Marian Ali J
Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, 6770 Bertner Street, DAC900, Houston, TX, 77030, USA.
Texas Heart Institute, 6770 Bertner Street, DAC900, Houston, TX, 77030, USA.
BMC Med Genet. 2017 Oct 18;18(1):116. doi: 10.1186/s12881-017-0480-x.
Mutations in LMNA gene, encoding Lamin A/C, cause a diverse array of phenotypes, collectively referred to as laminopathies. The most common manifestation is dilated cardiomyopathy (DCM), occurring in conjunction with variable skeletal muscle involvement but without involvement of the coronary arteries. Much less commonly, LMNA mutations cause progeroid syndromes, whereby an early-onset coronary artery disease (CAD) is the hallmark of the disease. We report a hitherto unreported compound cardiac phenotype, dubbed as "non-syndromic cardiac progeria", in a young patient who carried a rare pathogenic variant in the LMNA gene and developed progressive degeneration of various cardiac structures, as seen in the elderly. The phenotype resembled the progeroid syndromes, except that it was restricted to the heart and did not involve other organs.
The patient was a well-developed Caucasian female who presented at age 29 years with an acute myocardial infarction (MI) and was found to have extensive CAD. She had none of the conventional risk factors for atherosclerosis. She underwent coronary artery bypass surgery but continued to require multiple percutaneous coronary interventions for symptomatic obstructive coronary lesions. During the course of next 10 years, she developed mitral regurgitation, degenerative mitral and aortic valve diseases, atrial flutter, and progressive conduction defects. She died from progressive heart failure with predominant involvement of the right ventricle and severe tricuspid regurgitation. Cardiac phenotype in this young patient resembled degenerative cardiac diseases of the elderly and the progeroid syndromes. However, in contrast to the progeroid syndromes, the phenotype was restricted to the heart and did not involve other organs. Thus, the phenotype was dubbed as a non-syndromic cardiac progeria. Genetic screening of several cardiomyopathy genes, including LMNA, which is a causal gene for progeroid syndromes, led to identification of a very rare pathogenic p.Asp300Asn variant in the LMNA gene.
We infer that the LMNA p.Asp300Asn mutation is pathogenic in non-syndromic cardiac progeria. Mutations involving codon 300 in the LMNA gene have been associated with progeroid syndromes involving multiple organs. Collectively, the data provide credence to the causal role of p.Asp300Asn mutation in the pathogenesis of non-syndromic cardiac progeria.
编码核纤层蛋白A/C的LMNA基因突变会导致多种表型，统称为核纤层蛋白病。最常见的表现是扩张型心肌病（DCM），常伴有不同程度的骨骼肌受累，但不累及冠状动脉。较少见的是，LMNA基因突变会导致早衰综合征，其特征是早发性冠状动脉疾病（CAD）。我们报告了一名年轻患者，其携带LMNA基因的罕见致病变异，并出现了各种心脏结构的进行性退化，这在老年人中较为常见，我们将这种迄今为止未报告的复合心脏表型称为“非综合征性心脏早衰”。该表型类似于早衰综合征，但仅限于心脏，不涉及其他器官。
患者为一名发育良好的白种女性，29岁时因急性心肌梗死（MI）就诊，被发现患有广泛的CAD。她没有传统的动脉粥样硬化危险因素。她接受了冠状动脉搭桥手术，但仍需要多次经皮冠状动脉介入治疗以缓解有症状的阻塞性冠状动脉病变。在接下来的10年中，她出现了二尖瓣反流、退行性二尖瓣和主动脉瓣疾病、心房扑动以及进行性传导缺陷。她死于进行性心力衰竭，主要累及右心室并伴有严重的三尖瓣反流。这位年轻患者的心脏表型类似于老年人的退行性心脏疾病和早衰综合征。然而，与早衰综合征不同的是，该表型仅限于心脏，不涉及其他器官。因此，该表型被称为非综合征性心脏早衰。对包括LMNA在内的几种心肌病基因进行基因筛查，LMNA是早衰综合征的致病基因，结果发现LMNA基因中存在一种非常罕见的致病性p.Asp300Asn变异。
我们推断LMNA p.Asp300Asn突变在非综合征性心脏早衰中具有致病性。LMNA基因中涉及密码子300的突变与涉及多个器官的早衰综合征有关。总体而言，这些数据证实了p.Asp300Asn突变在非综合征性心脏早衰发病机制中的因果作用。
