Genetic counseling for the dystrophinopathies-Practice resource of the National Society of Genetic Counselors.

The dystrophinopathies encompass the phenotypically variable forms of muscular dystrophy caused by pathogenic variants in the DMD gene. The dystrophinopathies include the most common inherited muscular dystrophy among 46,XY individuals, Duchenne muscular dystrophy, as well as Becker muscular dystrophy and other less common phenotypic variants. With increased access to and utilization of genetic testing in the diagnostic and carrier setting, genetic counselors and clinicians in diverse specialty areas may care for individuals with and carriers of dystrophinopathy. This practice resource was developed as a tool for genetic counselors and other health care professionals to support counseling regarding dystrophinopathies, including diagnosis, health risks and management, psychosocial needs, reproductive options, clinical trials, and treatment. Genetic testing efforts have enabled genotype/phenotype correlation in the dystrophinopathies, but have also revealed unexpected findings, further complicating genetic counseling for this group of conditions. Additionally, the therapeutic landscape for dystrophinopathies has dramatically changed with several FDA-approved therapeutics, an expansive research pathway, and numerous clinical trials. Genotype-phenotype correlations are especially complex and genetic counselors' unique skill sets are useful in exploring and explaining this to families. Given the recent advances in diagnostic testing and therapeutics related to dystrophinopathies, this practice resource is a timely update for genetic counselors and other healthcare professionals involved in the diagnosis and care of individuals with dystrophinopathies.

Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Background: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. Objective: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. Methods: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. Results: The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy. Conclusions: The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

Associations Between Self-Reported Behavioral and Learning Concerns and DMD Isoforms in Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder resulting from loss of dystrophin. In addition to its role in muscle, isoforms of dystrophin are expressed in different cell types of the brain, and DMD has been linked to language delays, behavioral abnormalities and learning disabilities. OBJECTIVE: To determine whether disruption of specific DMD isoforms, age, corticosteroid use, ambulation status, or country are associated with behavioral and/or learning concerns in DMD. METHODS: De-identified data were collected from the Duchenne Registry from 2007-2019. Females, patients with BMD, and those without genetic testing reports were excluded from the cohort. For the genetic analysis, patients were divided into four subgroups based on the location of their mutation and the predicted isoforms affected. Bivariate analysis was conducted using chi-square for categorical variables. Two multivariate logistic regressions were used to assess independent associations with behavioral and learning concerns, respectively, and to estimate the effect size of each variable. RESULTS: DMD mutations disrupting expression of Dp140 and Dp71 were associated with a higher likelihood of reported behavioral and learning concerns. Corticosteroid use, categorical age, and country were other factors associated with behavior and learning concerns. CONCLUSION: This data adds to our current understanding of DMD isoforms, their mutational consequence and impact on behavior and learning.

Web-Based Mindfulness-Based Interventions for Well-being: Randomized Comparative Effectiveness Trial.

BACKGROUND: Mindfulness can improve overall well-being by training individuals to focus on the present moment without judging their thoughts. However, it is unknown how much mindfulness practice and training are necessary to improve well-being. OBJECTIVE: The primary aim of this study was to determine whether a standard 8-session web-based mindfulness-based cognitive therapy (MBCT) program, compared with a brief 3-session mindfulness intervention, improved overall participant well-being. In addition, we sought to explore whether the treatment effects differed based on the baseline characteristics of the participants (ie, moderators). METHODS: Participants were recruited from 17 patient-powered research networks, web-based communities of stakeholders interested in a common research area. Participants were randomized to either a standard 8-session MBCT or a brief 3-session mindfulness training intervention accessed on the web. The participants were followed for 12 weeks. The primary outcome of the study was well-being, as measured by the World Health Organization-Five Well-Being Index. We hypothesized that MBCT would be superior to a brief mindfulness training. RESULTS: We randomized 4411 participants, 3873 (87.80%) of whom were White and 3547 (80.41%) of female sex assigned at birth. The mean baseline World Health Organization-Five Well-Being Index score was 50.3 (SD 20.7). The average self-reported well-being in each group increased over the intervention period (baseline to 8 weeks; model-based slope for the MBCT group: 0.78, 95% CI 0.63-0.93, and brief mindfulness group: 0.76, 95% CI 0.60-0.91) as well as the full study period (ie, intervention plus follow-up; baseline to 20 weeks; model-based slope for MBCT group: 0.41, 95% CI 0.34-0.48; and brief mindfulness group: 0.33, 95% CI 0.26-0.40). Changes in self-reported well-being were not significantly different between MBCT and brief mindfulness during the intervention period (model-based difference in slopes: -0.02, 95% CI -0.24 to 0.19; P=.80) or during the intervention period plus 12-week follow-up (-0.08, 95% CI -0.18 to 0.02; P=.10). During the intervention period, younger participants (P=.05) and participants who completed a higher percentage of intervention sessions (P=.005) experienced greater improvements in well-being across both interventions, with effects that were stronger for participants in the MBCT condition. Attrition was high (ie, 2142/4411, 48.56%), which is an important limitation of this study. CONCLUSIONS: Standard MBCT improved well-being but was not superior to a brief mindfulness intervention. This finding suggests that shorter mindfulness programs could yield important benefits across the general population of individuals with various medical conditions. Younger people and participants who completed more intervention sessions reported greater improvements in well-being, an effect that was more pronounced for participants in the MBCT condition. This finding suggests that standard MBCT may be a better choice for younger people as well as treatment-adherent individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT03844321; https://clinicaltrials.gov/ct2/show/NCT03844321.

Clinical Phenotypes of DMD Exon 51 Skip Equivalent Deletions: A Systematic Review.

BACKGROUND: Eteplirsen, the first FDA-approved RNA-modifying therapy for DMD, is applicable to ∼13% of patients with DMD. Because multiple exonic deletions are amenable to exon 51 skipping, the isoforms resulting from the various exon 51-skipped transcripts may vary in stability, function, and phenotype. OBJECTIVE/METHODS: We conducted a detailed review of dystrophinopathy published literature and unpublished databases to compile phenotypic features of patients with exon 51 "skip-equivalent" deletions. RESULTS: Theoretically, 48 different in-frame transcripts may result from exon 51 skipping. We found sufficient clinical information on 135 patients carrying mutations that would result in production of 11 (23%) of these transcripts, suggesting the remainder have not been identified in vivo. The majority had mild phenotypes: BMD (n = 81) or isolated dilated cardiomyopathy (n = 3). Particularly interesting are the asymptomatic (n = 10) or isolated hyperCKemia (n = 20) patients with deletions of exons 45- 51, 48- 51, 49- 51 and 50- 51. Finally, 16 (12%) had more severe phenotypes described as intermediate (n = 2) or DMD (n = 14), and 6 reports had no definitive phenotype. CONCLUSIONS: This review shows that the majority of exon 51 "skip-equivalent" deletions result in milder (BMD) phenotypes and supports that exon 51 skipping therapy could provide clinical benefit, although we acknowledge that other factors, such as age at treatment initiation or ongoing standard of care, may influence the degree of benefit.

Delays in diagnosis of Duchenne muscular dystrophy: An evaluation of genotypic and sociodemographic factors.

INTRODUCTION: In this study we investigate associations between genotypic and sociodemographic factors and the age of diagnosis of Duchenne muscular dystrophy (DMD). METHODS: Data were collected from the Duchenne Registry from 2007 to 2019, and then used to assess the impact genotype, race/ethnicity, neighborhood poverty levels, and other sociodemographics factors have on the age of diagnosis of DMD patients without a known family history, using univariate and multivariable linear regression. RESULTS: The mean age of diagnosis was 4.43 years. Non-Caucasian patients and patients from high-poverty neighborhoods were older at diagnosis (P < .01). Increased year of birth was associated with decreasing age of diagnosis (P < .001). Specific genetic mutation subtypes were associated with later ages of symptom onset and diagnosis (P = .005). DISCUSSION: After adjusting for genotype and year of birth, the average age of diagnosis was significantly later for traditionally at-risk patients.

Chart validation of an algorithm for identifying hereditary progressive muscular dystrophy in healthcare claims.

BACKGROUND: Muscular dystrophies (MDs) are a group of inherited conditions characterized by progressive muscle degeneration and weakness. The rarity and heterogeneity of the population with MD have hindered therapeutic developments as well as epidemiological and health outcomes research. The objective of the study was to develop and validate a case-finding algorithm utilizing administrative claims data to identify and characterize patients with MD. METHODS: This retrospective cohort study used medical chart validation to evaluate an ICD-9/10 coding algorithm in a large commercial claims database. Patients were identified who had ≥2 office visits with a diagnosis of hereditary progressive MDs from January 1, 2013 through December 31, 2016, were male, and younger than 18 years at the time of first MD diagnosis. Cases who met the algorithm were then validated against medical charts. Diagnoses of MD and specific type (Duchenne, Becker, or other MD) were confirmed by medical chart review by trained reviewers. Positive predictive value (PPV) and 95% confidence intervals (CI) were calculated using a 2 × 2 contingence table. Patient demographic, clinical, and health utilization characteristics were summarized using basic descriptive statistics. RESULTS: Charts were obtained and reviewed for 109 patients who met the algorithm. The PPV of the case-identifying algorithm for MD was 95% (95% CI 88-98%). Of the 103 confirmed MD cases, 87 patients (85%, 95% CI 76-91%) had Duchenne or Becker MD; 76 patients (74%, 95% CI 64-82%) had Duchenne MD, and 11 patients (11%, 95% CI 5-18%) had Becker MD. A total of 74 (67.9%) patients had ≥1 pediatric complex chronic condition (other than neurologic/neuromuscular disease); 54 (49.5%) had cardiovascular conditions; 14 (12.8%) had respiratory conditions; 50 (45.9%) had bone-related issues; 11 (10.1%) had impaired growth; and 6 (5.5%) had puberty delay. CONCLUSIONS: The results of this study demonstrate that the case-finding algorithm accurately identified patients with MD, primarily Duchenne MD, within a large administrative database. The algorithm, which was constructed using a few items easily accessible from claims, can be used to facilitate epidemiological and health outcomes research in the Duchenne patient population.

Evaluating Implementation of the Updated Care Considerations for Duchenne Muscular Dystrophy.

Care Considerations for Duchenne Muscular Dystrophy were published in 2010. However, little is known about the extent to which these considerations were implemented after publication. With this article, we provide direction on evaluating the uptake of the 2018 Duchenne Muscular Dystrophy Care Considerations. We identify key elements of care and present suggestions for their use in evaluation and research.

DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype.

Antisense oligonucleotide (AON)-mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in-frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, 53, and 55 is predicted to benefit 47% of affected individuals. We observed a correlation between mutation subgroups and age at loss of ambulation in the Duchenne Registry, a large database of phenotypic and genetic data for DMD (N = 765). Males amenable to exon 44 (N = 74) and exon 8 skipping (N = 18) showed prolonged ambulation compared to other exon skip groups and nonsense mutations (P = 0.035 and P < 0.01, respectively). In particular, exon 45 deletions were associated with prolonged age at loss of ambulation relative to the rest of the exon 44 skip amenable cohort and other DMD mutations. Exon 3-7 deletions also showed prolonged ambulation relative to all other exon 8 skippable mutations. Cultured myotubes from DMD patients with deletions of exons 3-7 or exon 45 showed higher endogenous skipping than other mutations, providing a potential biological rationale for our observations. These results highlight the utility of aggregating phenotypic and genotypic data for rare pediatric diseases to reveal progression differences, identify potentially confounding factors, and probe molecular mechanisms that may affect disease severity.

DuchenneConnect Registry Report.

Research activity in Duchenne/Becker muscular dystrophy has surged in recent years, requiring robust information networks to support ongoing development. Established by Parent Project Muscular Dystrophy in late 2007, DuchenneConnect was created to bridge the information gap between care providers, researchers and the patient community, thereby addressing medical care needs and accelerating the pace of therapeutic advancements. This report represents the first in a new series that will be regularly shared by DuchenneConnect and PPMD. Data in this report was collected through June 2011.

Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats.

We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.