Advanced Cardiovascular Disease in Marbach-Rustad Progeroid Syndrome (LEMD2 p.Ser479Phe)

BACKGROUND: Marbach-Rustad progeroid syndrome results from the recurrent heterozygous LEMD2 c.1436C>T (p.Ser479Phe) variant. Four cases have been reported, with cardiac involvement absent or only qualitatively described. CASE SUMMARY: A 30-year-old man with short stature, skeletal fragility, and facial dysmorphism presented with syncope from high-grade atrioventricular block. Echocardiography showed premature severe calcific aortic stenosis and mild mitral stenosis. Cardiac magnetic resonance showed preserved biventricular function with no late gadolinium enhancement; computed tomography confirmed valvular calcification but no coronary calcium. Chagas serology was negative. Whole-genome sequencing confirmed the p.Ser479Phe variant. He received a permanent pacemaker and, 6 months later, transcatheter aortic valve replacement. Evaluation also revealed overt type 2 diabetes, severe hypertriglyceridemia, and nephropathy: the most advanced metabolic phenotype reported. DISCUSSION: This case shows that the p.Ser479Phe variant can cause advanced, intervention-requiring cardiovascular disease (objectively quantified and, to our knowledge, the first in vivo characterization by cardiac magnetic resonance). These findings support routine cardiac and metabolic surveillance in LEMD2-associated progeroid syndromes.