Diagnoses of muscular dystrophy in a veterans health system.

INTRODUCTION/AIMS: Early diagnosis of a chronic neuromuscular disease such as muscular dystrophy (MD) generally excludes an individual from active-duty military service. However, it is not known whether veterans are sometimes diagnosed with milder forms of MD at a later timepoint. We aimed to determine the prevalence of MD in a veterans health system. METHODS: We abstracted clinical and genetic test data on patients who received care for a diagnosis of MD at the North Florida/South Georgia Veterans Health System between 2008 and 2021. We then determined which of these individuals would meet criteria for a definite diagnosis of MD, based on electrodiagnostic testing, muscle biopsy, and genetic testing of the individual or an affected first degree relative. RESULTS: We identified 12 patients with definite MD and 36 with possible or probable MD. The definite cases included myotonic dystrophy type 1 (4), myotonic dystrophy type 2 (3), oculopharyngeal MD (2), Becker MD (1), distal MD (1), and facioscapulohumeral MD (1). At least five of the cases classified as definite developed symptoms after discharge from active duty. DISCUSSION: Clinicians who care for veterans should be knowledgeable about, and have access to, diagnostic testing and treatment options for MD. When conducting MD surveillance, it is important to include veterans health systems as a data source. Mild cases of MD and those of later onset appear to be compatible in some cases with successful completion of military service.

A patient-focused survey to assess the effects of the COVID-19 pandemic and social guidelines on people with muscular dystrophy.

INTRODUCTION/AIMS: In this study, we examined the social and health impacts of the coronavirus disease 2019 (COVID-19) pandemic and social guidelines on people with muscular dystrophies. METHODS: A prospective de-identified electronic survey was distributed to adults with self-reported facioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (DM), and limb-girdle muscular dystrophy (LGMD) enrolled in national registries or with patient advocacy groups. The COVID-19 Impact Survey was developed by muscular dystrophy experts in association with patient collaborators and advocacy groups. The Perceived Stress Scale was used to measure perceived stress. RESULTS: Respondents (n = 774: 56% FSHD; 35% DM, and 9% LGMD) were mostly women and middle-aged (range 19-87 y). Rates of COVID-19 infections were low (<1%), compliance with local social distancing guidelines and policies high (98%). Major challenges reported during the pandemic included: obtaining treatment (40%), managing stress (37%), social distancing (36%), and obtaining essentials (34%). The majority reported a slight worsening in their disease state. Respondents reported moderate stress levels (stress score = 15.4; range = 0-35), with higher stress levels reported by women and those under age 30 y. Three-quarters of participants who participated in telemedicine visits were satisfied with the encounters; however, most reported a preference for in-person visits. DISCUSSION: People with muscular dystrophy reported moderate stress and challenges during the COVID-19 pandemic. Interventions such as exercise and stress-coping strategies, including strategies specific to women or individuals <30 y, may be important. Further investigation is needed into the role of telemedicine in the care of individuals with muscular dystrophy.

Cardiac and Neuromuscular Features of Patients With LMNA-Related Cardiomyopathy.

Background: Mutations in the LMNA (lamin A/C) gene have been associated with neuromuscular and cardiac manifestations, but the clinical implications of these signs are not well understood. Objective: To learn more about the natural history of LMNA-related disease. Design: Observational study. Setting: 13 clinical centers in Italy from 2000 through 2018. Patients: 164 carriers of an LMNA mutation. Measurements: Detailed cardiologic and neurologic evaluation at study enrollment and for a median of 10 years of follow-up. Results: The median age at enrollment was 38 years, and 51% of participants were female. Neuromuscular manifestations preceded cardiac signs by a median of 11 years, but by the end of follow-up, 90% of the patients had electrical heart disease followed by structural heart disease. Overall, 10 patients (6%) died, 14 (9%) received a heart transplant, and 32 (20%) had malignant ventricular arrhythmias. Fifteen patients had gait loss, and 6 had respiratory failure. Atrial fibrillation and second- and third-degree atrioventricular block were observed, respectively, in 56% and 51% of patients with combined cardiac and neuromuscular manifestations and 37% and 33% of those with heart disease only. Limitations: Some of the data were collected retrospectively. Neuromuscular manifestations were more frequent in this analysis than in previous studies. Conclusion: Many patients with an LMNA mutation have neurologic symptoms by their 30s and develop progressive cardiac manifestations during the next decade. A substantial proportion of these patients will have life-threatening neurologic or cardiologic conditions. Primary Funding Source: None.

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy.

Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive disorders caused by mutations in the DMD gene. Emerging therapies targeting patients with specific mutations are now becoming a reality for many of these patients. Precise molecular diagnosis is essential to facilitate the identification of possible new treatments for patients in the local context. In this study, we screened 145 dystrophinopathic patients in Singapore and assessed their molecular status for eligibility to current emerging genetic therapies. Overall, 140 (96.5%) of all patients harbored pathogenic DMD mutations comprising 95 exonic deletions (65.5%), 14 exonic duplications (9.7%), and 31 pathogenic small mutations (21.4%). Nonsense and frameshift mutations constitute 83.9% of all the small mutations. We found 71% (103/145) of all Singaporean dystrophinopathy patients to be theoretically amenable for exon skipping, either through skipping of single (53.1%) or multiple exons (17.9%). This approach is applicable to 81.1% (77/95) of patients carrying deletions and 83.9% (26/31) of those with small mutations. Eteplirsen induced skipping of exon 51 is applicable to 12.4% of local patients. Nonsense read-through therapy was found to be applicable in another 12.4% of all patients. Mutation screening is crucial for providing insights into the underlying genetic signature of the disease in the local population and contributes toward existing information on DMD mutations in Asia and globally. This will guide future targeted drug development and clinical trial planning for this disease.

Congenital muscular dystrophies in China.

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first-level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2-related CMD (36.4%), followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China.

The prevalence of muscular dystrophy and spinal muscular atrophy in Croatia: data from national and non-governmental organization registries.

AIM: To determine the prevalence of muscular dystrophy (MD) and spinal muscular atrophy (SMA) in Croatia by use of multiple epidemiological tools. METHODS: This epidemiological study collected data from three national patient registries and one database of a non-governmental organization (NGO) of MD and SMA patients. The study involved all individuals who either had undergone hospital treatment for MD or SMA, had consulted their primary health care providers for MD- and SMA-related symptoms, were listed as disabled due to MD or SMA, or were members of the mentioned NGO in 2016. In order to prevent double entries, we created a new database of all living individuals, each with a unique identification number. The prevalence rates for 2016 were calculated by age and sex groups. RESULTS: There were 926 patients diagnosed with MD (544 men). Most men diagnosed with MD were in the age group 10-19, whereas most women were in the age group 50-59. MD prevalence in Croatia was 22.2 per 100000 population. There were 392 patients diagnosed with SMA (198 men). Most men with SMA were in the age group 50-59, whereas most women were in the age group 60-69. SMA prevalence in Croatia was 9.3 per 100000 population. CONCLUSION: SMA prevalence rate in Croatia is similar to SMA prevalence worldwide. However, MD prevalence rate is higher than worldwide estimates. This difference could be attributed to the fact that we could not confirm whether every patient registered in these databases actually met the diagnostic criteria for MD and SMA.

Cardiac Involvement in Emery-Dreifuss Muscular Dystrophy and Related Management Strategies.

Emery-Dreifuss muscular dystrophy (EDMD) is a group of hereditary muscular dystrophy syndrome caused by deficiency of genes encoding nuclear envelope proteins. Patients having EDMD show the triad of muscle dystrophy, joint contracture, and cardiac disease. In almost all patients, cardiac involvement is prevalent and is the most severe aspect of EDMD. Cardiac disease is predominantly shown by conduction defects, atrial fibrillation/flutter, and atrial standstill. Sudden death and heart failure because of left ventricular dysfunction are important causes of mortality, particularly in those patients that have the LMNA mutation. Medical treatment of EDMD is limited to addressing symptoms and ambulation support; moreover, pacemaker implantation is necessary when there are severe conduction defects and bradycardia occurs. Note that automated defibrillation devices may be considered for those patients who have a high risk of sudden death, rate, or rhythm control. Also, anticoagulation should be initiated in those patients who have atrial fibrillation/flutter. Thus, for optimal management, a multidisciplinary approach is required.

Muscular dystrophies and myopathies: the spectrum of mutated genes in the Czech Republic.

Inherited neuromuscular disorder (NMD) is a wide term covering different genetic disorders affecting muscles, nerves, and neuromuscular junctions. Genetic and clinical heterogeneity is the main drawback in a routine gene-by-gene diagnostics. We present Czech NMD patients with a genetic cause identified using targeted next-generation sequencing (NGS) and the spectrum of these causes. Overall 167 unrelated patients presenting NMD falling into categories of muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, and other myopathies were tested by targeted NGS of 42 known NMD-related genes. Pathogenic or probably pathogenic sequence changes were identified in 79 patients (47.3%). In total, 37 novel and 51 known disease-causing variants were detected in 23 genes. In addition, variants of uncertain significance were suspected in 7 cases (4.2%), and in 81 cases (48.5%) sequence changes associated with NMD were not found. Our results strongly indicate that for molecular diagnostics of heterogeneous disorders such as NMDs, targeted panel testing has a high-clinical yield and should therefore be the preferred first-tier approach. Further, we show that in the genetic diagnostic practice of NMDs, it is necessary to take into account different types of inheritance including the occurrence of an autosomal recessive disorder in two generations of one family.

A Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies.

BACKGROUND: The muscular dystrophies are a heterogeneous group of genetic muscle diseases with variable distribution of weakness and mode of inheritance. METHODS: We previously performed a systematic review of worldwide population-based studies on Duchenne and Becker muscular dystrophies; the current study focused on the epidemiology of other muscular dystrophies using Medline and EMBASE databases. Two reviewers independently reviewed all abstracts, full-text articles, and abstracted data from 1985 to 2011. Pooling of prevalence estimates was performed using random-effect models. RESULTS: A total of 1104 abstracts and 167 full-text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The overall pooled prevalence of combined muscular dystrophies was 16.14 (confidence interval [CI], 11.21-23.23) per 100,000. The prevalence estimates per 100,000 were 8.26 (CI, 4.99-13.68) for myotonic dystrophy, 3.95 (CI, 2.89-5.40) for facioscapulohumeral dystrophy, 1.63 (CI, 0.94-2.81) for limb girdle muscular dystrophy, and 0.99 (CI, 0.62-1.57) for congenital muscular dystrophies. CONCLUSIONS: The studies differed widely in their approaches to case ascertainment, and substantial gaps remain in the global estimates of many other types of muscular dystrophies. Additional epidemiological studies using standardized diagnostic criteria as well as multiple sources of case ascertainment will help address the economic impact and health care burden of muscular dystrophies worldwide.

Hospitalizations and emergency room visits for adolescents and young adults with muscular dystrophy living in South Carolina.

INTRODUCTION: Transitioning from adolescence to adulthood can be problematic for individuals with rare disabilities such as muscular dystrophy (MD). METHODS: We identified a cohort of 220 individuals with MD and 440 matched comparison individuals and measured emergency room (ER) and inpatient (IP) encounters for the years 2000 through 2010, using all-payer hospital discharge uniform billing data. We compared ER and IP use rates for people with and without MD, and for 15-19-year-olds with MD to 20-24-year-olds with MD. RESULTS: ER and IP use rates were significantly higher among individuals with MD than the comparison group. In addition, ER and IP use rates were significantly higher in the 20-24-year age group than in the 15-19-year group. CONCLUSIONS: Additional research is needed to determine whether increased ER and IP use in young adults is attributable to difficulties in healthcare transition versus increased disease severity.

Burden, professional support, and social network in families of children and young adults with muscular dystrophies.

INTRODUCTION: This study explores burden and social and professional support in families of young patients with muscular dystrophies (MDs) in Italy. METHODS: The study was carried out on 502 key relatives of 4- to 25-year-old patients suffering from Duchenne, Becker, or Limb-Girdle MD who were living with at least 1 adult relative. RESULTS: A total of 77.1% of relatives reported feelings of loss, 74.0% had feelings of sadness, and 59.1% had constraints in leisure activities. Burden was higher among relatives of patients with higher disability and who spent more daily hours in caregiving. Practical difficulties were higher among relatives who perceived lower help in patient emergencies and less practical support by their social network. Psychological burden was higher in those relatives who were unemployed, those with poorer support in emergencies, and those with lower social contacts. CONCLUSIONS: Caring for patients with MDs may be demanding for relatives even in the early stages of these disorders, especially when social support is poor and the patient's disability increases.

Risk of fracture in patients with muscular dystrophies.

UNLABELLED: The aim of the study was to determine fracture risk in incident muscular dystrophy (MD) patients. Patients with MD are at a 1.4-fold increased risk of fracture as compared with population-based control patients. Risk further increased among elderly and female patients and among patients exposed to oral glucocorticoids. INTRODUCTION: Muscular dystrophies (MDs) are inherited diseases causing muscle weakness and thereby increase the risk of falling and detrimental effects on bone. Both are recognised risk factors for fracture. Therefore, the aim of this study was to determine the hazard ratio of fracture in patients with MD. METHODS: We conducted a retrospective cohort study using the UK General Practice Research Database (1987-2012). Each patient with MD was matched by year of birth, sex and practice to up to six patients without a history of MD. Outcome measure was all fractures. RESULTS: As compared with control patients, risk of any fracture was statistically significantly increased in MD patients (adjusted hazard ratio [AHR], 1.40; 95 % confidence interval [CI], 1.14-1.71). An increased risk of fracture was observed among MD patients with female gender (AHR, 1.78; 95 % CI, 1.33-2.40) and an increasing age as compared with control patients. Stratification to Duchenne MD showed no association with fracture, whereas risk of fracture was increased twofold among patients with myotonic dystrophy (AHR, 2.34; 95 % CI, 1.56-3.51). MD patients had an almost tripled risk of fracture when they used oral glucocorticoids in the previous 6 months as compared to non-users with MD. CONCLUSION: Patients with MD are at a 1.4-fold increased risk of fracture as compared with population-based control patients. Especially in older age groups and female gender, the fracture risk of MD versus non-MD patients is increased, whereas exposure to glucocorticoids further increased fracture risk among MD patients.

Use of state administrative data sources to study adolescents and young adults with rare conditions.

BACKGROUND: Effective care of young people with rare conditions requires ongoing coordinated medical treatment as well as educational and social support services. However, information on treatment is often lacking due to limited data. South Carolina has a repository of comprehensive health and human service data with which individuals may be tracked across the data systems of multiple state agencies and organizations. OBJECTIVE: To develop a method for studying health care of young persons with rare conditions using this repository. METHODS: We identified individuals aged 15 to 24 years diagnosed during 2000-2010 with Fragile X syndrome (FXS), spina bifida (SB), or muscular dystrophy (MD) using a series of algorithms. ICD-9-CM codes were used to initially identify the cohort from medical billing data. Demographics, medical care, employment, education, and socioeconomic status data were then extracted from linked administrative sources. RESULTS: We identified 1,040 individuals with these rare conditions: 125 with FXS, 695 with SB, and 220 with MD. The vast majority of the cases (95%) were identified in the Medicaid database. Half of the cohort was male, with a higher percentage in the FXS and MD groups. Sixty-two percent of the cohort was enrolled in the last year of high school. Over half of the cohort received support services from the state's disability and special-needs agency; 16% received food assistance. Thirty-eight percent were employed at some point during the study period. Forty-nine individuals with SB and 56 with MD died during the study period. CONCLUSIONS: We used a linked statewide data system to study rare conditions. Strengths include the diversity of information, rigorous identification strategies, and access to longitudinal data. Despite limitations inherent to administrative data, we found that linked state data systems are valuable resources for investigating important public health questions on rare conditions.

Prevalence of muscular dystrophies: a systematic literature review.

BACKGROUND: Determining the prevalence of neuromuscular disorders for the general population is important to identify the scope of burden on society and enable comparisons with other health conditions. This systematic review aims to identify and collate the findings of studies published between 1960 and 2013 on the prevalence of all types of muscular dystrophies. SUMMARY: Relevant articles were identified through electronic database searches and manual searches of reference lists. There were 38 articles from across 19 countries that met the inclusion criteria. The total combined prevalence for all muscular dystrophies for studies classified as having a low risk of bias ranged between 19.8 and 25.1 per 100,000 person-years. Myotonic dystrophy (0.5-18.1 per 100,000), Duchenne muscular dystrophy (1.7-4.2) and facioscapulohumeral muscular dystrophy (3.2-4.6 per 100,000) were found to be the most common types of disorder. There was wide variation in study methodology, case ascertainment, and verification procedures and populations studied, all of which may contribute to the wide prevalence range, in addition to the likely variation in prevalence by country. Key Messages: Greater consistency in the conduct and reporting of neuroepidemiological studies is urgently needed to enable comparisons to be made between studies, countries, and over time.

Cancer Risk in Patients With Muscular Dystrophy and Myotonic Dystrophy: A Register-Based Cohort Study.

BACKGROUND AND OBJECTIVES: Muscular dystrophies and myotonic disorders are genetic disorders characterized by progressive skeletal muscle degeneration and weakness. Epidemiologic studies have found an increased cancer risk in myotonic dystrophy, although the cancer risk spectrum is poorly characterized. In patients with muscular dystrophy, the cancer risk is uncertain. We aimed to determine the overall cancer risk and cancer risk spectrum in patients with muscular dystrophy and myotonic dystrophy using data from the Swedish National registers. METHODS: We performed a matched cohort study in all patients with muscular dystrophy or myotonic dystrophy born in Sweden 1950-2017 and 50 matched comparisons by sex, year of birth, and birth county per individual. The association with cancer overall and specific malignancies was estimated using stratified Cox proportional hazard models. RESULTS: We identified 2,355 and 1,968 individuals with muscular dystrophy and myotonic dystrophy, respectively. No increased overall cancer risk was found in muscular dystrophy. However, we observed an increased risk of astrocytomas and other gliomas during childhood (hazard ratio [HR] 8.70, 95% CI 3.57-21.20) and nonthyroid endocrine cancer (HR 2.35, 95% CI 1.03-5.34) and pancreatic cancer (HR 4.33, 95% CI 1.55-12.11) in adulthood. In myotonic dystrophy, we found an increased risk of pediatric brain tumors (HR 3.23, 95% CI 1.16-9.01) and an increased overall cancer risk in adults (HR 2.26, CI 1.92.2.66), specifically brain tumors (HR 10.44, 95% CI 7.30-14.95), thyroid (HR 3.92, 95% CI 1.70-9.03), and nonthyroid endocrine cancer (HR 7.49, 95% CI 4.47-12.56), endometrial (HR 8.32, 95% CI 4.22-16.40), ovarian (HR 4.00, 95% CI 1.60-10.01), and nonmelanoma skin cancer (HR 3.27, 95% CI 1.32-8.13). DISCUSSION: Here, we analyze the cancer risk spectrum of patients with muscular dystrophy and myotonic dystrophy. To the best of our knowledge, this is the first report of an increased risk for CNS tumors in childhood and adult nonthyroid endocrine and pancreatic cancer in muscular dystrophy. Furthermore, for myotonic dystrophy, we confirmed previously reported associations with cancer and expanded the cancer spectrum, finding an unreported increased risk for nonthyroid endocrine cancer. Additional studies confirming the cancer risk and delineating the cancer spectrum in different genetic subtypes of muscular dystrophies are warranted before considering altered cancer screening recommendations than for the general population.

Rapidly progressive scoliosis and respiratory deterioration in Ullrich congenital muscular dystrophy.

OBJECTIVE: To characterise the natural history of Ullrich congenital muscular dystrophy (UCMD). PATIENTS AND METHODS: Questionnaire-based nationwide survey to all 5442 certified paediatric and adult neurologists in Japan was conducted from October 2010 to February 2011. We enrolled the 33 patients (age at assessment, 11 ± 6.6 years) who were reported to have collagen VI deficiency on immunohistochemistry in muscle biopsies. We analysed the development, clinical manifestations, Cobb angle and %vital capacity (%VC) in spirogram. RESULTS: Cobb angle over 30° was noted at age 9.9 ± 5.3 years (n=17). The maximum progression rate was 16.2 ± 10°/year (n=13). %VC was decreased exponentially with age, resulting in severe respiratory dysfunction before pubescence. Scoliosis surgery was performed in 3 patients at ages 5 years, 9 years and 10 years. Postoperative %VC was relatively well maintained in the youngest patient. Non-invasive ventilation was initiated at age 11.2 ± 3.6 years (n=13). Twenty-five (81%) of 31 patients walked independently by age 1.7 ± 0.5 years but lost this ability by age 8.8 ± 2.9 years (n=11). Six patients never walked independently. CONCLUSIONS: The natural history of scoliosis, respiratory function and walking ability in UCMD patients were characterised. Although the age of onset varied, scoliosis, as well as restrictive respiratory dysfunction, progressed rapidly within years, once they appeared.

Prevalence of early childhood disability in a rural district of Sind, Pakistan.

AIM: Children born in low- and mid-income countries are at a high risk of developing disabilities, yet estimates of population-based prevalence are sparse. Our aim was to determine the prevalence of early childhood (0-5 year) disability in Sind, a rural area of Pakistan. METHOD: We conducted a cross-sectional household survey in a population of 25,196 households. The Ten Questions screen and the Signs of Disability in Newborn and Infants screen were used. RESULTS: The disability prevalence in a population of 176,364 individuals was 5.5 out of 1000 in children under 2 years and 5.4 out of 1000 in children aged 2-5 years. Fifty-six per cent were males, and 56% had the disability recognized from birth or soon after. The mortality rate of children aged 0-5 years in the area was estimated as 30 out of 1000 live births. Cerebral palsy was the most common disability identified. The Ten Questions screen had better interrater agreement than the Signs of Disability in Newborn and Infants screen. INTERPRETATION: This is the largest reported household screening survey for early childhood disability at a population level from rural Pakistan. The comparatively low prevalence may be due to the younger age studied and high early childhood mortality. Our data highlight the importance of prospective surveillance at a population level and the need for preventive and support services.

Epidemiology of muscular dystrophies in the Mediterranean area.

The Mediterranean countries are distinguished with their peculiar genetic pool and diversities. Recessive diseases often present with their own founder mutations. In some instances this is shared with neighboring populations. Dominant disorders in the area are increasingly recognized as health care providing systems and technology improve. Among muscular dystrophies Duchenne and Becker types constitute the major fraction in almost all societies. This is followed by various forms of limb-girdle muscular dystrophy. Congenital dystrophies and other related rare types are a matter of recognition. The identification and registry of facio-scapulo-humeral and myotonic dystrophies vary in different states.

Estimating the Prevalence of LAMA2 Congenital Muscular Dystrophy using Population Genetic Databases.

BACKGROUND: Recessive pathogenic variants in LAMA2 resulting in complete or partial loss of laminin α2 protein cause congenital muscular dystrophy (LAMA2 CMD). The prevalence of LAMA2 CMD has been estimated by epidemiological studies to lie between 1.36-20 cases per million. However, prevalence estimates from epidemiological studies are vulnerable to inaccuracies owing to challenges with studying rare diseases. Population genetic databases offer an alternative method for estimating prevalence. OBJECTIVE: We aim to use population allele frequency data for reported and predicted pathogenic variants to estimate the birth prevalence of LAMA2 CMD. METHODS: A list of reported pathogenic LAMA2 variants was compiled from public databases, and supplemented with predicted loss of function (LoF) variants in the Genome Aggregation Database (gnomAD). gnomAD allele frequencies for 273 reported pathogenic and predicted LoF LAMA2 variants were used to calculate disease prevalence using a Bayesian methodology. RESULTS: The world-wide birth prevalence of LAMA2 CMD was estimated to be 8.3 per million (95% confidence interval (CI) 6.27 -10.5 per million). The prevalence estimates for each population in gnomAD varied, ranging from 1.79 per million in East Asians (95% CI 0.63 -3.36) to 10.1 per million in Europeans (95% CI 6.74 -13.9). These estimates were generally consistent with those from epidemiological studies, where available. CONCLUSIONS: We provide robust world-wide and population-specific birth prevalence estimates for LAMA2 CMD, including for non-European populations in which LAMA2 CMD prevalence hadn't been studied. This work will inform the design and prioritization of clinical trials for promising LAMA2 CMD treatments.