Susan T. Iannaccone

Introduction/Aims: Data on respiratory, feeding, ambulatory outcomes and prognostic factors for congenital myopathies (CM) and congenital muscular dystrophies (CMD) remain limited. Therefore, in this study, we report the characteristics of a large single‐center cohort of patients with CM and CMD, focusing on long‐term outcomes and aiming to identify factors associated with invasive ventilation, feeding tube, and wheelchair dependence. Methods: Patients with a diagnosis of CM or CMD evaluated at Children's Health Dallas between 2011 and 2024 were identified using ICD codes and their medical records were reviewed. Genetic, clinical, histopathologic, electrodiagnostic, imaging and laboratory data were collected. Results: There were 145 patients, with the most common genes being RYR1 (29), COL6A1/2/3 (16), MTM1 (16), TTN (15), LAMA2 (14), NEB (12). Of 128 patients above 3 years old, 65 (51%) were ambulatory. Thirty‐three of 145 (23%) required invasive ventilation and 50 of 145 (34%) had a feeding tube. The causative gene significantly correlated with ventilation (Cramer's V 0.46, moderate effect, p < 0.001) and feeding tube (Cramer's V 0.48, moderate effect, p < 0.001) dependence, whereas contractures in multiple joints correlated with wheelchair dependence across the cohort (Cramer's V 0.58, large effect, p < 0.001). Discussion: In this study, the causative gene was the major driver of ventilation and feeding support whereas multiple joint contractures correlated with wheelchair dependence. These results may help guide clinicians in counseling families on respiratory, feeding and ambulatory outcomes; however, prospective multicenter studies are needed to confirm the findings and identify additional prognostic factors.

Nemaline myopathy (NM) is a congenital myopathy with a wide severity spectrum, from severe, generalized muscle weakness and respiratory failure in the neonatal period to mild, distal weakness in young adulthood. Eleven genes have been definitively established to cause the condition. Although some recurrent variants have been identified, the overall correlation of genotype with clinical severity in NM remains poor. This poses challenges when counseling families about prognosis after a diagnosis of NM is made. Better clinical and molecular predictors of outcome are needed for clinical trial readiness. A retrospective cohort analysis of 275 patients with a histopathologic diagnosis of NM and/or pathogenic variants in NM-associated genes was performed to identify relationships between early clinical findings and long-term outcomes, including need for respiratory and feeding support. Early clinical predictors of long-term outcomes were identified: patients with hypotonia at birth had increased odds of requiring gastrostomy tubes, and patients with respiratory distress at birth had increased odds of requiring both gastrostomy tubes and invasive ventilation. Individuals with ACTA1-NM were more likely to require feeding tubes and invasive ventilation in the first year of life compared with those with NEB-related NM, but the odds of requiring invasive ventilation were similar after the first year of age. Additional clinical information is presented by genotype and severity class. Neonatal findings of individuals with NM are correlated with long-term clinical outcomes, and there are some relationships between genotype and disease severity. Prospective longitudinal studies are needed to confirm these findings and evaluate for additional early clinical predictors of prognosis.

Structural variants (SVs) of the nebulin gene (NEB), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathies. Here we provide an overview of 35 families with muscle disorders caused by such SVs in NEB. Using custom Comparative Genomic Hybridization arrays, exome sequencing, short-read genome sequencing, custom Droplet Digital PCR, or Sanger sequencing, we identified pathogenic SVs in 35 families with NEB-related myopathies. In 23 families, recessive intragenic deletions and duplications or pathogenic gains of the triplicate region segregating with the disease in compound heterozygous form, together with a small variant in trans, were identified. In two families the SV was, however, homozygous. Eight of these families have not been described previously. In 12 families with a distal myopathy phenotype (of which 10 are previously unpublished), eight unique, large deletions encompassing 52–97 exons in either heterozygous (n = 10) or mosaic (n = 2) state were identified. In the families where inheritance was recessive, no correlation could be made between the types of variants and the severity of the disease. In contrast, all patients with large dominant deletions in NEB had milder, predominantly distal muscle weakness. For the first time, we establish a clear and statistically significant association between large NEB deletions and a form of distal myopathy. In addition, we provide the hitherto largest overview of the spectrum of SVs in NEB.

Chronic kidney disease (CKD) and the genetic disorder myotonic dystrophy type 1 (DM1) each are associated with progressive muscle wasting, whole-body insulin resistance, and impaired systemic metabolism. However, CKD is undocumented in DM1 and the molecular pathogenesis driving DM1 is unknown to involve the kidney. Here we use urinary extracellular vesicles (EVs), RNA sequencing, droplet digital PCR, and predictive modeling to identify downregulation of metabolism transcripts Phosphoenolpyruvate carboxykinase-1, 4-Hydroxyphenylpyruvate dioxygenase, Dihydropyrimidinase, Glutathione S-transferase alpha-1, Aminoacylase-1, and Electron transfer flavoprotein B in DM1. Expression of these genes localizes to the kidney, especially the proximal tubule, and correlates with muscle strength and function. In DM1 autopsy kidney tissue, characteristic ribonuclear inclusions are evident throughout the nephron. We show that urinary organic acids and acylglycines are elevated in DM1, and correspond to enzyme deficits of downregulated genes. Our study identifies a previously unrecognized site of DM1 molecular pathogenesis and highlights the potential of urinary EVs as biomarkers of renal and metabolic disturbance in these individuals.

Introduction: Structural variants (SVs) of the nebulin gene ( NEB ), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathies. Here we provide an overview of 35 families with muscle disorders caused by such SVs in NEB . Methods: Using custom Comparative Genomic Hybridization arrays, exome sequencing, short-read genome sequencing, custom Droplet Digital PCR, or Sanger sequencing, we identified pathogenic SVs in 35 families with NEB -related myopathies. Results: In 23 families, recessive intragenic deletions and duplications or pathogenic gains of the triplicate region segregating with the disease in compound heterozygous form, together with a small variant in trans, were identified. In two families the SV was, however, homozygous. Eight families have not been described previously. In 12 families with a distal myopathy phenotype, eight unique, large deletions encompassing 52 to 97 exons in either heterozygous (n = 10) or mosaic (n = 2) state were identified. In the families where inheritance was recessive, no correlation could be made between the types of variants and the severity of the disease. In contrast, all patients with large dominant deletions in NEB had milder, predominantly distal muscle weakness. Discussion: For the first time, we establish a clear and statistically significant association between large NEB deletions and a form of distal myopathy. In addition, we provide the hitherto largest overview of the spectrum of SVs in NEB .

Introduction Studies have reported health-related quality-of-life impacts of Duchenne muscular dystrophy (DMD); however, further research is needed to understand how those with DMD experience their condition and how psychosocial impacts evolve over time in response to disease progression. This qualitative study explores the social and emotional implications of key transitions, challenges and adaptations throughout the disease course from the perspective of patients and family caregivers. Methods Semi-structured interviews were conducted with men and boys with DMD, and/or their caregivers, in the USA. Thematic analysis was used to examine patterns in data collected across the interviews. Results Nineteen participants were included. Three major themes were identified: (1) barriers to participation are multifaceted; (2) an emotional journey shaped by ‘inevitable progression;' (3) family provides critical tangible and emotional support. This study illustrates that psychosocial impacts of DMD are shaped by knowledge of the condition’s natural history alongside other factors including the extent of social barriers, personal growth and adaptation, and family support. Conclusions Findings provide insight into the strength and resilience with which individuals and their families respond to daily challenges and major clinical milestones and highlight the relative importance of loss of upper limb function as a transition in DMD affecting health-related quality-of-life.

Introduction Spinal muscular atrophy (SMA) is a genetic, neuromuscular disease caused by deletions and/or mutations in the survival of motor neuron 1 (SMN1) gene leading to reduced SMN protein levels. Nusinersen, an intrathecally administered antisense oligonucleotide therapy that increases SMN protein levels, is approved for use in adult and pediatric patients with SMA. Data to inform real-world patient adherence and persistence to nusinersen are limited, with disparities in the population with SMA, study design, and results. The objective of this study is to characterize real-world nusinersen adherence and persistence in patients with SMA. Methods This retrospective study examined nusinersen adherence and persistence over a 2-year period in patients with SMA in the USA from the IQVIA PharMetrics Plus claims database. Patients were followed from the date of first evidence of nusinersen treatment (occurring after 1 July 2017) until the end of the study period (31 December 2019) or end of continuous pharmacy and medical benefit enrollment, whichever came first. Subgroup analyses for nusinersen adherence and persistence were performed on the basis of age and presence or absence of spinal complications. Results The final cohort consisted of 179 patients with SMA treated with nusinersen. Adherence to nusinersen treatment was 41% at 56 weeks and 39% at 104 weeks. In the base-case persistence analysis, there was a decrease in persistence before 6 months (67%) and further decline at 1 (57%) and 2 years (55%). Patients with spinal complication versus without had numerically higher persistence with nusinersen. Conclusions The findings suggest that adherence and persistence to nusinersen treatment appear low. Demographic (age ≥ 18 years) and clinical factors (no spinal complications) may contribute to nusinersen treatment discontinuation. Future research should explore possible reasons for low adherence and persistence to nusinersen treatment, such as clinical or logistical factors, patient preferences, and payer restrictions.

SPR1NT (NCT03505099) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelicSMN1mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies ofSMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26;P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening.