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.

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.

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.

Dystrophin Genotype and Risk of Neuropsychiatric Disorders in Dystrophinopathies: A Systematic Review and Meta-Analysis.

BACKGROUND: Dystrophinopathies are associated with neuropsychiatric disorders due to alterations in dystrophin/DMD expression. OBJECTIVE: The objective was to estimate the association of developmental disorders, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), depression, anxiety disorders, and obsessive-compulsive disorder with the dystrophin/DMD genotype in population with dystrophinopathies. METHODS: Systematic searches of Medline, Scopus, Web of Science, and Cochrane Library were performed from inception to September 2022. We included observational studies in the population with Becker or Duchenne muscular dystrophies (BMD, DMD) that estimated the prevalence of these disorders according to Dp140 and/or Dp71 genotype. Meta-analysis of the prevalence ratio (PR) of genotype comparisons was conducted for each disorder. RESULTS: Ten studies were included in the systematic review. In BMD, Dp140+ vs. Dp140- and Dp71+ vs. Dp71- were associated with developmental disorders with a PR of 0.11 (0.04, 0.34) and 0.22 (0.07, 0.67), respectively. In DMD, Dp140+/Dp71+ vs. Dp140- /Dp71- had a PR of 0.40 (0.28, 0.57), and Dp71+ vs. Dp71- had a PR of 0.47 (0.36, 0.63) for ADHD. However, there was no association of genotype with ASD, only a trend was observed for Dp71+ vs. Dp71-, with a PR of 0.61 (0.35, 1.06). Moreover, the data showed no association of these isoforms with emotional-related disorders. CONCLUSIONS: In BMD, Dp140 and Dp71 could be associated with developmental disorders, while ADHD might be associated with the Dp71 genotype in DMD. Further research is needed regarding Dp140 and Dp71, especially in DMD for ASD.

A population-based study of mortality due to muscular dystrophies across a 36-year period in Spain.

Muscular dystrophies (MD) are a group of rare hereditary degenerative diseases. Our aim was to analyze the mortality pattern in Spain from 1981 to 2016 to assess the temporal trend and discern possible geographic differences using population-based data. Annual deaths related to MD were obtained from the National Statistics Institute with codes 359.1 of the ICD-9 (1981-1998) and G71.0 of the ICD-10 (1999-2016). Age-adjusted mortality rates were calculated and changes in mortality trends were identified. The standardized mortality ratios (SMR) and their respective 95% confidence intervals were calculated by district for 1999-2016. Smoothed SMRs and posterior probability were also assessed and then mapped to look for patterns or geographic distribution. All rates were expressed per 1,000,000 inhabitants. A total of 2,512 deaths (73.8% men) were identified. The age-adjusted mortality rates varied from 0.63 (95% CI 0.40-0.95) in 1981 to 1.51 (95% CI 1.17-1.93) in 2016. MD mortality showed a significant increase of 8.81% per year (95% CI 5.0-12.7) from 1981 to 1990, remaining stable afterwards. Areas with risk of death higher than expected for Spain as a whole were identified, not showing a specific regional pattern. In conclusion, the rising trend in MD mortality might be attributable to advanced improvements in diagnostic techniques leading to a rise in prevalence. Further research on the districts with the highest mortality would be necessary.

Global prevalence of Duchenne and Becker muscular dystrophy: a systematic review and meta-analysis.

BACKGROUND: A variety of mutations in the largest human gene, dystrophin, cause a spectrum from mild to severe dystrophin-associated muscular dystrophies. Duchenne (DMD) and Becker (BMD) muscular dystrophies are located at the severe end of the spectrum that primarily affects skeletal muscle. Progressive muscle weakness in these purely genetic disorders encourages families with a positive history for genetic counseling to prevent a recurrence, which requires an accurate prevalence of the disorder. Here, we provide a systematic review and meta-analysis to determine the prevalence of DMD and BMD worldwide. METHOD: The current systematic review and meta-analysis was carried out using Cochrane seven-step procedure. After determining the research question and inclusion and exclusion criteria, the MagIran, SID, ScienceDirect, WoS, ProQuest, Medline (PubMed), Embase, Cochrane, Scopus, and Google Scholar databases were searched to find relevant studies using defined keywords and all possible keyword combinations using the AND and OR, with no time limit until 2021. The heterogeneity of studies was calculated using the I2 test, and the publication bias was investigated using the Begg and Mazumdar rank correlation test. Statistical analysis of data was performed using Comprehensive Meta-Analysis software (version 2). RESULTS: A total of 25 articles involving 901,598,055 people were included. The global prevalence of muscular dystrophy was estimated at 3.6 per 100,000 people (95 CI 2.8-4.5 per 100,000 people), the largest prevalence in the Americans at 5.1 per 100,000 people (95 CI 3.4-7.8 per 100,000 people). According to the subgroup analysis, the prevalence of DMD and BMD was estimated at 4.8 per 100,000 people (95 CI 3.6-6.3 per 100,000 people) and 1.6 per 100,000 people (95 CI 1.1-2.4 per 100,000 people), respectively. CONCLUSION: Knowing the precise prevalence of a genetic disorder helps to more accurately predict the likelihood of preventing its occurrence in families. The global prevalence of DMD and BMD was very high, indicating the urgent need for more attention to prenatal screening and genetic counseling for families with a positive history.

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort.

BACKGROUND: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. OBJECTIVE: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. METHODS: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999-2019) was reviewed. RESULTS: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4% of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3% of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17% of patients). These disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5% of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. CONCLUSIONS: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

Prevalence and incidence of neuromuscular conditions in the UK between 2000 and 2019: A retrospective study using primary care data.

BACKGROUND: In the UK, large-scale electronic primary care datasets can provide up-to-date, accurate epidemiological information on rarer diseases, where specialist diagnoses from hospital discharges and clinic letters are generally well recorded and electronically searchable. Current estimates of the number of people living with neuromuscular disease (NMD) have largely been based on secondary care data sources and lacked direct denominators. OBJECTIVE: To estimate trends in the recording of neuromuscular disease in UK primary care between 2000-2019. METHODS: The Clinical Practice Research Datalink (CPRD) database was searched electronically to estimate incidence and prevalence rates (per 100,000) for a range of NMDs in each year. To compare trends over time, rates were age standardised to the most recent CPRD population (2019). RESULTS: Approximately 13 million patients were actively registered in each year. By 2019, 28,230 active patients had ever received a NMD diagnosis (223.6), which was higher among males (239.0) than females (208.3). The most common classifications were Guillain-Barre syndrome (40.1), myasthenia gravis (33.7), muscular dystrophy (29.5), Charcot-Marie-Tooth (29.5) and inflammatory myopathies (25.0). Since 2000, overall prevalence grew by 63%, with the largest increases seen at older ages (≥65-years). However, overall incidence remained constant, though myasthenia gravis incidence has risen steadily since 2008, while new cases of muscular dystrophy fell over the same period. CONCLUSIONS: Lifetime recording of many NMDs on primary care records exceed current estimates of people living with these conditions; these are important data for health service and care planning. Temporal trends suggest this number is steadily increasing, and while this may partially be due to better recording, it cannot be simply explained by new cases, as incidence remained constant. The increase in prevalence among older ages suggests increases in life expectancy among those living with NMDs may have occurred.

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.

The Prevalence, Characteristics and Impact of Chronic Pain in People With Muscular Dystrophies: A Systematic Review and Meta-Analysis.

Chronic pain is a frequent, yet under-recognized and under-assessed problem in people with muscular dystrophies (MDs). Knowledge of the prevalence and characteristics of chronic pain, and its impact on function and quality of life is limited and lacks systematic exploration. This article aims to systematically review and synthesize existing literature that addresses chronic pain prevalence, characteristics and impact in people with different types of MDs. The present meta-analysis showed that the estimated prevalence of chronic pain in MDs is high and appears to be similar across different diagnostic groups: 68% (95% CI: 52%-82%) in FSHD, 65% (95% CI: 51%-77%) in DM, 62% (95% CI: 50%-73%) in BMD/DMD, and 60% (95% CI: 48%-73%) in LGMD, although it should be noted that heterogeneity was high in some diagnostic groups. On average, people with FSHD and DM present with moderate pain intensity. The lumbar spine, shoulders and legs are the most frequent sites of chronic pain among people with FSHD, DM, BMD/DMD, and LGMD, with little variation. Diffuse pain across multiple body sites was reported by a notable proportion of these individuals. Chronic pain has a negative impact on daily life activities in people with MDs, and may also contribute to decreased quality of life. The protocol for this review has been published on PROSPERO (CRD42020168096). PERSPECTIVES: This is the first systematic review and meta-analysis exploring the prevalence, and nature and impact of chronic pain in people with MDs. The present study demonstrates how common chronic pain is across various MD populations and highlights the need for better recognition and understanding of the nature and impact of pain from health professionals.

Mental health and coping strategies in families of children and young adults with muscular dystrophies.

BACKGROUND: Living with a progressive disease as muscular dystrophy (MD) can be challenging for the patient and the entire family from both emotional and practical point of view. We aimed to extend our previously published data about mental health in patients with MDs, also investigating coping profiles of both themselves and their parents. Furthermore, we wanted to verify whether psychological adaptation of patients can be predicted by coping strategies, taking also into account physical impairment, cognitive level and socioeconomic status. METHODS: 112 patients with MDs, aged 2-32 were included. Their emotional and behavioural features were assessed through parent- and self-report Achenbach System for Empirically Based Assessment questionnaires and Strength and Difficulties Questionnaires. Development and Well-Being Assessment or Autism Diagnostic Observation Schedule were administered to confirm suspected diagnoses. Coping profile of both parents and patients was assessed through the self-administered New Italian Version of the Coping Orientation to the Problems Experienced questionnaire and its relationship with emotional/behavioural outcome was examined in linear regression analyses. RESULTS: High prevalence of intellectual disability and autism spectrum disorders was confirmed in Duchenne MD. Despite the high rate of internalizing symptomatology, we did not report higher rate of psychopathological disorders compared to general population. Parents tend to rely more on positive reinterpretation and less on disengagement coping. Avoidance coping, whether used by parents or patients, and ID, predicted increased emotional/behavioural problems. CONCLUSIONS: Psychosocial interventions should address problems of anxiety and depression that people with MDs frequently experience, even through fostering parents' and childrens' engagement coping over disengagement coping.

Functional performance and muscular strength in symptomatic female carriers of Duchenne muscular dystrophy / Desempenho funcional e força muscular em portadoras sintomáticas de distrofia muscular de Duchenne

Abstract Duchenne muscular dystrophy (DMD) usually affects men. However, women are also affected in rare instances. Approximately 8% of female DMD carriers have muscle weakness and cardiomyopathy. The early identification of functional and motor impairments can support clinical decision making. Objective: To investigate the motor and functional impairments of 10 female patients with dystrophinopathy diagnosed with clinical, pathological, genetic and immunohistochemical studies. Methods: A descriptive study of a sample of symptomatic female carriers of DMD mutations. The studied variables were muscular strength and functional performance. Results: The prevalence was 10/118 (8.4%) symptomatic female carriers. Deletions were found in seven patients. The age of onset of symptoms in female carriers of DMD was quite variable. Pseudohypertrophy of calf muscles, muscular weakness, compensatory movements and longer timed performance on functional tasks were observed in most of the cases. Differently from males with DMD, seven female patients showed asymmetrical muscular weakness. The asymmetric presentation of muscle weakness was frequent and affected posture and functionality in some cases. The functional performance presents greater number of compensatory movements. Time of execution of activities was not a good biomarker of functionality for this population, because it does not change in the same proportion as the number of movement compensations. Conclusion: Clinical manifestation of asymmetrical muscle weakness and compensatory movements, or both can be found in female carriers of DMD mutations, which can adversely affect posture and functional performance of these patients.

Resumo A distrofia muscular de Duchenne (DMD) geralmente afeta indivíduos do sexo masculino. No entanto, mulheres também são acometidas em casos raros. Aproximadamente 8% das portadoras de DMD têm fraqueza muscular ou cardiomiopatia. A identificação precoce das alterações funcionais e motoras pode alterar a tomada de decisão clínica. Objetivo: Investigar as deficiências motoras e funcionais de 10 pacientes do sexo feminino com distrofinopatia diagnosticada por estudos clínicos, patológicos, genéticos e imuno-histoquímicos. Método: Estudo descritivo de uma amostra de portadoras sintomáticas de mutações DMD. As variáveis estudadas foram força muscular e desempenho funcional. Resultados: A prevalência foi de 10/118 (8,4%) de portadoras sintomáticas de DMD. Foram encontradas deleções em sete pacientes. A idade de início dos sintomas em portadoras de DMD foi variável. Pseudo-hipertrofia de panturrilhas, movimentos compensatórios, fraqueza muscular e aumento no tempo de execução de tarefas funcionais foram observados na maioria dos casos. Diferentemente dos homens com DMD, sete pacientes apresentaram fraqueza muscular assimétrica. A apresentação assimétrica da fraqueza muscular foi frequente, podendo afetar a postura e a funcionalidade. O desempenho funcional geralmente apresenta aumento no número de movimentos compensatórios. Não podemos sempre considerar o tempo como um bom marcador de funcionalidade para essa população, uma vez que não muda na mesma proporção que o número de compensações em todas essas pacientes. Conclusão: Fraqueza muscular assimétrica e movimentos compensatórios, ou ambos, podem ser encontrados em portadoras sintomáticas de DMD, o que pode afetar a postura e a funcionalidade dessas pacientes.

Functional performance and muscular strength in symptomatic female carriers of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) usually affects men. However, women are also affected in rare instances. Approximately 8% of female DMD carriers have muscle weakness and cardiomyopathy. The early identification of functional and motor impairments can support clinical decision making. OBJECTIVE: To investigate the motor and functional impairments of 10 female patients with dystrophinopathy diagnosed with clinical, pathological, genetic and immunohistochemical studies. METHODS: A descriptive study of a sample of symptomatic female carriers of DMD mutations. The studied variables were muscular strength and functional performance. RESULTS: The prevalence was 10/118 (8.4%) symptomatic female carriers. Deletions were found in seven patients. The age of onset of symptoms in female carriers of DMD was quite variable. Pseudohypertrophy of calf muscles, muscular weakness, compensatory movements and longer timed performance on functional tasks were observed in most of the cases. Differently from males with DMD, seven female patients showed asymmetrical muscular weakness. The asymmetric presentation of muscle weakness was frequent and affected posture and functionality in some cases. The functional performance presents greater number of compensatory movements. Time of execution of activities was not a good biomarker of functionality for this population, because it does not change in the same proportion as the number of movement compensations. CONCLUSION: Clinical manifestation of asymmetrical muscle weakness and compensatory movements, or both can be found in female carriers of DMD mutations, which can adversely affect posture and functional performance of these patients.

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.

Emergency room visits and admission rates of children with neuromuscular disorders: A 10-year experience in a medical center in Taiwan.

BACKGROUND: No previous studies have explored emergency medical care for children with chronic neuromuscular disorders (NMDs). We aimed to determine the major reasons for the emergency room (ER) readmission of pediatric patients with NMDs and suggest changes to the care plan to decrease readmissions. METHODS: Children with chronic NMDs (aged <18 years) who visited a medical center-based ER between January 2005 and January 2015 were included. The following data were extracted from the patient's ER records: presentations; demographic data, including sex and age; NMD diagnosis; triage classification; emergency examination; initial management and outcomes. The outcomes were death inside or outside the ER, admission to the ward or pediatric intensive care unit (PICU), uneventful discharge, and repeated ER visits. RESULTS: In 10 years, 44 children with heterogeneous NMDs (boys/girls: 30/14, mean age: 9.9 years) visited the ER for a total of 204 times. Repeated ER visits and readmissions occurred in 56.8% and 55.6% of the patients, respectively. Most NMD children belonged to triage class 3 (35.3%), with underlying congenital hereditary muscular dystrophy (44.1%). The major symptoms were usually multiple and concurrent, and primarily respiratory (62.3%) or gastrointestinal (28.9%). The most common causes of hospitalization were pneumonia (48.5%) or acute gastritis (20.4%), and approximately half of the ER visits required further hospitalization, of which 28.2% involved PICU admission. Twenty of the 36 children admitted to the ER required readmission. The most commonly prescribed examinations were complete blood count (38%) and C-reactive protein (38%), and the most common therapy was intravenous fluid administration (34%). Although respiratory compromise caused most ER visits and admissions, pulmonary assessments, including chest films (28%), pulse oximetry (15%), and blood gas analysis (11%), were performed in a relatively small proportion. CONCLUSION: The ER staff must recognize patients' unmet needs for respiratory and gastrointestinal care related to underlying NMDs.

A Review of MD STAR net's Research Contributions to Pediatric-Onset Dystrophinopathy in the United States; 2002-2017.

Population studies of rare disorders, such as Duchenne and Becker muscular dystrophies (dystrophinopathies), are challenging due to diagnostic delay and heterogeneity in disorder milestones. To address these challenges, the Centers for Disease Control and Prevention established the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STAR net) in 2002 in the United States. From 2002 to 2012, MD STAR net longitudinally tracked the prevalence, clinical, and health care outcomes of 1054 individuals born from 1982 to 2011 with pediatric-onset dystrophinopathy through medical record abstraction and survey data collection. This article summarizes 31 MD STAR net peer-reviewed publications. MD STAR net provided the first population-based prevalence estimates of childhood-onset dystrophinopathy in the United States. Additional publications provided insights into diagnostic delay, dystrophinopathy-specific growth charts, and health services use. Ongoing population-based surveillance continually improves our understanding of clinical and diagnostic outcomes of rare disorders.