Cardiac manifestations of congenital LMNA-related muscular dystrophy in children: three case reports and recommendations for care

Abstract

Skeletal and cardiac muscle laminopathies, caused by mutations in the lamin A/C gene, have a clinical spectrum from congenital LMNA-related muscular dystrophy to later-onset Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, and dilated cardiomyopathy. Although cardiac involvement is observed at all ages, it has only been well described in adults. We present the evolution of cardiac disease in three children with congenital muscular dystrophy presentation of LMNA-related muscular dystrophy. In this series, atrial arrhythmia was the presenting cardiac finding in all three patients. Heart failure developed up to 5 years later. Symptoms of right heart failure, including diarrhoea and peripheral oedema, preceded a rapid decline in left ventricular ejection fraction. Recommendations for cardiac surveillance and management in these patients are made.

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

“…These amino acid substitutions are analogous to human Lamin A/C R190W and G449V, respectively. Mutations in LMNA that give rise to Lamin A/C R190W are associated with progressive cardiac defect (including conduction defects) and reduced cardiac performance (Arbustini et al., 2002; Heller et al., 2017; Hermida‐Prieto et al., 2004). Mutations in LMNA that give rise to Lamin A/C G449V cause congenital muscular dystrophy, which is characterized by skeletal muscle defects in childhood and age‐dependent dilated cardiomyopathy (Dialynas et al., 2015).…”

“…Hearts from 3‐week‐old female flies expressing R205W and G489V showed significant dilation and restriction, respectively. Consistent with our finding, mutations in human LMNA result in dominant dilated, hypertrophic, and idiopathic cardiomyopathy (Arbustini et al., 2002; Heller et al., 2017; Marian, 2017). Furthermore, expression of mutant LamC resulted in dysrhythmic beating patterns when compared to hearts from age‐matched controls expressing wild‐type LamC and the Hand‐Gal4 driver alone (Figure 1b).…”

“…Mutations in the human LMNA gene are associated with a collection of diseases called laminopathies in which the most common manifestation is progressive cardiac disease (Brayson & Shanahan, 2017; Heller et al., 2017; Marian, 2017; Naetar, Ferraioli & Foisner, 2017). We have generated Drosophila melanogaster models of age‐dependent cardiac dysfunction.…”

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

“…Mutations in LMNA, which encodes nuclear Lamin A/C, precipitates a premature aging syndrome called Hutchinson-Gilford Progeria (HGPS) that is characterized by the accumulation of protein aggregates [89]. Of particular relevance to this review, a common manifestation of Lamin A/C mutations and the subsequent accumulation of progerin caused cardiac dysfunction manifested by atrial arrhythmia and hypertrophic cardiomyopathy [90,91]. Evidence supporting this link is provided by a fly model of cardiolaminopathy exhibiting repressed autophagy, accumulation of cytoplasmic Lamin C aggregates, impaired cardiac function, severe myofibrillar degeneration, nuclear morphological defects, and evidence of oxidative stress [92].…”

Clinical aspects of Emery-Dreifuss muscular dystrophy

“…Respiratory failure is frequent as a result of respiratory muscle involvement. Cardiac involvement can manifest initially as atrial arrhythmia, preceding development of fast-progressing heart failure [ 51 , 53 ]. Along with a wider availability of new diagnostic techniques, in particular next-generation sequencing, it became clear that L-CMD might be more frequent than it was assumed previously.…”