Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency

Area of Science:

• Neurology
• Genetics
• Cardiology

Background:

• Congenital muscular dystrophies (CMD) represent a group of inherited disorders characterized by muscle weakness present from birth.
• Reduced glycosylation of alpha-dystroglycan (α-DG) is a common molecular feature in several subtypes of CMD, impacting muscle structure and function.
• Understanding the systemic manifestations, particularly cardiac and respiratory involvement, is crucial for patient management and prognosis.

Purpose of the Study:

• To retrospectively assess the prevalence and spectrum of cardiac and respiratory dysfunction in a large cohort of patients with CMD characterized by reduced α-DG glycosylation.
• To investigate the correlation between specific genetic mutations and the occurrence of cardiac or respiratory complications.
• To identify potential genotype-phenotype correlations regarding cardiovascular and pulmonary health in this patient population.

Main Methods:

• Retrospective analysis of clinical data from 115 patients diagnosed with CMD and reduced α-DG glycosylation.
• Systematic review of medical records to evaluate cardiac function (including echocardiography and ECG findings) and respiratory function (including pulmonary function tests and need for respiratory support).
• Genetic analysis to identify mutations in genes associated with α-DG glycosylation, including FKRP, POMT1, POMT2, and POMGnT1.

Main Results:

• Out of 115 patients, 6% (7 patients) exhibited cardiac involvement, including dilated cardiomyopathy, conduction defects, and mitral regurgitation.
• Respiratory function was impaired in 12% (14 patients), with 10 requiring non-invasive nocturnal ventilation and 4 requiring invasive ventilation.
• Cardiac or respiratory involvement was observed in patients with mutations in FKRP, POMT1, and POMT2 genes.
• Notably, all patients with mutations in the POMGnT1 gene presented with normal cardiac and respiratory function.

Conclusions:

• Congenital muscular dystrophies with reduced α-DG glycosylation pose a significant risk for cardiac and respiratory complications.
• Specific genetic mutations (FKRP, POMT1, POMT2) are associated with increased likelihood of cardiovascular and pulmonary involvement.
• Mutations in POMGnT1 appear to be protective against cardiac and respiratory dysfunction in the context of CMD with reduced α-DG glycosylation, suggesting distinct pathomechanisms.