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This study aimed to study the diagnostic value of targeted next-generation sequencing (NGS) in limb-girdle muscular dystrophies (LGMDs), and investigate the mutational spectrum of Chinese LGMD patients. We performed targeted NGS covering 420 genes in 180 patients who were consecutively suspected of LGMDs and underwent muscle biopsies from January 2013 to May 2015. The association between genotype and myopathological profiles was analyzed in the genetically confirmed LGMD patients. With targeted NGS, one or more rare variants were detected in 138 patients, of whom 113 had causative mutations, 10 sporadic patients had one pathogenic heterozygous mutation related to a recessive pattern of LGMDs, and 15 had variants of uncertain significance. No disease-causing mutation was found in the remaining 42 patients. Combined with the myopathological findings, we achieved a positive genetic diagnostic rate as 68.3% (123/180). Totally 105 patients were diagnosed as LGMDs with genetic basis. Among these 105 patients, the most common subtypes were LGMD2B in 52 (49.5%), LGMD2A in 26 (24.8%) and LGMD 2D in eight (7.6%), followed by LGMD1B in seven (6.7%), LGMD1E in four (3.8%), LGMD2I in three (2.9%), and LGMD2E, 2F, 2H, 2K, 2L in one patient (1.0%), respectively. Although some characteristic pathological changes may suggest certain LGMD subtypes, both heterogeneous findings in a certain subtype and overlapping presentations among different subtypes were not uncommon. The application of NGS, together with thorough clinical and myopathological evaluation, can substantially improve the molecular diagnostic rate in LGMDs. Confirming the genetic diagnosis in LGMD patients can help improve our understanding of their myopathological changes.

Purpose Limb-girdle muscular dystrophies (LGMD) are a genetically heterogeneous category of autosomal inherited muscle diseases. Many genes causing LGMD have been identified, and clinical trials are beginning for treatment of some genetic subtypes. However, even with the gene-level mechanisms known, it is still difficult to get a robust and generalizable prevalence estimation for each subtype due to the limited amount of epidemiology data and the low incidence of LGMDs. Methods Taking advantage of recently published exome and genome sequencing data from the general population, we used a Bayesian method to develop a robust disease prevalence estimator. Results This method was applied to nine recessive LGMD subtypes. The estimated disease prevalence calculated by this method was largely comparable with published estimates from epidemiological studies; however, it highlighted instances of possible underdiagnosis for LGMD2B and 2L. Conclusion The increasing size of aggregated population variant databases will allow for robust and reproducible prevalence estimates of recessive disease, which is critical for the strategic design and prioritization of clinical trials.

The limb-girdle muscular dystrophies (LGMD) are a collection of genetic diseases united in their phenotypical expression of pelvic and shoulder area weakness and wasting. More than 30 subtypes have been identified, five dominant and 26 recessive. The increase in the characterization of new genotypes in the family of LGMDs further adds to the heterogeneity of the disease. Meanwhile, better understanding of the phenotype led to the reconsideration of the disease definition, which resulted in eight old subtypes to be no longer recognized officially as LGMD and five new diseases to be added to the LGMD family. The unique variabilities of LGMD stem from genetic mutations, which then lead to protein and ultimately muscle dysfunction. Herein, we review the LGMD pathway, starting with the genetic mutations that encode proteins involved in muscle maintenance and repair, and including the genotype–phenotype relationship of the disease, the epidemiology, disease progression, burden of illness, and emerging treatments.

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. Revue systématique et méta-analyse de l’épidémiologie des dystrophies musculaires. Contexte: Les dystrophies musculaires constituent un groupe hétérogène de maladies musculaires génétiques ayant une distribution de la faiblesse et une hérédité variables. Méthode: Nous avons effectué antérieurement une revue systématique des études populationnelles du monde entier sur la dystrophie musculaire de Duchenne et celle de Becker. Cette étude, effectuée dans les bases de données Medline et EMBASE, cible l’épidémiologie d’autres dystrophies musculaires. Deux examinateurs indépendants ont revu tous les résumés, le texte intégral des articles et les données publiées de 1985 à 2011. Le regroupement des estimés de prévalence a été effectué au moyen de modèles à effets aléatoires. Résultats: En tout, 1104 résumés et 167 articles en texte intégral ont été revus. Trente et une études rencontraient tous les critères d’éligibilité et ont été incluses dans l’analyse finale. La prévalence globale des dystrophies musculaires combinées était de 16,14 (intervalle de confiance [IC] de 11,21 à 23,23) par 100,000 de population. Les estimés de prévalence par 100,000 étaient de 8,26 (IC : 4,99 à 13,68) pour la dystrophie myotonique, 3,95 (IC : 2,89 à 5,40) pour la myopathie facio-scapulo-humérale, 1,63 (IC : 0,94 à 2,81) pour la myopathie scapulo-humérale et 0,99 (IC : 0,62 à 1,57) pour les dystrophies musculaires congénitales. Conclusions: Les études utilisaient des approches sensiblement différentes pour l’identification des cas et il existe des écarts considérables dans les estimés globaux de plusieurs autres types de dystrophies musculaires. D’autres études épidémiologiques utilisant des critères diagnostiques standardisés ainsi que de multiples sources d’identification des cas aideront à faire face à l’impact économique et au fardeau des soins de santé engendrés par les dystrophies musculaires à l’échelle mondiale.

Background Limb‐girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders characterized by progressive proximal weakness. LGMD D3 is an extremely rare autosomal dominant myopathy caused by pathogenic variants in the HNRNPDL gene encoding a protein related to RNA processing. To date, only six countries and seven families have been reported worldwide: Brazil, China and Italy with the pathogenic variant c.1132G>A p.(Asp378Asn), Uruguay, Argentina and Spain with the pathogenic variant c.1132G>C p.(Asp378His). Methods The study was conducted in the city of Nueva Palmira in Uruguay between March 2019 to August 2024. Forty‐nine patients with LGMD D3 and 10 asymptomatic individuals carrying the mutation were examined. Serum CK, electromyography, MRI, and pulmonary function testing results were reviewed when available. Whole exome sequencing and screening test for the mutation were performed. Statistical analysis was done using STATA 16.1. Results LGMD D3 in Uruguay presents as a slowly progressive adult‐onset scapulo‐pelvic‐peroneal dystrophy. Pathogenic variant c.1132G>C p.(Asp378His) was confirmed in all participants. Estimated prevalence of LGMD D3 was 3.75/1000 in Nueva Palmira. Mean age of onset differed by sex, with men presenting younger (p = 0.006). Characteristic MRI features were observed. Conclusions LGMD D3 presents with a distinctive scapulo‐pelvic‐peroneal phenotype. To our knowledge, this is the largest LGMD D3 cluster and the first report of sex‐dependent age of onset. Our study illustrates how genetic isolation can lead to high LGMD D3 prevalence in an admixed population and explores its potential origin. LGMD D3 in Uruguay presents as a slowly progressive adult‐onset scapulo‐pelvic‐peroneal dystrophy. Pathogenic variant c.1132G>C p.(Asp378His) was confirmed in all participants. This is the largest LGMD D3 cluster and first report of sex‐dependent age of onset. This study illustrates how genetic isolation can lead to high LGMD D3 prevalence in an admixed population.

Background and Objectives: Limb–girdle muscular dystrophies (LGMDs) are a group of muscular dystrophies characterized by predominantly proximal-muscle weakness, with a highly heterogeneous genetic etiology. Despite recent efforts, the epidemiology of LGMDs is still under-evaluated. However, a better understanding of the distribution and genetic characteristics of LGMDs is required to optimize the diagnostic process and to address future research. Therefore, the aim of the present study is to investigate and identify new pathogenic variants, to better characterize LGMDs in Sicily. Methods: We enrolled patients with genetic and clinical diagnosis of LGMD referred to our clinic between the years 2019 and 2025. A targeted next-generation-sequencing (NGS) panel was performed, based on the reported disease frequency. A retrospective analysis of the clinical, laboratory, electrophysiological, and histological features was performed. Results: A total of 28 LGMDs patients aged 56.6 years (47.2–60.5 IQR) were identified (16 males, 57%). A molecular diagnosis was achieved in 24 (85.7%) of patients, most commonly carrying mutations in CAPN3 (14 patients, 50%), followed by DYSF, LAMA2, ANO5, FKTN and TTN genes. Pathogenic variants in CAPN3 and LAMA2 were associated with earlier onset and longer disease duration, whereas ANO5 presented later with a milder course. Cardiac involvement was observed more frequently in patients with LAMA2 and FKTN mutations. Association between heterozygous mutations in the CAPN3 and DYSF, as well as between CAPN3 and DMD variants were reported. Discussion: The findings of this study provide valuable insights into the epidemiology of LGMDs in the Western Sicily, offering important contributions to genotype–phenotype correlations. Our analysis highlights the role of genetic diagnosis in achieving accurate classification of the disease and optimizing clinical management.

Limb-girdle muscular dystrophy R9 (LGMDR9) is a progressive and disabling genetic muscle disease. Sleep is relevant in the patient care as it impacts on health, functioning, and well-being. LGMDR9 may potentially affect sleep by physical or emotional symptoms, myalgia, or sleep-disordered breathing (SDB) through cardiorespiratory involvement. The objective was to investigate the occurrence of insomnia and unrecognized or untreated SDB in LGMDR9, associated factors, and relationships with fatigue and health-related quality of life (HRQoL). All 90 adults in a Norwegian LGMDR9 cohort received questionnaires on sleep, fatigue, and HRQoL. Forty-nine of them underwent clinical assessments and 26 without mask-based therapy for respiration disorders additionally underwent polysomnography (PSG) and capnometry. Among 77 questionnaire respondents, 31% received mask-based therapy. The prevalence of insomnia was 32% of both those with and without such therapy but was significantly increased in fatigued respondents (54% vs 21%). Insomnia levels correlated inversely with mental HRQoL. Among 26 PSG candidates, an apnea–hypopnea index (AHI) ≥ 5/h was observed in 16/26 subjects (≥ 15/h in 8/26) with median 6.8 obstructive apneas and 0.2 central apneas per hour of sleep. The AHI was related to advancing age and an ejection fraction < 50%. Sleep-related hypoventilation was detected in one subject. Fatigue severity did not correlate with motor function or nocturnal metrics of respiration or sleep but with Maximal Inspiratory Pressure (r = − 0.46). The results indicate that insomnia and SDB are underrecognized comorbidities in LGMDR9 and associated with HRQoL impairment and heart failure, respectively. We propose an increased attention to insomnia and SDB in the interdisciplinary care of LGMDR9. Insomnia and pulmonary function should be examined in fatigued patients.

Limb–girdle muscular dystrophies (LGMD) designate diverse types of muscular dystrophies that predominantly affect proximal skeletal muscles. Although both autosomal recessive and dominant forms exist, the majority of cases are inherited in an autosomal recessive manner. Since the spectrum of genetic variants that cause this disorder is quite broad, next-generation sequencing techniques are the best diagnostic tools for LGMD. In this study, we provide an overview of mutation spectrum of LGMD-related genes in the Iranian patients using whole exome sequencing. Notably, CAPN3 and LAMA2 genes were the genes encompassing the highest frequencies of pathogenic or likely pathogenic variants in this cohort. Pathogenic and likely pathogenic variants were identified in CAPN3 gene in total of 10 cases out of 48 cases tested (20%). In addition, different variants in each of POMGNT1 and TTN genes were detected in five and four patients, respectively. Three patients had DYSF variants (6%). While the inheritance of the majority of cases was supposed to be in an autosomal recessive manner, in three cases, the disease inheritance was best explained by the dominant type (c.947 C > T variant in the DNAJB6 , c.746G > A variant in the LMNA , and c.1417G > A variant in the TNPO3 ). The current study broadens the spectrum of LGMD-related mutations among Iranian patients and facilitates genetic counseling in the affected families.

Dysferlinopathies are a group of limb-girdle muscular dystrophies causing significant disability in the young population. There is a need for studies on large cohorts to describe the clinical, genotypic and natural history in our subcontinent. To describe and correlate the clinical, genetic profile and natural history of genetically confirmed dysferlinopathies. We analysed a retrospective cohort of patients with dysferlinopathy from a single quaternary care centre in India. A total of 124 patients with dysferlinopathy were included (40 females). Median age at onset and duration of illness were 21 years (range, 13–50) and 48 months (range, 8–288), respectively. The average follow-up period was 60 months (range, 12–288). Fifty-one percent had LGMD pattern of weakness at onset; 23.4% each had Miyoshi and proximo-distal type while isolated hyperCKemia was noted in 1.6%. About 60% were born to consanguineous parents and 26.6% had family history of similar illness. Twenty-three patients (18.6%) lost ambulation at follow-up; the median time to loss of independent ambulation was 120 months (range, 72–264). Single-nucleotide variants (SNVs) constituted 78.2% of patients; INDELs 14.5% and 7.3% had both SNVs and INDELs. Earlier age at onset was noted with SNVs. There was no correlation between the other clinical parameters and ambulatory status with the genotype. Thirty-seven (45.7%) novel pathogenic/likely pathogenic (P/LP) variants were identified out of a total of 81 variations. The c.3191G > A variant was the most recurrent mutation. Our cohort constitutes a clinically and genetically heterogeneous group of dysferlinopathies. There is no significant correlation between the clinico-genetic profile and the ambulatory status.

BackgroundDystroglycanopathies are a heterogeneous group of membrane-related muscular dystrophies. The dystroglycanopathy phenotype includes a spectrum of severity ranging from severe congenital muscular dystrophy to adult-onset limb–girdle muscular dystrophy (LGMD). LGMDR9 is a dystroglycanopathy caused by mutations in the FKRP gene. Previous studies have characterized electroretinogram findings of dystroglycanopathy mouse models but have not been reported in humans.PurposeThis study set out to characterize the electroretinogram in eight participants with LGMDR9.MethodsEight participants were recruited from an ongoing dystroglycanopathy natural history study at the University of Iowa (NCT00313677). Inclusion criteria for the current study were children and adults > 6 years old with confirmed LGMDR9. Age similar controls were identified from our electrophysiology service normative control database. Full-field electroretinograms were recorded using ISCEV standards. Six of the eight participants underwent light-adapted ON/OFF testing.ResultsThe electronegative electroretinogram was not seen in any participants with LGMDR9. An unusual sawtooth pattern in the 30 Hz flicker with faster rise than descent was noted in all 8 participants. Our cases showed a decreased b-wave amplitude in light-adapted ON responses (p = 0.011) and decreased d-wave amplitude in light-adapted OFF responses (p = 0.015). Decreased b-wave amplitude in light-adapted 3.0 testing (p = 0.015) and decreased flicker ERG amplitudes were also detected (p = 0.0018). Additionally, compared to controls, participants with LGMDR9 had decreased a-wave amplitudes on dark-adapted 10 testing (p = 0.026).ConclusionsAbnormal ON/OFF bipolar cell responses and sawtooth 30 Hz flicker waveforms on full-field electroretinogram may be specific for LGMDR9. If confirmed in a larger population and if related to disease stage, these tests are potential biomarkers which could be useful as endpoints in clinical treatment trials.