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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.

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 Pelvic girdle pain (PGP) is a multifactorial condition, which can be mentally and physically compromising both during and after pregnancy. However, long-term pregnancy-related PGP has been poorly investigated. This longitudinal follow-up study uniquely aimed to describe prevalence and predictors of PGP and its consequences on women’s health and function up to 11 years after pregnancy. Methods/Design A postal questionnaire was sent to 530 women who participated in 1 of 3 randomized controlled studies for PGP in pregnancy. Women who reported experiencing lumbopelvic pain were offered a clinical examination. Main outcome measure was the presence of long term PGP as assessed by an independent examiner. Secondary outcomes were: working hours/week, function (the Disability Rating Index, and Oswestry Disability Index), self-efficacy (the General Self-Efficacy Scale), HRQL (Euro-Qol 5D and EQ-Visual scale), anxiety and depression, (Hospital anxiety and depression scale,) and pain-catastrophizing (Pain Catastrophizing Scale), in women with PGP compared to women with no PGP. Results A total of 371/530 (70 %) women responded and 37/ 371 (10 %) were classified with long-term PGP. Pregnancy-related predictors for long-term PGP were number of positive pain provocation tests (OR = 1.79), history of low back pain (LBP) (OR = 2.28), positive symphysis pressure test (OR = 2.01), positive Faber (Patrick’s) test (OR = 2.22), and positive modified Trendelenburg test (OR = 2.20). Women with PGP had significantly decreased ability to perform daily activities ( p  < .001), lower self-efficacy ( p  = 0.046), decreased HRQL ( p  < .001), higher levels of anxiety and depression ( p  < .001), were more prone to pain catastrophizing, and worked significantly fewer hours/week ( p  = 0.032) compared to women with no PGP. Conclusions This unique long-term follow up of PGP highlights the importance of assessment of pain in the lumbopelvic area early in pregnancy and postpartum in order to identify women with risk of long term pain. One of 10 women with PGP in pregnancy has severe consequences up to 11 years later. They could be identified by number of positive pain provocation tests and experience of previous LBP. Access to evidence based treatments are important for individual and socioeconomic reasons.

Muscular dystrophy‐dystroglycanopathy (limb‐girdle), type C, 9 (MDDGC9) is the rarest type of autosomal recessive muscular dystrophies. MDDGC9 is manifested with an early onset in childhood. Patients with MDDGC9 usually identified with defective glycosylation of DAG1, hence it is known as “dystroglycanopathies”. Here, we report a Chinese pedigree presented with mild MDDGC9. The proband is a 64 years old Chinese man. In this family, both the proband and proband's younger brother have been suffering from mild and late onset MDDGC9. Muscle biopsy showed that the left deltoid muscle with an advanced stage of dystrophic change. Immunohistochemistry staining of dystrophin, α‐sarcoglycan, β‐sarcoglycan and dysferlin are normal. Molecular genetic analysis of the proband has been done with whole exome sequencing. A homozygous novel missense mutation (c.2326C>T; p.R776C) in the exon 3 of the DAG1 gene has been identified in the proband. Sanger sequencing revealed that this missense mutation is co‐segregated well among the affected and unaffected (carrier) family members. This mutation is not detected in 200 normal healthy control individuals. This novel homozygous missense mutation (c.2326C>T) causes substitution of arginine by cystine at the position of 776 (p.R776C) which is evolutionarily highly conserved. Immunoblotting studies revealed that a significant reduction of α‐dystroglycan expression in the muscle tissue. The novelty of our study is that it is a first report of DAG1 associated muscular dystrophy‐dystroglycanopathy (limb‐girdle), type C, 9 (MDDGC9) with mild and late age of onset. In Chinese population this is the first report of DAG1 associated MDDGC9.

Background Limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A) is a progressive myopathy caused by deficiency of calpain 3, a calcium-dependent cysteine protease of skeletal muscle, and it represents the most frequent type of LGMD worldwide. In the last few years, muscle magnetic resonance imaging (MRI) has been proposed as a tool for identifying patterns of muscular involvement in genetic disorders and as a biomarker of disease progression in muscle diseases. In this study, 57 molecularly confirmed LGMDR1 patients from a European cohort (age range 7–78 years) underwent muscle MRI and a global evaluation of functional status (Gardner-Medwin and Walton score and ability to raise the arms). Results We confirmed a specific pattern of fatty substitution involving predominantly the hip adductors and hamstrings in lower limbs. Spine extensors were more severely affected than spine rotators, in agreement with higher incidence of lordosis than scoliosis in LGMDR1. Hierarchical clustering of lower limb MRI scores showed that involvement of anterior thigh muscles discriminates between classes of disease progression. Severity of muscle fatty substitution was significantly correlated with CAPN3 mutations: in particular, patients with no or one “null” alleles showed a milder involvement, compared to patients with two null alleles (i.e., predicting absence of calpain-3 protein). Expectedly, fat infiltration scores strongly correlated with functional measures. The “pseudocollagen” sign (central areas of sparing in some muscle) was associated with longer and more severe disease course. Conclusions We conclude that skeletal muscle MRI represents a useful tool in the diagnostic workup and clinical management of LGMDR1.

Background Water T2 (T2H2O) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. Methods Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3‐tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. Results A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6‐min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. Conclusions In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter‐patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. The identification of pathogenic mutations within prion-like domains (PrLDs) of the RNA-binding proteins hnRNPA2B1 and hnRNPA1 add to our understanding of how mutations in these proteins lead to degenerative disease, and highlight the potential importance of PrLDs in degenerative diseases of the nervous system, muscle and bone. Disease link to prion-like RNA-binding protein How do mutations in RNA-binding proteins cause human disease, and neurodegeneration in particular? Hong Joo Kim et al . have identified mutations in two RNA-binding proteins, hnRNPA2B1 and hnRNPA1, in two families with inclusion body myopathy with frontotemporal dementia. Both of the mutations lie within a highly conserved part of a protein domain that has similarities to prion proteins, and a tendency to aggregate. This aggregation is enhanced by the mutations. The mutated prion-like domain of hnRNPA2 can functionally replace that of a yeast prion protein and reproduce its prion-like behaviour. These findings have relevance to the pathogenesis of degenerative diseases and proteinopathies such as amyotrophic lateral sclerosis.

Establishing well-described mouse models of hereditary diseases is increasingly important for testing new therapeutic approaches, such as gene replacement therapy. In particular, a detailed description of muscle pathology, especially at early timepoints of the disease, is crucial for determining the optimal timepoint for drug delivery and evaluation of therapeutic success. In this study, we aimed to characterize and quantify the muscle pathology and myofibre morphology of different muscles in a new mouse model for calpainopathy as an example of the heterogenous group of limb girdle muscular dystrophies compared to wildtype controls during the disease. We analysed motor function and muscle tissue of wildtype and Capn3- transgenic mice per gender from 1.5 to 15 months of age. While transgenic mice did not develop restrictions in motor function, tested with grip strength measurement, beam walk and four limb wire hanging test, during this period, gastrocnemius, soleus and psoas muscles showed progressive histopathological and ultrastructural changes. Importantly, we also detected gender-specific differences in general muscle structure and in muscle pathology in the mouse model of calpainopathy. We developed a score to classify pathology of muscles in this mouse model using percentage of myocytes with centralized nuclei to increase objectivity and comparability when using this mouse model.

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.

Muscle loss due to fibrotic or adipogenic replacement of myofibers is common in muscle diseases and muscle-resident fibro/adipogenic precursors (FAPs) are implicated in this process. While FAP-mediated muscle fibrosis is widely studied in muscle diseases, the role of FAPs in adipogenic muscle loss is not well understood. Adipogenic muscle loss is a feature of limb girdle muscular dystrophy 2B (LGMD2B) – a disease caused by mutations in dysferlin. Here we show that FAPs cause the adipogenic loss of dysferlin deficient muscle. Progressive accumulation of Annexin A2 (AnxA2) in the myofiber matrix causes FAP differentiation into adipocytes. Lack of AnxA2 prevents FAP adipogenesis, protecting against adipogenic loss of dysferlinopathic muscle while exogenous AnxA2 enhances muscle loss. Pharmacological inhibition of FAP adipogenesis arrests adipogenic replacement and degeneration of dysferlin-deficient muscle. These results demonstrate the pathogenic role of FAPs in LGMD2B and establish these cells as therapeutic targets to ameliorate muscle loss in patients. Fibroadipogenic precursor cells (FAPs) contribute to fibrosis and adipogenic replacement in muscular dystrophies. Here, the authors show that FAPs contribute to adipogenic loss in mouse models of limb girdle muscular dystrophy 2B via a mechanism dependent on expression of Annexin A2, and that this process can be prevented by its pharmacologic inhibition in mice.