A Journey with LGMD: From Protein Abnormalities to Patient Impact

Abstract

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.

Keywords: Anoctaminopathy—LGMD R12 (2L); Calpainopathy—LGMD R1 (2A); Dysferlinopathy—LGMD R2 (2B); Dystroglycanopathies—LGMD R9 (2I); Limb-girdle muscular dystrophy (LGMD); Sarcoglycanopathies—LGMD R3-6 (2C-2F).

Fig. 1

Schematic diagram with the cellular localizations of proteins within the sarcolemma, cytosol or nucleus of myocytes, associated with various LGMD subtypes (note: R15 related protein is also found in endoplasmic reticulum). Both the reclassified subtypes (R# and D# in rectangles) and the recently removed dominant subtypes (1# in circles) are included in this diagram; the decommissioned recessive subtypes are not shown in the figure. The top part of the diagram shows the extracellular space, including the extracellular matrix and basal lamina; the sarcolemma is in the middle; located at the bottom are the nucleus and cytoplasm, including sarcomere, Golgi apparatus, and endoplasmic reticulum. The proteins related to the different LGMD subtypes are individually labeled in the figure

Fig. 2

Overview of range of patient journeys for five of the most prevalent recessive LGMD subtypes. Journey pathway I: severe disease progression involving early loss of ambulation, early-onset cardiac and/or respiratory complications, and likely ending in very early death; most common among LGMD R3-R6. Journey pathway II: early onset disease that progresses rapidly and results in early loss of ambulation and mortality; most common among LGMD R3-R6. Journey pathway III: slower progressing disease with onset in adolescence to early adulthood and loss of ambulation within a decade; common among LGMD R1. Journey pathway IV: slowly progressing disease with onset in adulthood and lower probability of losing ambulation; common among LGMD R2. Journey pathway V: very slowly progressing disease with onset in middle-to-late adulthood, mild symptoms, and a low probability of losing ambulation; common among LGMD R12

Fig. 3

Age of symptom onset for common LGMD R subtypes. Lower range (light grey), upper range (darker grey), and average (darkest grey bar) age at symptom onset for common recessive LGMD subtypes

Fig. 4

Burden of illness that includes the cost of care, including the physical and emotional symptoms of the disease, the assistive services and home adaptive modifications, compounded by the loss of productivity and the additive effect of comorbidities