The option of tracheostomy and prolonged invasive mechanical ventilation (IMV) for chronic respiratory failure in myotonic dystrophy type 1 (DM1) poses challenges in decision-making. The Myotonic Dystrophy Foundation consensus recommendations on respiratory management do not directly address the implications of this intervention given the progressive physical and cognitive manifestations of DM1. Here, we consider IMV in DM1 using the ethical principles of beneficence, non-maleficence, autonomy and justice. We call for further research on post-tracheostomy morbidity, mortality, and quality of life (QOL) to help guide decision-making. Our ethical analysis has yielded programmatic changes we hope will improve patient outcomes.
Background/ObjectivePathogenic 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.MethodsThis 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.ResultsMyocardial 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.ConclusionsDixon 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.
BACKGROUND AND OBJECTIVES: While there has been an increase in Duchenne muscular dystrophy (DMD) clinical trials over the last couple of decades, there is still no cure. Many individuals with DMD spend much of their lives participating in clinical trials. The impact of clinical trial participation on quality of life (QoL) is not well understood. This study aimed to understand the aspects of clinical trial participation that impact QoL for families affected by DMD. METHODS: Qualitative interviews were conducted with patients aged ≥ 12 years and caregivers using a semi-structured interview guide. Participants described the clinical trial factors that impacted QoL and rated the impact of each factor using a 7-point Likert scale. Transcripts were single coded for themes. A Participant-Specific Total Impact Factor (PSTIF) score was derived using the mean score across factors identified as impacting QoL. Agreement was calculated using Cohen's Kappa between PSTIF score and the participant's reported net trial experience (positive, neutral, or negative). RESULTS: A total of 24 caregivers and 7 patients participated. Participants mentioned 23 clinical trial factors with an impact on QoL. While most participants (82%) had a negative PSTIF score, the majority (65%) described a positive overall experience with clinical trials. There was poor agreement (Kappa = 0.12) between PSTIF score and net clinical trial experience. CONCLUSION: When patients and caregivers quantified the impact of specific clinical trial factors on QoL, the impact was primarily negative; however, the majority of participants described their overall trial experience as positive. The study's findings have implications for the collection and interpretation of QoL data in interventional studies.
BACKGROUND: Pediatric female dystrophinopathy may be asymptomatic at evaluation or may show skeletal muscle and cardiac manifestations, but childhood presentations are often subtle. We aimed to characterize the clinical spectrum, ascertainment pathways, subclinical muscle involvement, and inheritance patterns in this population. METHODS: This single-center retrospective case series was conducted between January 2024 and December 2025 and included 35 girls with genetically confirmed DMD gene variants identified from existing clinical records. Primary ascertainment route was recorded separately from cross-sectional clinical status at evaluation and classified as symptom-driven presentation, incidental or unexplained hyperCKemia, family-based cascade screening, or incidental genomic discovery. Clinical status at evaluation was assigned after systematic clinical review with reference to published female dystrophinopathy classifications. Statistical analyses were exploratory. RESULTS: The median age was 5 years (range, 1-10). Primary ascertainment routes were symptom-driven presentation in 8/35 (22.9%), incidental or unexplained hyperCKemia in 18/35 (51.4%), family-based cascade screening in 8/35 (22.9%), and incidental genomic discovery in 1/35 (2.9%). After systematic clinical review, clinical status at evaluation was classified as asymptomatic in 29 participants, BMD-like in 1, DMD-like in 3, and cardiac-symptom/CMR observations in 2. All 18 girls initially identified through incidental or unexplained hyperCKemia were classified as asymptomatic because no muscle weakness was documented on neurological examination, although some had exercise intolerance, easy fatigue, myalgia, or cramps. EMG abnormalities were identified in 14/34 participants, including definite myopathic findings in 5 and subtle short-duration motor-unit-potential changes in 9. Variants were apparently de novo in 15 cases, maternally inherited in 18, and paternally inherited in 2, including one case inherited from a father with low-level mosaicism in peripheral blood. CONCLUSIONS: Pediatric female dystrophinopathy shows a broad childhood spectrum and may be recognized before objective muscle weakness is documented. Separating ascertainment route from clinical status highlights recurrent or persistent hyperCKemia and mild exercise-related complaints as practical entry points for targeted neuromuscular assessment and longitudinal follow-up. Earlier recognition in childhood may support timely neuromuscular and cardiac surveillance, parental evaluation when appropriate, family-based genetic counseling, and future reproductive planning.
Nuclear poly(A)-binding protein N1 (PABPN1) is a poly(A)-binding protein widely expressed in the nuclei of eukaryotic cells. As a key regulator of mRNA 3'-end processing, it participates not only in poly(A) tail synthesis and length regulation but also in alternative polyadenylation (APA). Recent studies have demonstrated that PABPN1 undergoes liquid-liquid phase separation (LLPS) to form dynamic membraneless compartments, such as nuclear speckles and nuclear poly(A) domains (NPADs), and contributes to its physiological functions. Emerging evidence has further implicated PABPN1 in a range of cellular processes. These include downstream consequences of APA dysregulation, such as altered stress responses and cell fate decisions, as well as APA-independent molecular functions, including its direct roles in DNA repair and cell cycle control. Dysregulation of PABPN1 LLPS, driven either by intrinsic expansion of its N-terminal alanine stretch or by altered interactions with regulatory cofactors, promotes a transition from dynamic liquid-like condensates to pathological solid-like aggregates. This phase transition is associated with the pathogenesis of oculopharyngeal muscular dystrophy (OPMD) and contributes to oncogenic APA patterns in various cancers. This review summarizes recent findings on the emerging physiological functions of PABPN1, its phase separation characteristics, and the molecular mechanisms underlying its transition into pathological aggregates.