Mitral Valve Prolapse 1

Description

Mitral valve prolapse (MVP) has a prevalence of approximately 2 to 3% in the general population. It is characterized by fibromyxomatous changes in mitral leaflet tissue, with upward displacement of 1 or both leaflets into the left atrium during systole; MVP is diagnosed when the movement of the mitral leaflets exceeds 2 mm. In classic MVP, leaflets are at least 5 mm thick, whereas in nonclassic MVP, they are less than 5 mm thick. Auscultatory findings, when present, consist of a midsystolic click and/or a late systolic murmur. The natural history of MVP varies from benign, with a normal life expectancy, to severe complications associated with the development of significant mitral regurgitation, including congestive heart failure, bacterial endocarditis, atrial fibrillation, thromboembolism, and even sudden death. However, complications are uncommon, affecting less than 3% of individuals with MVP (Freed et al., 1999; Grau et al., 2007; Delling and Vasan, 2014).

Grau et al. (2007) provided a detailed review of the genetics of mitral valve prolapse. Delling and Vasan (2014) reviewed the epidemiology and pathophysiology of MVP, with discussion of disease progression, genetics, and molecular basis.

Genetic Heterogeneity of Familial Mitral Valve Prolapse

Several loci for mitral valve prolapse (MVP) have been been mapped: MVP1 to chromosome 16p; MVP2 (607829) to chromosome 11p; and MVP3 (610840) to chromosome 13q.

Clinical Features

Prolapse or buckling of one or both of the mitral leaflets into the left atrium during systole is common, occurring in 4 to 8% of young adults and more often in females than in males (Procacci et al., 1976; Darsee et al., 1979; Sbarbaro et al., 1979). The auscultatory findings are a midsystolic, nonejection click, a holo- or late-systolic mitral regurgitation murmur, or both; about 20% have 'silent' prolapse. M-mode and particularly cross-sectional echocardiography are sensitive, noninvasive methods of detecting the abnormal valve motion. Fibromyxomatous degeneration is generally found on histopathologic examination. In functional terms, mitral valve prolapse results from a valve-ventricle mismatch. Hutchins et al. (1986) pointed out that the fundamental fault is often not in the valve leaflets, but in the mitral annulus which is stretched with resulting disjunction between the atrium and ventricle. Because many abnormalities of the left ventricle or mitral valve apparatus can lead to prolapse, a wide range of etiologic and pathogenetic heterogeneity exists. Thus, MVP is associated with coronary artery disease, congestive or hypertrophic cardiomyopathy, atrial septal defect, papillary muscle or chorda tendinea rupture, and various heritable disorders of connective tissue (Marfan syndrome, Ehlers-Danlos syndrome, and osteogenesis imperfecta). Most persons with MVP have none of these conditions and their MVP has been called idiopathic. Many such persons have chest pain, dyspnea, thoracic cage deformity (Bon Tempo et al., 1975; Salomon et al., 1975), dysrhythmia (Gooch et al., 1972), and distinctive anthropomorphic characteristics (Schutte et al., 1981) which suggest a syndrome. In some cases, a modicum of loose-jointedness may suggest a mild form of the Ehlers-Danlos syndrome.

Roberts (2005) noted a reported prevalence of 2.4% for MVP, based primarily on studies in European and North American populations.

Familial occurrence of MVP, often with associated features, was noted in early reports (Barlow and Bosman, 1966; Hunt and Sloman, 1969; Stannard et al., 1967; Shell et al., 1969). Some instances of panic attacks (neurocirculatory asthenia) reported in families represented MVP in all likelihood (Cohen et al., 1951). Screening pedigrees for MVP after relatively unbiased ascertainment of the proband has supported autosomal dominant inheritance in a high proportion of idiopathic MVP (Weiss et al., 1975; Fortuin et al., 1977; Devereux et al., 1982). Devereux et al. (1982) examined 45 probands and 179 first-degree relatives and found at least one relative affected by MVP in 29 families. Expression was age- and sex-dependent, with MVP more commonly found in young adult females than in children, the elderly, or men of any age. Except for anthropomorphic characteristics of narrower A-P chest diameter and longer arm spans than controls (Schutte et al., 1981), none of the other associated (perhaps pleiotropic) features of MVP syndrome have been demonstrated to follow dominant inheritance. The extent of genetic heterogeneity is also unclear. Nonetheless, MVP appears to be the most common mendelian cardiovascular abnormality in humans. The condition is usually benign and nonprogressive, although chordal rupture, bacterial endocarditis and sudden death occur, and myxomatous degeneration/MVP is the most common cause of severe, isolated mitral regurgitation in adults. No prospective, unbiased study of natural history has been performed, but prognosis in idiopathic MVP appears to be far better than for MVP in the Marfan syndrome, in which over 12% of patients developed progressive severe mitral regurgitation by age 22 years (Pyeritz and Woppel, 1982). Malcolm (1985) gave an exhaustive review.

Rogan et al. (1989) described a family in which multiple members developed severe atrioventricular valvular regurgitation and at least 1 also had aortic regurgitation. Myxomatous proliferation in heart valves was demonstrated in all cases. The proband was a 23-year-old asymptomatic soldier who was found to have a systolic murmur on routine physical examination; echocardiography showed a calcified mass in the left ventricular outflow tract. Rogan et al. (1989) suggested the designation 'familial myxomatous valvular disease.' The patient also showed 'soft' connective tissue signs, mild dolichostenomelia (arm span 7 cm greater than height), a highly arched palate, reversal of the usual vertebral column curves, mild pectus excavatum, and marked striae atrophica over his lower back and hips.

James et al. (2003) described a family in which 8 individuals in 4 generations were affected by a dominantly inherited disorder involving MVP, short stature, dolichocephalic face, broad forehead, posteriorly angulated ears, long philtrum, thin upper lip, high arched palate, and small mandible. The proband presented at age 8 years with infective mastoiditis, bacterial endocarditis, and supraventricular tachycardia. One other family member also had infective mastoiditis and bacterial endocarditis, and both the proband's mother and grandmother died suddenly at the ages of 30 and 25 years, respectively. The occurrence of infective mastoiditis in 2 members of this family was thought to be related to abnormal development of the temporal bone, which may have contributed to the distinctive facial appearance of the affected individuals. This family was thought to most closely resemble that reported by Collins et al. (1990): a mother and her 2 daughters had MVP associated with short stature, disproportionately short limbs, and small hands. The growth retardation was more severe than that in the family reported by James et al. (2003), with the 2 adults reported as having heights of 147 and 140 cm. Valvular heart disease included both MVP and pulmonary stenosis.

Digilio et al. (2004) evaluated a mother and daughter with a constellation of anomalies similar to those reported by James et al. (2003) and Collins et al. (1990). The proband was a 14-year-old female with thin body habitus, long face, upslanting palpebral fissures, beaked nose and nasal septum below alae, short philtrum, high-arched palate, and crowded teeth. Height was 140 cm (below 3rd centile). Developmental milestones were mildly retarded and a mild cognitive deficit with learning difficulties was present. Echocardiography showed polyvalvular disease, with quadricuspid aortic valve with mild regurgitation and prolapse of the mitral and tricuspid valves with mild regurgitation. The mother had thin body habitus with marked short stature (height 139 cm; below 3rd centile). She had moderate mental retardation. Echocardiography showed thickening of the aortic valve leaflets without regurgitation or stenosis, and mitral and tricuspid valve prolapse with mild regurgitation. Skeletal x-rays showed no abnormalities.

Diagnosis

Freed et al. (1999) examined echocardiographic data from 1,845 women and 1,646 men who participated in the offspring cohort of the Framingham Heart Study and observed a prevalence of MVP of 2.4%, including 1.3% with classic prolapse and 1.1% with nonclassic prolapse, which they stated was substantially lower than that previously reported. Noting that diagnosis of prolapse requires demonstration of abnormal displacement of the mitral leaflets relative to their surrounding structures, the authors stated that because M-mode echocardiography fails to display the leaflets in relation to their surrounding annular attachments, results vary widely depending on orientation of the transducer. In addition, 2-dimensional views must be interpreted in the context of the 3-dimensional saddle-like shape of the valve, and side-to-side views can show leaflets apparently bulging upward relative to the low points of the annular saddle in the absence of any leaflet disease. Freed et al. (1999) concluded that eliminating such views reduces the frequency of diagnosis without excluding individuals with thickening of the leaflets, regurgitation, or valve-related complications, and noted that estimates of the prevalence of prolapse are lower when more specific criteria are used.

Mapping

On the basis of linkage studies, Henney et al. (1989) and Wordsworth et al. (1989) excluded the involvement of the COL1A1 (120150), COL1A2 (120160), COL3A1 (120180), and COL5A2 (120190) in the pathogenesis of familial mitral valve prolapse.

By systematic echocardiographic screening of the first-degree relatives of 17 patients who underwent mitral valve repair for myxomatous mitral valve prolapse, Disse et al. (1999) identified 4 pedigrees showing autosomal dominant inheritance. Genomewide linkage analysis of the most informative pedigree, which had 24 individuals in 3 generations, showed a significant linkage for markers mapping to 16p, with a 2-point maximum lod score for D16S3068 of 3.30 at theta = 0.0. Linkage to D16S3068 was confirmed in a second family that showed a maximum lod score of 2.02 at theta = 0.0, but was excluded for the 2 remaining families, thus demonstrating the genetic heterogeneity of the disease. This linkage placed the locus, which Disse et al. (1999) referred to as MMVP1, at 16p12.1-p11.2 (see also Towbin (1999)).