A recurrent familial partial lipodystrophy due to a monoallelic or biallelic LMNA founder variant highlights the multifaceted cardiac manifestations of metabolic laminopathies

Abstract

Aims LMNA-linked familial partial lipodystrophy type 2 (FPLD2) leads to insulin resistance-associated metabolic complications and cardiovascular diseases. We aimed to characterise the disease phenotype in a cohort of patients carrying an LMNA founder variant. Methods We collected clinical and biological data from patients carrying the monoallelic or biallelic LMNA p.(Thr655Asnfs*49) variant (n =  65 and 13, respectively) and 19 non-affected relative controls followed-up in Reunion Island Lipodystrophy Competence Centre, France. Results Two-thirds of patients with FPLD2 (n = 51) and one-third of controls (n = 6) displayed lipodystrophy and/or lean or android morphotype (P  = 0.02). Although age and BMI were not statistically different between the two groups, the insulin resistance index (median HOMA-IR: 3.7 vs 1.5, P  = 0.001), and the prevalence of diabetes, dyslipidaemia, and non-alcoholic fatty liver disease were much higher in patients with FPLD2 (51.3 vs 15.8%, 83.3 vs 42.1%, and 83.1 vs 33.3% (all P ≤ 0.01), respectively). Atherosclerosis tended to be more frequent in patients with FPLD2 (P  = 0.07). Compared to heterozygous, homozygous patients displayed more severe lipoatrophy and metabolic alterations (lower BMI, fat mass, leptin and adiponectin, and higher triglycerides P ≤ 0.03) and tended to develop diabetes more frequently, and earlier (P  = 0.09). Dilated cardiomyopathy and/or rhythm/conduction disturbances were the hallmark of the disease in homozygous patients, leading to death in four cases. Conclusions The level of expression of the LMNA ‘Reunionese’ variant determines the severity of both lipoatrophy and metabolic complications. It also modulates the cardiac phenotype, from atherosclerosis to severe cardiomyopathy, highlighting the need for careful cardiac follow-up in affected patients.