John Vissing

Limb‐girdle muscular dystrophy type D4 is caused by a single pathogenic variant of the CAPN3 gene coding for calpain‐3 and is clinically milder than the more common recessive form, type R1. It is likely underdiagnosed, and expanding the phenotype–genotype relationship is needed to establish a clinical guideline for this disorder.

Introduction/Aims: Patients with McArdle disease demonstrate exercise intolerance with muscle contractures and episodic rhabdomyolysis. Additionally, some patients show progressive fat replacement of paraspinal and shoulder muscles with aging. The cause of fat replacement in older McArdle patients is unknown but could relate to a higher glycogen accumulation in these muscles in line with what is found in Pompe disease. The aim of the study was to investigate if this is also the case in McArdle disease, which could imply that excess levels of glycogen accumulation are a potential driver of fat replacement of muscle. Methods: Using 7 Tesla ¹³ C magnetic resonance spectroscopy, we measured glycogen noninvasively in lumbar, thigh, and calf muscles in 14 patients with McArdle disease and 19 healthy controls. Results: Patients with McArdle disease showed increased levels of glycogen in all muscles compared to controls; calf (3.2 times normal, p < 0.005), hamstrings (2.7 times normal, p < 0.005), anterior thigh compartment (2.7 times normal, p < 0.005), and lumbar muscle (2.1 times normal, p < 0.005). Glycogen was evenly distributed among muscle groups in both patients with McArdle disease and healthy controls. Discussion: Our results are in line with previous studies showing two to three times increased glycogen compared to control in muscle biopsies. We found no variability in glycogen concentration among muscles that could indicate glycogen as a predictor of muscle injury in McArdle disease.

Objective: Adults with cerebral palsy (Gross Motor Function Classification System, GMFCS, levels III–V) have severely impaired motor function, causing fatigue, pain, constipation, and sleep disturbance, reducing life quality. Whether standard exercise is feasible or beneficial in this population is unknown, as spasticity, low muscle mass, and cognitive challenges may limit participation. Unable to engage in conventional exercise, they require tailored modalities. This study investigated whether assisted cycling is feasible and could improve key symptoms. Methods: 14 adults with cerebral palsy (GMFCS III-V) completed a 10-week control period and 10 weeks of supervised, assisted cycling (3 x 20 min/week). Assessments at baseline, post-control, and post-exercise included key symptoms, feasibility, Gross Motor Function Measure-88, and a timed 1-km cycle test (time, power output, cadence). Results: Median attendance was 24/30 sessions. Heart rate increased during exercise (median 25.5 bpm). No significant group-level changes were observed, but individual improvements in pain, constipation, and power output were observed in some. Two participants experienced moderate adverse events affecting daily living. Conclusion: Assisted cycling is feasible and generally well tolerated in non-ambulant adults with cerebral palsy. While no group-level effects were detected, exploratory individual improvements in symptoms and cycling performance were observed in some, supporting further research on tailored exercise.

Objectives: Peripheral neuropathy (PN) is considered a frequent complication of Waldenström's macroglobulinemia (WM). Establishing a causal relationship between PN and WM is complicated by confounding factors such as age‐related axonal loss and diabetes. This scoping review aims to summarize the current evidence on WM‐associated PN with a focus on prevalence, phenotype, and disability. Methods: We searched PubMed, Embase, Web of Science, CINAHL, and Cochrane Library and included studies describing either prevalence, phenotype, and/or disability of adults with WM and PN. Results: Thirty‐four studies were eligible for inclusion where most studies were retrospective case series. The most frequently reported phenotype was a sensory axonal PN while demyelinating PN only ranged from 8% to 37.5% in unselected WM cohorts. Eight different disability scales were used, primarily in anti‐MAG studies. Prevalence of WM‐associated PN ranged from 0% to 52% where small cross‐sectional studies reported higher prevalence than larger retrospective studies. Conclusion: Our findings suggest PN in WM is a frequent complication often presented as a sensory axonal PN. Interpretation of results is confounded by referral bias, lack of PN definition, missing clinical and electrophysiological examination, and limited comparable disability measures across PN subtypes. This review underscores the need for a definition of WM‐associated PN.

Limb-girdle muscular dystrophy type 2I (LGMD2I/R9) is caused by biallelic variants in the gene for Fukutin-related protein (FKRP), an enzyme required for proper glycosylation of α-dystroglycan (⍺DG), a critical structural protein of the dystrophin glycoprotein complex. Hypoglycosylation of αDG results in impaired function of αDG, which in turn leads to chronic myocyte injury and muscular dystrophy. The “Biomarker Development in LGMD2I/R9” (MLB-01-001) natural history study explored glycosylated ⍺DG as a muscle biomarker for LGMD2I/R9 to support clinical trial design for the development of potential therapeutics. MLB-01-001 was a prospective, 12-month observational study of clinically affected participants 10–65 years of age with genetically confirmed LGMD2I/R9 at 11 academic centers in the United States and Denmark. Tibialis anterior (TA) muscle biopsies were obtained at baseline, month 6, month 9, and/or month 12 and measured for glycosylated ⍺DG levels relative to that of an unaffected human control using a validated, quantitative western blot assay. Of 96 participants enrolled, 71 participants underwent at least 1 TA biopsy (54 homozygous for the c.826C>A variant and 17 with other FKRP genotypes). Participants who were homozygous for the c.826C>A variant tended to be older, to be composed of a higher percentage of females, to have had less time since diagnosis, and to be composed of a greater percentage of ambulatory participants than those who had other FKRP genotypes. Glycosylated ⍺DG levels were consistently lower in LGMD2I/R9 participants than in the control at baseline (median 8.5% of control, interquartile range [IQR] 10.8%) and reflected disease severity by genotype, with c.826C>A homozygotes showing higher median glycosylated ⍺DG levels (10.5% of control, IQR 10.9%, n = 54) than participants with other FKRP genotypes (4.6% of control, IQR 4.3%, n = 17). Glycosylated αDG levels remained stable over 6–12 months. Glycosylated ⍺DG was consistently lower in participants with LGMD2I/R9 than in the unaffected control, reflected disease severity by genotype, and remained stable over 6–12 months, suggesting that it may be an appropriate biomarker for assessing the effect of potential therapies for LGMD2I/R9. ClinicalTrials.gov ID NCT04202627, first posted 17 Dec 2019.

Background: Patients with generalized Myasthenia Gravis (gMG) may develop respiratory involvement, which can be life-threatening. In clinical practice, the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) is often used to assess patient-reported respiratory impairment, as spirometry can be time-consuming and require specialized equipment and expertise. However, it is unclear whether the MG-ADL is a sufficient screening tool for identifying respiratory insufficiency. Methods: In this cross-sectional study with a longitudinal subgroup, patients completed the MG-ADL, the Myasthenia Gravis Composite scale (MGC), and the Quantitative Myasthenia Gravis score (QMG). As a part of the QMG, spirometry was conducted. All patients had one evaluation, and a subgroup of patients had an additional evaluation after 3 years. Results: One hundred patients were screened, and 70 were included and tested. Of these, 25 were retested 3 years later. Respiratory symptoms were reported by 30 (43%) of the 70 patients, though none reported severe symptoms. There was a poor correlation ( r = − 0.24, p = .048) between the respiratory item of the MG-ADL and spirometry. Patients with respiratory insufficiency showed improvement over time, as did the MGC score. Conclusions: Our findings indicate limited agreement between patient-reported respiratory symptoms (MG-ADL) and spirometry measures, suggesting that spirometry remains essential for accurate assessment of respiratory function in gMG.