In this issue of the journal, Le Tourneau et al. report genotype–phenotype correlations in a genetically determined X-linked mitral valve disease due to mutations of the filamin A (FLNA) gene. The study was carried out by two-dimensional echocardiography in a large cohort of subjects from four families harbouring three different FLNA mutations, for a total of 65 carrier vs. 97 non-carrier relatives. The disease was confined to the heart, with mostly mitral valve abnormalities and no significant extra-cardiac findings, but joint hypermobility and a narrow palate in some individuals. Thus, it is not a syndromic disease. There was a large spectrum of mitral valve abnormalities in carriers, and the penetrance was partial or complete in two-thirds of cases. The echocardiographic phenotype consists of valvular and subvalvular apparatus abnormalities: leaflet thickening and elongation; papillary muscle anomalies, with a short distance from the tip to the mitral annulus, abnormal position, or even absence; and annular enlargement. In contrast to mitral valve prolapse, chordae are shortened in women and chordal rupture has never been observed. Lesions are less severe in women, as expected in an X-linked disease. Overall, the morphological features of FLNA mitral valve disease are in keeping with a developmental valve defect (‘dysplasia’), as also supported by polyvalvular involvement. It is noteworthy that mitral valve abnormalities are similar in adult and younger patients from early childhood, clearly pointing to a congenital heart disease, as confirmed by the few, exceptional cases at foetal echocardiography examinations. These features are in agreement with findings in transgenic mice. Filamin A is a protein involved in cardiac development, particularly of the cushions from which valve leaflets originate even during foetal morphogenesis, thus explaining multiple valve lesions in FLNA mutation carriers. Unfortunately, gross pictures or detailed descriptive anatomy from valve specimens are not available in the study by Le Tourneau et al. Only histology of a surgical pathology resection was provided, showing mitral valve leaflet thickening with myxoid degeneration. To the best of our knowledge, no pathology report has been yet published on the topic. The pathological substrate accounts functionally for mitral regurgitation (more rarely stenosis) with restrictive leaflet motion during diastole. There is clear-cut evidence of a developmental abnormality, worsening with time by progressive degenerative changes. The reported phenotype mimics carcinoid-phen fen drug-induced lesions or rheumatic valve disease, a finding which is not surprising since classical congenital mitral stenosis is also grossly quite similar to acquired post-rheumatic subvalvular mitral stenosis. Clearly the phenotype should not be confused with mitral valve prolapse (Barlow’s disease), in which restrictive motion of the leaflets is quite unusual, or with classical congenital mitral valve malformations (congenital stenosis, parachute, arcade, and Stone complex). FLNA mitral valve disease is a rare, new nosographic entity, both congenital and genetic, to be added in the taxonomy of heart valve diseases. Non-syndromic mitral valve prolapse, nowadays the most common form of mitral valve disease, encompasses different phenotypes from fibro-elastic deficiency to classical Barlow disease. It affects 2–3% of the population and is a major cause of valve surgery in adults and the elderly, and even carries a risk of arrhythmic complications in a subgroup of patients. The condition described in this study presents unique features compared with mitral valve prolapse and, to the best of our knowledge, represents the first isolated, genetically determined, congenital malformation of the mitral valve which is X-linked and hereditary in origin. As far as the nomenclature used in this study is concerned, the prefix ‘FLNA’ to mitral valve dystrophy is correct, in the absence of an eponym, since it points to the genetic aetiology. The time has come for establishment of a molecular nomenclature of genetic cardiovascular diseases. However, from an etymological perspective, the term ‘dystrophy’ would point to a genetically determined degenerative disease. In the degenerative theory, the mitral valve

中文翻译：

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Filamin A 二尖瓣疾病：脱垂、营养不良或发育不良？

在本期杂志中，Le Tourneau 等人。报告了由于细丝蛋白 A (FLNA) 基因突变导致的基因决定的 X 连锁二尖瓣疾病的基因型-表型相关性。该研究是通过二维超声心动图在来自四个家庭的大量受试者中进行的，这些受试者来自具有三种不同 FLNA 突变的家庭，总共有 65 名携带者与 97 名非携带者亲属。该疾病仅限于心脏，主要是二尖瓣异常，没有明显的心脏外发现，但有些人的关节活动过度和上颚狭窄。因此，它不是综合症。携带者中存在大量二尖瓣异常，三分之二的病例为部分或完全外显。超声心动图表型包括瓣膜和瓣下器异常：小叶增厚和伸长；乳头肌异常，从尖端到二尖瓣环的距离很短，位置异常，甚至缺失；和环形扩大。与二尖瓣脱垂相反，女性的腱索缩短，从未观察到腱索断裂。正如 X 连锁疾病所预期的那样，女性的病变不太严重。总体而言，FLNA 二尖瓣疾病的形态特征与发育性瓣膜缺陷（“发育不良”）一致，多瓣膜受累也支持这一点。值得注意的是，从儿童早期开始，成人和年轻患者的二尖瓣异常相似，这清楚地表明先天性心脏病，胎儿超声心动图检查中的少数特殊病例证实了这一点。这些特征与转基因小鼠的发现一致。细丝蛋白 A 是一种参与心脏发育的蛋白质，尤其是在胎儿形态发生期间瓣叶起源的垫子，从而解释了 FLNA 突变携带者中的多个瓣膜病变。不幸的是，Le Tourneau 等人的研究中没有瓣膜标本的大体图片或详细的描述性解剖结构。仅提供了手术病理切除的组织学，显示二尖瓣小叶增厚并伴有粘液样变性。据我们所知，目前还没有关于该主题的病理报告发表。病理基础在功能上解释了二尖瓣关闭不全（更罕见的狭窄）和舒张期限制性瓣叶运动。有明确的证据表明发育异常，随着时间的推移通过进行性退行性变化而恶化。报道的表型类似于类癌-苯芬药物引起的病变或风湿性瓣膜病，这一发现并不奇怪，因为经典的先天性二尖瓣狭窄也与获得性风湿性后瓣下二尖瓣狭窄非常相似。显然，该表型不应与二尖瓣脱垂（巴洛氏病）混淆，其中瓣叶的限制性运动非常罕见，或与经典的先天性二尖瓣畸形（先天性狭窄、降落伞、拱廊和石复合体）混淆。FLNA 二尖瓣疾病是一种罕见的、先天性和遗传性的新病灶实体，将被添加到心脏瓣膜疾病的分类中。非综合征性二尖瓣脱垂是当今最常见的二尖瓣疾病形式，包括从纤维弹性缺陷到经典巴洛病的不同表型。它影响 2-3% 的人口，是成人和老年人瓣膜手术的主要原因，甚至在一部分患者中存在心律失常并发症的风险。与二尖瓣脱垂相比，本研究中描述的病症具有独特的特征，据我们所知，它代表了第一个孤立的、遗传决定的、先天性二尖瓣畸形，其起源于 X 连锁和遗传。就本研究中使用的命名法而言，二尖瓣营养不良的前缀“FLNA”是正确的，在没有同名的情况下，因为它指向遗传病因。现在是建立遗传性心血管疾病分子命名法的时候了。然而，从词源学的角度来看，“营养不良”一词指的是遗传决定的退行性疾病。在退行性理论中，二尖瓣