The Limb-Girdle Muscular Dystrophies

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.

Address correspondence to Dr Nicholas E. Johnson, Virginia Commonwealth University, 1101 East Marshall St, Box 980599, Richmond, VA 23298, [email protected].

RELATIONSHIP DISCLOSURE: Dr Johnson has received personal compensation in the range of $500 to $4999 for serving as a consultant for Acceleron Pharma, Avidity Biosciences, Dyne Therapeutics, Entrada Therapeutics, Juvena Therapeutics, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharmaceuticals and for serving on a scientific advisory or data safety monitoring board for Biogen; in the range of $10,000 to $49,999 for serving as a consultant for Arthex Biotech; and in the range of $50,000 to $99,999 for serving as a consultant for ML Bio Solutions. Dr Johnson holds stock in ML Bio Solutions and has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr Johnson has received research support from AMO Pharma, Dyne Therapeutics, Entrada Therapeutics, Fulcrum Therapeutics, ML Bio Solutions, Novartis Gene Therapies, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharmaceuticals. Dr Statland has received personal compensation in the range of $500 to $4999 for serving as a consultant for Arrowhead Pharmaceuticals, Mitsubishi Tanabe Pharma, and ML Bio Solutions, and for serving on a scientific advisory or data safety monitoring board for Avidity Biosciences; in the range of $5000 to $9999 for serving on a scientific advisory or data safety monitoring board for Fulcrum Therapeutics; and in the range of $10,000 to $49,999 for serving on a scientific advisory or data safety monitoring board for Dyne Therapeutics. The institution of Dr Statland has received research support from Friends of FSH Research, FSHD Canada, FSHD Society, the Muscular Dystrophy Association, and the National Institutes of Health.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Drs Johnson and Statland report no disclosures.