Nanna Scharff Poulsen

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.

Background: Wheelchair users with muscular dystrophy face health challenges from their condition, sedentary lifestyle, and wheelchair use. While exercise benefits are well-documented in healthy individuals, its effects in wheelchair users with muscular dystrophy are underexplored: low muscle mass might limit exercise benefits. This study investigates benefits and adverse events of assisted leg cycling to improve fatigue, pain, constipation, and quality of life in wheelchair users with muscular dystrophy. Methods: Wheelchair users with muscular dystrophy were tested at baseline, after a 10-week control period, and after 10 weeks of assisted leg cycling (20 minutes, 3 times/week). Efficacy outcomes were changes in fatigue, lower back/leg pain, constipation, and quality of life. Secondary outcomes included changes in exercise performance, cardiovascular response, and metabolic health. A 1.5-year follow-up of voluntary training evaluated long-term effects. Results: Nineteen participants enrolled; two dropped out. Lower back pain and fatigue decreased and physical quality of life improved. Constipation did not change overall but improved in more than half of participants. HbA1c decreased by 2 mmol/mol, mainly in two participants with diabetes. Blood lipids, leg pain, cycling time, and power output showed no changes. Benefits persisted or improved over 1.5 years in participants with a high adherence. Discussion: Assisted cycling may reduce lower back pain, improve quality of life, and possibly decrease fatigue and constipation in wheelchair users with muscular dystrophy. Furthermore, exercise likely lowers HbA1c, particularly in individuals with diabetes. These findings suggest that assisted cycling is a feasible health intervention for wheelchair users with muscular dystrophy.

Background/Objective: Pathogenic variants in the dystrophin gene ( DMD ) cause dystrophinopathies. These variants can cause skeletal and cardiac involvement. Disease progression in skeletal muscle is characterized by fatty replacement, but whether similar processes occur in the myocardium remain unclear. Dixon cardiovascular magnetic resonance (CMR) can quantify myocardial fat fraction (FF). This study used Dixon CMR to quantify myocardial FF in patients with BMD and women carrying DMD gene variants, and to explore associations with cardiac function, assessed by left ventricular ejection fraction (LVEF), age, and skeletal muscle FF. Methods: This cross-sectional study included 20 patients with BMD, 27 women carrying DMD gene variants, and 40 healthy controls who underwent three-point Dixon CMR to quantify myocardial FF. Muscle MRI was performed to assess lower-limb muscle FF. Results: Myocardial FF did not differ significantly among the three groups ( p = 0.11); mean values were 10.0% in patients with BMD, 11.2% in women carrying DMD gene variants, and 10.4% in healthy controls. Subgroup analyses showed no significant differences between patients with BMD and healthy men or between women carrying DMD gene variants and healthy women. Myocardial FF was not associated with LVEF, age, or skeletal muscle FF. Conclusions: Dixon CMR revealed no increase in myocardial FF in patients with BMD or women carrying DMD gene variants compared with healthy controls. Unlike skeletal muscle, myocardial remodeling in dystrophinopathies does not appear to be adipogenic and is likely predominantly fibrotic. Dixon CMR is useful for skeletal muscle imaging but has limited clinical use for myocardial assessment.

Tubulinopathies encompass a spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, spastic ataxia, and recently, an isolated congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation. The coexistence of neuromuscular and neurodegenerative features with protein aggregation defines a multisystem proteinopathy. These two families thus establish the first association between TUBA4A and multisystem proteinopathy. Our cohort exhibited diverse genotypes and inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies showed heterogenous myopathic changes, including myofibre size variation, nemaline bodies, core-like regions, and internal nuclei. Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6). Complementary in silico and in vitro investigations suggested that the identified TUBA4A variants cause significant protein abnormalities and may differentially impact microtubule dynamics. Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.

Background and Objective: Women carrying pathogenic DMD gene variants can develop muscle affection, such as muscle weakness and fat replacement. The long-term progression of the muscle involvement is unknown. This study investigates the 6.5-year changes in muscle function and -fat fraction in women carrying pathogenic DMD gene variants to enhance understanding of disease progression and its natural history. Methods: Muscle structure and -function were investigated at baseline and after 6.5 years in 34 women carrying pathogenic DMD gene variants (19 predicted to confer Duchenne Muscular Dystrophy (DMD), 15 Becker Muscular Dystrophy (BMD)). After a clinical evaluation, muscle fat fraction was assessed using Dixon MRI, muscle strength with isokinetic dynamometry, and muscle biomarkers with blood samples for creatine kinase and myoglobin. Results: Muscle fat fraction in the lower back, thigh, and calf increased significantly over 6.5 years. The average increases were generally less than 2%, but some carriers with significant baseline abnormalities experienced a more substantial increase in fat fraction, reaching as high as 31%. Although overall disease progression did not differ significantly between DMD and BMD carriers, all women who showed rapid progression were DMD carriers. Small but significant changes occurred in muscle strength and biomarkers. Discussion: The progression of muscle involvement in women carrying pathogenic DMD gene variants is generally slow. However, those with severe baseline abnormalities on MRI—often associated with a lower age of symptom onset—experience a more rapid progression of muscle fat fraction, suggesting that baseline MRI findings could help predict future disease progression in this population.

Background: Spinal muscular atrophy (SMA) is a motor neuron disease with loss of musculature, which is replaced by fat. Previous magnetic resonance imaging (MRI) studies have focused on imaging muscles either in lower or upper extremities, but whole-body MRI can provide additional information on the involvement pattern. This study examined whole-body muscle fat replacement and the relationship between muscle structure, function, and bulbar symptoms. Method: We conducted a descriptive, cross-sectional study. We assessed the fat replacement in skeletal muscles using whole-body MRI, the muscle function using the Motor Function Measurement 32, and bulbar muscle strength using the Bulbar Rating Scale. The presence of bulbar symptoms and function was assessed using the Voice Handicap Index, Eating Assessment Tool questionnaires, and a swallowing test. Results: We recruited 20 adult patients with type II and III SMA. The most affected muscles were the psoas major, soleus and rectus femoris, while the least affected muscles were the biceps brachii, deltoideus, and pterygoideus medialis. The tongue was involved in nearly half of the patients. Most patients reported issues with swallowing (75%) and voice (95%) but had relatively preserved strength of bulbar muscles. Conclusion: Certain muscles are more prone to fat replacement than others in SMA, with a predominant proximal–distal and extensor-flexor involvement. Nearly half of the patients had increased fat content in the tongue, which is associated with dysphagia. In addition, most patients retained muscle strength in the bulbar muscles, despite advanced muscle weakness in the rest of the body.

Objective: Wheelchair users with neuromuscular disorders have symptoms related to the disease and complications to the sedentary lifestyle, such as constipation and lower back pain. Physical training might be beneficial. This systematic review investigates the potential benefits and harms of physical training for wheelchair users with neuromuscular disorders. Methods: We systematically searched PubMed including studies published until July 2024. Inclusion criteria: 1) participants with a neuromuscular disorder, 2) at least 60% of participants in a study were wheelchair users, 3) physical training and its effects were investigated, 4) studies were prospective, and 5) English language was used. Non-peer-reviewed articles were excluded. Search results were screened by title, abstract, and full text. Two independent authors assessed the quality with the Downs and Black Quality Index. Results: We included 14 studies of 140 patients from 5 types of neuromuscular disorders (Duchenne muscular atrophy, spinal muscular atrophy, limb-girdle muscular atrophy, facioscapulohumeral muscular dystrophy, and amyotrophic lateral sclerosis). The mean quality was low (16/32) due to flaws in study design, selection bias, and power. Even though many were of low quality and lacked descriptions of adverse events, they all showed positive effects. Most studies investigated physical training of mastication or respiration with improvements in both. Other findings were improvements in endurance, extremity strength, and range of motion. Conclusions: Physical training of wheelchair users with neuromuscular disorders is not well investigated. Physical training seems safe and beneficial, but training of respiratory and masticatory muscles is the only well-documented exercise modality that can be advised in patients with Duchenne Muscular Dystrophy or Duchenne Muscular Dystrophy/Spinal Muscular Atrophy, respectively. Larger, high-quality trials, including other neuromuscular disorders, are needed to assess the effects and adverse events of physical training.

Introduction/Aims: Primary hypokalemic periodic paralysis (HypoPP) can present with periodic paralysis and/or permanent muscle weakness. Permanent weakness is accompanied by fat replacement of the muscle. It is unknown whether the permanent muscle weakness is solely due to fat replacement or if other factors affect the ability of the remaining muscle fibers to contract. We aimed to investigate muscle fat replacement and contractility in persons with HypoPP‐causing variants in CACNA1S and to compare the results to healthy controls.Methods: In this cross‐sectional study, we used T1‐weighted and 2‐point Dixon magnetic resonance imaging (MRI) to assess fat replacement of the muscle and stationary dynamometry to assess muscle strength. Contractility was determined by maximal muscle contraction divided by the contractile cross‐sectional muscle area.Results: We included 45 persons with HypoPP‐causing variants in CACNA1S and data from 37 healthy controls. We found that fat fraction was increased in ankle dorsiflexors and knee extensors and flexors, and further found that muscle strength was decreased in knee extensors and flexors in persons with HypoPP‐causing variants in CACNA1S compared to healthy controls. Additionally, we found decreased contractility of thigh muscles in persons with HypoPP‐causing variants in CACNA1S compared to healthy controls.Discussion: The decreased contractility could relate to skeletal muscle voltage‐gated calcium channel dysfunction, subclinical attacks of paralysis, and/or changed muscle architecture, but this needs further investigation.