Clinical and Genetic Characterizations to Diagnose Sarcoglycanopathies

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By Michael Rubin, MD. Professor of Clinical Neurology, Weill Cornell Medical College

Sarcoglycanopathies are a subset of limb-girdle muscular dystrophies (LGMD) caused by mutations in the sarcoglycan (SG) genes, leading to autosomal recessive disorders classified as LGMD 2C, 2D, 2E, and 2F. These disorders primarily affect the proximal muscles of the pelvic and shoulder girdles and often involve cardiac and respiratory systems. Sarcoglycanopathies typically manifest in childhood and progress to premature death, but there are limited data on disease prevalence and predictors of progression. This study aimed to address these gaps through a retrospective analysis of 100 genetically confirmed sarcoglycanopathy patients from 80 families across multiple neuromuscular centers in Paris, France.

Study Design and Methods

The researchers reviewed the medical records of patients with confirmed sarcoglycanopathies from hospitals including Pitie-Salpetriere, Raymond Poincare, Necker, Armand-Trousseau, and Cochin. Data on neurological, cardiac, and pulmonary evaluations, along with muscle biopsy findings, were included. Muscle strength was assessed in 15 groups using the Medical Research Council (MRC) scale. Pulmonary insufficiency was defined as a forced vital capacity (FVC) < 70%, and cardiomyopathy was indicated by a left ventricular ejection fraction (LVEF) < 50%. Skeletal muscle disease severity was primarily measured by the age at loss of ambulation (LoA). Sarcoglycan gene mutations were analyzed, and immunohistochemistry (IHC) was performed to assess sarcoglycan, dystrophin, and dysferlin expression in muscle biopsies. Statistical analyses were conducted using t-tests, Chi-square tests, and regression models, with significance set at P ≤ 0.05.

Key Findings

Demographic and Genetic Distribution

The study cohort consisted of 54% women and 46% men, with a high prevalence of consanguinity (44%). Genetically, γ-SG mutations were the most common, affecting 54% of patients, followed by α-SG mutations (41%), and β-SG mutations (5%). There was a distinct geographic distribution: 88.9% of γ-SG patients were from North Africa (Algeria, Morocco, Tunisia), while 70.7% of α-SG patients were from Europe. β-SG patients were less common, with a few from Europe, Guadeloupe, and Tunisia.

Age of Onset and Symptom Presentation

The mean age of symptom onset was 7.6 years, but this varied by sarcoglycan subtype. γ-SG patients had the earliest onset at an average of 5.5 years, while β-SG patients exhibited the latest onset at 24.4 years. Initial symptoms were most commonly gait difficulties (54%), followed by exercise intolerance or myalgia (11%), and, rarely, elevated creatine kinase levels (4%).

Muscle Biopsy and Sarcoglycan Expression

Among 58 patients who underwent muscle biopsy, 52.4% showed complete absence of sarcoglycan expression, while 47.6% exhibited decreased expression. The absence of sarcoglycan was more frequently associated with an earlier onset of disease and was linked to more severe outcomes.

Clinical Outcomes and Disease Progression

At the time of the last clinical evaluation, the mean age of the patients was 30.8 years. All patients demonstrated proximal weakness in all four limbs. Other prominent findings included joint contractures (69%), axial muscle weakness (65%), and loss of ambulation (63%). Common secondary features included calf hypertrophy (48%) and scapular winging (44%).

• Pulmonary Function: Pulmonary insufficiency (FVC < 70%) was present in 66% of patients, and 30% required mechanical ventilation.

• Cardiac Involvement: Dilated cardiomyopathy was observed in 21% of the cohort, with the γ-SG group being particularly affected.

Patients with an earlier age of disease onset and absence of sarcoglycan in muscle biopsy samples had a significantly earlier LoA. The time to LoA was shorter in patients with more severe sarcoglycan deficiencies, making the age of onset a key predictor of both disease severity and progression. These findings suggest that the age of onset should be a critical factor in designing clinical trials for emerging sarcoglycanopathy therapies.

Commentary on Sarcoglycanopathies and Future Research

Sarcoglycanopathies result from mutations in the sarcoglycan genes, which encode glycosylated transmembrane proteins critical for the integrity of the muscle cell membrane during contraction. These proteins form part of the larger dystrophin glycoprotein complex (DGC), and their deficiency leads to muscle weakness and degeneration. Most mutations in sarcoglycanopathies are missense mutations, leading to reduced or absent protein expression.

Interestingly, while mutations in other components of the DGC result in structural abnormalities of the neuromuscular junction (NMJ), γ-SG deficiency does not appear to cause such defects. Recent research has shown that age-related NMJ alterations can occur in mice with reduced α-SG expression, and overexpression of α-SG may prevent these changes by inhibiting degradation of LRP4, a critical NMJ component. However, the exact mechanisms remain unclear, warranting further investigation.

Conclusion

This multicenter study highlights the clinical and genetic heterogeneity of sarcoglycanopathies, with significant variability in age of onset, severity, and progression. The findings underscore the importance of early diagnosis, particularly in populations with high rates of consanguinity. Age of onset and sarcoglycan expression levels emerged as key predictors of disease severity and progression, suggesting that these factors should be considered in future clinical trials for novel therapies. As research into sarcoglycanopathies advances, further understanding of the molecular mechanisms underlying NMJ stability and muscle degeneration will be crucial for developing targeted treatments.

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