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Continuum (Minneapolis, Minn.) Dec 2022The limb-girdle muscular dystrophies (LGMDs) are a group of inherited muscle disorders with a common feature of limb-girdle pattern of weakness, caused by over 29... (Review)
Review
PURPOSE OF REVIEW
The limb-girdle muscular dystrophies (LGMDs) are a group of inherited muscle disorders with a common feature of limb-girdle pattern of weakness, caused by over 29 individual genes. This article describes the classification scheme, common subtypes, and the management of individuals with LGMD.
RECENT FINDINGS
Advances in genetic testing and next-generation sequencing panels containing all of the LGMD genes have led to earlier genetic confirmation, but also to more individuals with variants of uncertain significance. The LGMDs include disorders with autosomal recessive inheritance, which are often due to loss-of-function mutations in muscle structural or repair proteins and typically have younger ages of onset and more rapidly progressive presentations, and those with autosomal dominant inheritance, which can have older ages of presentation and chronic progressive disease courses. All cause progressive disability and potential loss of ability to walk or maintain a job due to progressive muscle wasting. Certain mutations are associated with cardiac or respiratory involvement. No disease-altering therapies have been approved by the US Food and Drug Administration (FDA) for LGMDs and standard treatment uses a multidisciplinary clinic model, but recessive LGMDs are potentially amenable to systemic gene replacement therapies, which are already being tested in clinical trials for sarcoglycan and FKRP mutations. The dominant LGMDs may be amenable to RNA-based therapeutic approaches.
SUMMARY
International efforts are underway to better characterize LGMDs, help resolve variants of uncertain significance, provide consistent and improved standards of care, and prepare for future clinical trials.
Topics: Humans; Muscular Dystrophies, Limb-Girdle; Mutation; Genetic Testing; Genetic Therapy; Ambulatory Care Facilities; Pentosyltransferases
PubMed: 36537976
DOI: 10.1212/CON.0000000000001178 -
Annals of Physical and Rehabilitation... Jan 2021Several studies reported the importance of glenohumeral and scapular muscle activity and scapular kinematics in multidirectional shoulder instability (MDI), yet a... (Review)
Review
BACKGROUND
Several studies reported the importance of glenohumeral and scapular muscle activity and scapular kinematics in multidirectional shoulder instability (MDI), yet a systematic overview is currently lacking.
OBJECTIVE
This systematic review evaluates and summarizes the evidence regarding muscle activity and shoulder kinematics in individuals with MDI compared to healthy controls.
METHOD
The electronic databases PubMed and Web of Science were searched in September 2020 with key words regarding MDI (population), muscle activity, and glenohumeral and scapular movement patterns (outcomes). All studies that compared muscle activity or scapular kinematics between shoulders with MDI and healthy shoulders were eligible for this review, except for case reports and case series. All articles were screened on the title and abstract, and remaining eligible articles were screened on full text. The risk of bias of included articles was assessed by a checklist for case-control data, as advised by the Cochrane collaboration.
RESULTS
After full text screening, 12 articles remained for inclusion and one study was obtained by hand search. According to the guidelines of the Dutch Institute for Healthcare Improvement, most studies were of moderate methodological quality. We found moderate evidence that MDI individuals show increased or prolonged activity of several rotator cuff muscles that control and centre the humeral head. Furthermore, we found evidence of decreased and/or shortened activity of muscles that move or accelerate the arm and shoulder girdle as well as increased and/or lengthened activity of muscles that decelerate the arm and shoulder girdle. The most consistent kinematic finding was that MDI individuals show significantly less upward rotation and more internal rotation of the scapula during elevation of the arm in the scapular plane as compared with controls. Finally, several studies also suggest that the humeral head demonstrates increased translations relative to the glenoid surface.
CONCLUSION
There is moderate evidence for altered muscle activity and altered humeral and scapular kinematics in MDI individuals as compared with controls.
Topics: Biomechanical Phenomena; Humans; Joint Instability; Muscle, Skeletal; Range of Motion, Articular; Scapula; Shoulder; Shoulder Joint
PubMed: 33221471
DOI: 10.1016/j.rehab.2020.10.008 -
Clinical Genetics Aug 2019In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular...
In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.
Topics: Alleles; Biomarkers; Biopsy; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Muscular Dystrophies, Limb-Girdle; Netherlands; Phenotype; Population Surveillance; Retrospective Studies
PubMed: 30919934
DOI: 10.1111/cge.13544 -
Neuromuscular Disorders : NMD Oct 2021Sarcoglycanopathies are the most severe forms of autosomal recessive limb-girdle muscular dystrophies (LGMDs), constituting about 10-25% of LGMDs. The clinical phenotype... (Review)
Review
Sarcoglycanopathies are the most severe forms of autosomal recessive limb-girdle muscular dystrophies (LGMDs), constituting about 10-25% of LGMDs. The clinical phenotype is variable, but onset is usually in the first decade of life. Patients present muscle hypertrophy, elevated CK, variable muscle weaknesses, and progressive loss of ambulation. Four subtypes are known: LGMDR3, LGMDR4, LGMDR5 and LGMDR6, caused, respectively, by mutations in the SGCA, SGCB,SGCG and SGCD genes. Their four coded proteins, α-SG, ß-SG, λ-SG and δ-SG are part of the dystrophin-glycoprotein complex (DGC) present in muscle sarcolemma, which acts as a linker between the cytoskeleton of the muscle fiber and the extracellular matrix, providing mechanical support to the sarcolemma during myofiber contraction. Many different mutations have already been identified in all the sarcoglycan genes, with a predominance of some mutations in different populations. The diagnosis is currently based on the molecular screening for these mutations. Therapeutic approaches include the strategy of gene replacement mediated by a vector derived from adeno-associated virus (AAV). Pre-clinical studies have shown detectable levels of SG proteins in the muscle, and some improvement in the phenotype, in animal models. Therapeutic trials in humans are ongoing.
Topics: Dependovirus; Genetic Therapy; Humans; Muscle, Skeletal; Mutation; Phenotype; Sarcoglycanopathies; Sarcoglycans
PubMed: 34404573
DOI: 10.1016/j.nmd.2021.07.014 -
Journal of Clinical Medicine Jul 2023Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes. This review article presents 39 genes associated with LGMDs. Some forms are inherited... (Review)
Review
Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes. This review article presents 39 genes associated with LGMDs. Some forms are inherited in a dominant fashion, while for others this occurs recessively. The classification of LGMDs has evolved through time. Lately, to be considered an LGMD, the mutation has to cause a predominant proximal muscle weakness and must be found in two or more unrelated families. This article also presents therapies for LGMDs, examining both available treatments and those in development. For now, only symptomatic treatments are available for patients. The goal is now to solve the problem at the root of LGMDs instead of treating each symptom individually. In the last decade, multiple other potential treatments were developed and studied, such as stem-cell transplantation, exon skipping, gene delivery, RNAi, and gene editing.
PubMed: 37510884
DOI: 10.3390/jcm12144769 -
Cells Feb 2020Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there... (Review)
Review
Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there are six ferlin genes encoding, in humans, dysferlin, otoferlin, myoferlin, Fer1L5 and 6 and the long noncoding RNA Fer1L4. Mutations in (dysferlin) can cause a range of muscle diseases with various clinical manifestations collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. A mutation in (myoferlin) was linked to a muscular dystrophy accompanied by cardiomyopathy. Mutations in (otoferlin) can be the cause of nonsyndromic deafness DFNB9. Dysregulated expression of any human ferlin may be associated with development of cancer. This review provides a detailed description of functions of the vertebrate ferlins with a focus on muscle ferlins and discusses the mechanisms leading to disease development.
Topics: Animals; Humans; Muscular Dystrophies, Limb-Girdle; Vertebrates
PubMed: 32106631
DOI: 10.3390/cells9030534 -
Clinical Genetics Dec 2022Dysferlinopathies are a clinically heterogeneous group of diseases caused by mutations in the DYSF gene encoding the dysferlin protein. Dysferlin is mostly expressed in... (Review)
Review
Dysferlinopathies are a clinically heterogeneous group of diseases caused by mutations in the DYSF gene encoding the dysferlin protein. Dysferlin is mostly expressed in muscle tissues and is localized in the sarcolemma, where it performs its main function of resealing and maintaining of the integrity of the cell membrane. At least four forms of dysferlinopathies have been described: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset, and isolated hyperCKemia. Here we review the clinical features of different forms of dysferlinopathies and attempt to identify genotype-phenotype correlations. Because of the great clinical variability and rarety of the disease and mutations little is known, how different phenotypes develop as a result of different mutations. However, missense mutations seem to induce more severe disease than LoF, which is typical for many muscle dystrophies. The role of several specific mutations and possible gene modifiers is also discussed in the paper.
Topics: Humans; Dysferlin; Muscle Proteins; Membrane Proteins; Muscular Dystrophies, Limb-Girdle; Distal Myopathies; Mutation
PubMed: 36029111
DOI: 10.1111/cge.14216 -
Current Gene Therapy 2020The Limb-Girdle Muscular Dystrophies (LGMD) are genetically heterogeneous disorders, responsible for muscle wasting and severe form of dystrophies. Despite the critical... (Review)
Review
The Limb-Girdle Muscular Dystrophies (LGMD) are genetically heterogeneous disorders, responsible for muscle wasting and severe form of dystrophies. Despite the critical developments in the insight and information of pathomechanisms of limb-girdle muscular dystrophy, any definitive treatments do not exist, and current strategies are only based on the improvement of the signs of disorder and to enhance the life quality without resolving an underlying cause. There is a crucial relationship between pharmacological therapy and different consequences; therefore, other treatment strategies will be required. New approaches, such as gene replacement, gene transfer, exon skipping, siRNA knockdown, and anti-myostatin therapy, which can target specific cellular or molecular mechanism of LGMD, could be a promising avenue for the treatment. Recently, genome engineering strategies with a focus on molecular tools such as CRISPR-Cas9 are used to different types of neuromuscular disorders and show the highest potential for clinical translation of these therapies. Thus, recent advancements and challenges in the field will be reviewed in this paper.
Topics: Animals; CRISPR-Cas Systems; Disease Models, Animal; Exons; Gene Editing; Genetic Therapy; Humans; Induced Pluripotent Stem Cells; Mesenchymal Stem Cells; Mice; Muscular Dystrophies, Limb-Girdle; RNA, Small Interfering; Transplants
PubMed: 32067617
DOI: 10.2174/1566523220666200218113526