Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice.

H Mosbah ,Pascale Richard,Sophie Benabbou,Elisabeth Sarrazin,Isabelle Jéru,Ariel Cohen,Fabien Picard,Corinne Vigouroux,Bruno Donadille,Jocelyn Inamo,Franck Boccara,Camille Vatier,Bruno Fève,Olivier Lascols,Karim Wahbi,Alban Redheuil,Marie-Christine Vantyghem,B Néraud ,Stéphane Éderhy ,Sophie Christin-Maître

doi:10.3390/cells9030765

Abstract

Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects. A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.

Highlights

Pathogenic variants in the LMNA gene are responsible for several rare clinical disorders collectively called laminopathies
The first patient, diagnosed with a progeroid lipoatrophy, illustrates the cardiovascular phenotype complexity of laminopathies. She presented with atherosclerosis, aortic valvular disease and mild left ventricular hypertrophy with rhythm and conduction system defects due to a novel heterozygous LMNA p.(Asp136Val) pathogenic variant
The patient had a generalized lipodystrophy with progeroid features, diabetes, acute pancreatitis and liver steatosis, no valvular disease but left ventricular hypertrophy without any other information about the cardiac phenotype

Summary

Introduction

Pathogenic variants in the LMNA gene are responsible for several rare clinical disorders collectively called laminopathies. Laminopathies affect either striated muscle (skeletal and cardiac muscle dystrophy), adipose tissue (lipodystrophies), peripheral nerve (Charcot Marie Tooth axonal neuropathy) or multiple organs with clinical signs of accelerated ageing (progeroid syndromes) [1]. The clinical heterogeneity of laminopathies mirrors the multiple roles of the LMNA-encoded A-type lamins, which are ubiquitously expressed essential components of the cell nucleus. In Hutchinson–Gilford progeria syndrome (HGPS) and LMNA-associated progeroid syndromes, multitissular features of accelerated ageing, including lipoatrophy, are associated with major atherosclerosis and/or valvular calcifications [7,8,9]. Cardiovascular involvement, according to this classification of laminopathies, is mainly expressed as cardiomyopathy with rhythm and conduction disturbances in laminopathies of the striated muscle, and as arterial wall dysfunction and/or valvulopathy in lipodystrophy-associated laminopathies such as FPLD2 and progeroid syndromes

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