Cardiac and Pulmonary Spectrum of LGMDR: Subtype-Specific Phenotypes and Long-Term Outcomes

Background. Autosomal recessive limb-girdle muscular dystrophies (LGMDR) are genetically heterogeneous disorders primarily characterized by progressive proximal muscle weakness. However, cardiac complications and respiratory insufficiency represent primary, life-limiting features in specific subtypes. This study aims to assess the prevalence, severity, and phenotype of cardio-pulmonary involvement across different LGMDR forms.

Methods. We retrospectively analyzed longitudinal clinical, cardiac, and respiratory data from a cohort of 205 LGMDR patients from 154 families followed at the Cardiomyology and Medical Genetics Unit of the University of Campania "Luigi Vanvitelli". Cardiological evaluation included ECG, 24-hour Holter monitoring, and transthoracic echocardiography. Pulmonary function was evaluated through serial spirometry.

Results: Calpainopathy (LGMDR1) and dysferlinopathy (LGMDR2) represented 56.0% of the cohort, demonstrating highly preserved cardio-pulmonary function. Sarcoglycanopathies (LGMDR3–R6, 19.5%) and FKRP-related dystrophy (LGMDR9, 7.3%) exhibited the highest risk of cardiac and/or respiratory complications. Early-onset restrictive respiratory syndrome (RRS; FVC < 60%) and dilated cardiomyopathy (DCM) were heavily clustered in LGMDR3–R6 and LGMDR9, frequently requiring non-invasive ventilation (NIV). Phenotypically, DCM and heart failure were prominent in LGMDR5, LGMDR6, LGMDR9, and LGMDR13 whereas cardiac conduction system abnormalities were specifically observed in LGMDR4. Notably, severe respiratory decline occurred in LGMDR9 patients while they were still fully ambulatory.

Conclusions. Cardiac and pulmonary involvement in LGMDR are highly subtype-specific and frequently independent of skeletal muscle weakness severity. Sarcoglycanopathies and FKRP-related forms require aggressive, longitudinal screening utilizing annual spirometry and specialized cardiological surveillance. Genetic subtyping is crucial for clinical risk stratification, enabling timely therapeutic interventions to optimize long-term patient survival and quality of life.