LMNA cardiomyopathy: cell biology and genetics meet clinical medicine

Abstract

Mutations in the LMNA gene, which encodes A-type nuclear lamins (intermediate filament proteins expressed in most differentiated somatic cells), cause a diverse range of diseases, called laminopathies, that selectively affect different tissues and organ systems. The most prevalent laminopathy is cardiomyopathy with or without different types of skeletal muscular dystrophy. LMNA cardiomyopathy has an aggressive clinical course with higher rates of deadly arrhythmias and heart failure than most other heart diseases. As awareness among physicians increases, and advances in DNA sequencing methods make the genetic diagnosis of LMNA cardiomyopathy more common, cardiologists are being faced with difficult questions regarding patient management. These questions concern the optimal use of intracardiac cardioverter defibrillators to prevent sudden death from arrhythmias, and medical interventions to prevent heart damage and ameliorate heart failure symptoms. Data from a mouse model of LMNA cardiomyopathy suggest that inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways are beneficial in preventing and treating cardiac dysfunction; this basic research discovery needs to be translated to human patients.

Fig. 1.

Laminopathies affecting striated muscles. Classically defined distinct clinical disorders that present in childhood or adulthood (Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy 1B and isolated cardiomyopathy with conduction defects) are shown with affected muscle groups indicated in purple. The adult-onset diseases are actually a spectrum of the same disease that can have overlapping phenotypes and be caused by the same LMNA mutation (indicated by dashed arrows); note that the heart is always affected. These laminopathies affecting striated muscle can therefore be defined as LMNA cardiomyopathy with or without different types of skeletal muscular dystrophy. Mutations in LMNA can also present in infants as congenital muscular dystrophy, usually with heart involvement. Purple arrows indicate the location of contractures (permanent shortening) in the elbows, Achilles and the back of the neck that are characteristic of Emery-Dreifuss muscular dystrophy.