The Limb-Girdle Muscular Dystrophies

Abstract

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 recessiveLGMDs 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.

Molecular Diagnosis of Limb-Girdle Muscular Dystrophy Using Next-Generation Sequencing Panels

“…In this respect, our study shows that invasive diagnostic methods shifted to genetic analysis methods. In the current literature, NGS takes the first place in the diagnosis of the LGMD diagnostic algorithm, and genetic confirmation is recommended even in patients diagnosed with muscle biopsy [Johnson and Statland, 2022]. In this respect, our study supports the accuracy of this approach.…”

“…In recent years, NGS has become the primary diagnostic method for LGMD [Johnson and Statland, 2022]. In our study, the diagnosis rate achieved 61.1%.…”

Current Classification of Canine Muscular Dystrophies and Identification of New Variants

“…In people, the discovery in 1987 of the gene encoding dystrophin ( DMD ), responsible for X-linked Duchenne and Becker muscular dystrophy, paved the way for identifying and characterizing the role of many other sarcolemmal and extracellular matrix proteins, such as the sarcoglycans and laminin α2, and their own roles in other forms of muscular dystrophies [ 1 ]. Defects in other membrane proteins including dysferlin, caveolin 3, telethonin, as well as the enzyme calpain 3 also result in forms of limb–girdle and congenital muscular dystrophies [ 2 ]. Mutations in nuclear membrane proteins such as emerin, lamin A/C and nesprins are responsible for Emery–Dreifuss forms of muscular dystrophy [ 3 ].…”

Trials for Slowly Progressive Neurogenetic Diseases Need Surrogate Endpoints

“…However, to be conservative, clinical trials in these diseases will likely be initially powered to detect slowing of disease progression. Investigators have therefore developed clinical outcome assessments (COAs) and disease biomarkers to track disease progression 10–14 …”

“…Investigators have therefore developed clinical outcome assessments (COAs) and disease biomarkers to track disease progression. [10][11][12][13][14] CMT is a good model of these challenges. Variants in >100 CMT genes/encoded proteins, and an even larger number of genes that cause neuropathy as part of complex inherited syndromes, 15 constitute a large group of genes/ proteins that are necessary for the normal function of myelinated axons in the human PNS.…”