13.4%). The vastus lateralis was the most common biopsy site (34.8%), and 91% were open biopsies. Histopathologic findings included atrophic fibres (87.5%), rimmed vacuoles (72.3%), endomysial fibrosis (58.0%), and protein aggregates (51.8%), primarily p62 (60.3%) and VCP (36.2%). Degeneration niches with fibrofatty replacement and atrophic fibres were seen in 33.3% of biopsies without frequency differences by clinical phenotypes. There were no differences in biopsy findings among the 4 most common VCP gene variants, except for the absence of degeneration niches in muscle biopsies of 12 patients with c.277C>T (p.Arg93Cys). MRI data from 30 patients showed fat pockets corresponding to these niches and STIR hyperintensity correlated with inflammatory infiltrates in 42.9%. Concordance between clinical phenotype, biopsy, and neurophysiology was observed in only 49.4% of cases, indicating significant heterogeneity. Discussion:VCP-MSP muscle biopsies consistently show myopathic or mixed patterns with rimmed vacuoles and p62/VCP-positive inclusions, regardless of clinical phenotype, age, or progression. Some lack vacuoles, challenging diagnosis. Discrepancies between clinical, neurophysiology, and biopsy findings should prompt consideration of VCP-MSP to improve detection and management.

Background: Titin, the largest human protein, is essential for sarcomere structure and function. The TTN gene, spanning 364 exons, undergoes extensive alternative splicing thus producing multiple isoforms. The M-band region, encoded by exons 359-364, plays a critical role in sarcomere integrity and mechanical stability. Exon 363 is of interest due to its involvement in titinopathies. Pathogenic truncating variants in this exon have been linked to recessive myopathies, including and mainly young-onset recessive distal titinopathy. Methods: A multicenter study was conducted on six patients from five unrelated families with confirmed recessive titinopathy and truncating variants in exon 363. Clinical evaluations were performed. Genetic testing and segregation analysis confirmed the phase of the variants. Results: A novel truncating variant c.107578C>T, p.(Gln35860Ter) was identified in four unrelated patients of Eastern European ancestry, all carrying a second pathogenic variant in a canonical TTN exon. These patients exhibited juvenile/young-adult onset recessive distal titinopathy with progressive lower limb weakness, frequently asymmetric muscle involvement, and no cardiac or respiratory complications. A Belgian family presented with a congenital myopathy caused by a novel frameshift deletion c.107430delA, p.(Ser35811AlafsTer32) in exon 363, in compound heterozygosity with a truncating variant in exon 208. These patients showed a more severe phenotype. Conclusions: This study expands the spectrum of TTN-related myopathies, emphasizing exon 363's pathogenic significance. Truncating exon 363 variants contribute to young onset recessive distal and sometimes early onset titinopathy with contractures, and the phenotype severity is influenced by the second variant's location and exon usage.