By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Sarcoglycanopathies, caused by various genetic mutations, may cause limb-girdle forms of muscular dystrophy early in life. Although there are no specific treatments for these disorders at this time, the clinical and genetic characterizations will assist in more precise diagnosis that will be critical to develop new molecular-based therapies.
SOURCE: Guimarães-Costa RG, Fernández-Eulate G, Wahbi K, et al. Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies. Eur J Neurol 2021;28:660-669.
Sarcoglycanopathies, caused by mutations of the α-, β-, γ-, or δ-sarcoglycan (SG) genes, are autosomal recessive limb-girdle muscular dystrophies (LGMD 2C, 2D, 2E, 2F), characterized by slowly progressive proximal muscle weakness of the pelvic and shoulder girdles with various degrees of cardiorespiratory involvement, most often of childhood onset, and resulting in premature death. Little is known regarding the prevalence or predictors of disease progression. Hence, this multicenter retrospective study encompassing 100 patients from 80 families was undertaken.
Medical records of genetically confirmed sarcoglycan patients seen at the neuromuscular centers of Pitie-Salpetriere, Raymond Poincare, Necker, and Armand-Trousseau Hospitals’ Nord-Est/Ile-de-France, and in the cardiology department of Cochin Hospital in Paris, were reviewed. Neurologic, cardiac, and pulmonary evaluations, muscle biopsy data, and ethics committee approval were obtained. Muscle strength was measured in 15 muscle groups using the Medical Research Council (MRC) scale. Pulmonary insufficiency was defined as forced vital capacity (FVC) < 70% of predicted value, cardiomyopathy by a left ventricle ejection fraction (LVEF) < 50% based on transthoracic echocardiography, and skeletal muscle disease severity by the age at loss of ambulation (LoA). All patients underwent sarcoglycan gene analysis, and immunohistochemistry (IHC) was performed on muscle biopsies for dystrophin, dysferlin, and sarcoglycans, with muscle protein analysis done by multiplex Western blot. Statistical analysis encompassed Student t test, Chi-square test, and regression analyses, with statistical significance established at P ≤ 0.05.
Among 100 patients in the study, 54% women and 46% men, consanguinity was observed in 44%, with γ-SG patients accounting for 54%, α-SG patients for 41%, and β-SG patients for 5%. Most γ-SG patients (88.9%) came from North Africa (Algeria, Morocco, and Tunisia), most α-SG patients from Europe (70.7%), and one each of the β-SG patients came from Europe and Guadeloupe, and three from Tunisia. Mean age at symptom onset was 7.6 years, ranging from birth to 42 years, earliest in the γ-SG group (5.5 years of age), and latest in the β-SG group (24.4 years of age), usually with gait difficulties (54%), rarely with elevated creatine kinase (4%), and with exercise intolerance or myalgia (11%). Among 58 patients who underwent muscle biopsy, sarcoglycan expression was absent in 52.4% and decreased in 47.6%.
At last examination, mean age 30.8 years, all patients demonstrated proximal weakness in all four limbs, with joint contractures in 69%, axial weakness in 65%, LoA in 63%, calf hypertrophy in 48%, and scapular winging in 44%. Low FVC was seen in 66%, with 30% requiring ventilation, and dilated cardiomyopathy was seen in 21%, particularly the γ-SG group. Earlier time to LoA was associated with younger age of onset and absence of sarcoglycan on muscle biopsy, with the former an independent predictor of both severity and time to LoA. Age of onset should be considered in any future clinical trials for new therapies.
All four sarcoglycans are glycosylated transmembrane proteins, essential for membrane integrity during muscle contraction, forming a tetrameric complex linked to the major dystrophin glycoprotein complex (DGC). Missense mutations comprise the majority of sarcoglycanopathies, resulting in absence or decreased amounts of sarcoglycan. Curiously, although absence of other DGC proteins results in aberrant neuromuscular junctions (NMJ), deficiency of γ-SG results in no detectable NMJ structural defect. However, age-related NMJ structural alteration has been reported recently in aging mice with reduced α-SG expression, such that overexpression of α-SG mitigated these alterations by preventing degradation of LRP4. How this is accomplished remains a mystery.