Hereditary ventricular hypertrophy (CMH, HCM, ASH, or IHSS) in early stages produces a presystolic gallop due to an atrial heart sound, and EKG changes of ventricular hypertrophy. Progressive ventricular outflow obstruction may cause palpitation associated with arrhythmia, congestive ... Hereditary ventricular hypertrophy (CMH, HCM, ASH, or IHSS) in early stages produces a presystolic gallop due to an atrial heart sound, and EKG changes of ventricular hypertrophy. Progressive ventricular outflow obstruction may cause palpitation associated with arrhythmia, congestive heart failure, and sudden death. Seidman (2000) reviewed studies of hypertrophic cardiomyopathy in man and mouse. - Genetic Heterogeneity of Hypertrophic Cardiomyopathy Additional forms of hypertrophic cardiomyopathy include CMH2 (115195), caused by mutation in the TNNT2 gene (191045) on chromosome 1q32; CMH3 (115196), caused by mutation in the TPM1 gene (191010) on chromosome 15q22.1; CMH4 (115197), caused by mutation in the MYBPC3 gene (600958) on chromosome 11p11.2; CMH6 (600858), caused by mutation in the PRKAG2 gene (602743) on chromosome 7q36; CMH7 (613690), caused by mutation in the TNNI3 gene (191044) on chromosome 19q13.4; CMH8 (608751), caused by mutation in the MYL3 gene (160790) on chromosome 3p21.3-p21.2; CMH9 (see 188840),is caused by mutation in the TTN gene (188840) on chromosome 2q31; CMH10 (see 160781), caused by mutation in the MYL2 gene (160781) on chromosome 12q23-q24; CMH11 (612098), caused by mutation in the ACTC1 gene (102540) on chromosome 15q14; CMH12 (612124), caused by mutation in the CSRP3 gene (600824) on chromosome 11p15.1; CMH13 (613243), caused by mutation in the TNNC1 gene (191040) on chromosome 3p21.3-p14.3; CMH14 (613251), caused by mutation in the MYH6 gene (160710) on chromosome 14q12; CMH15 (613255), caused by mutation in the VCL gene (193065) on chromosome 10q22.1-q23; CMH16 (613838), caused by mutation in the MYOZ2 gene (605602) on chromosome 4q26-q27; CMH17 (613873), caused by mutation in the JPH2 gene (605267) on chromosome 20q12; CMH18 (613874), caused by mutation in the PLN gene (172405) on chromosome 6q22.1; CMH19 (613875), caused by mutation in the CALR3 gene (611414) on chromosome 19p13.11; CMH20 (613876), caused by mutation in the NEXN gene (613121) on chromosome 1p31.1; CMH21, mapped to chromosome 7p12.1-q21; and CMH22 (see 615248), caused by mutation in the MYPN gene (608517) on chromosome 10q21. The CMH5 designation was initially assigned to a CMH family showing genetic heterogeneity. Subsequently, affected individuals were found to carry mutations in the MYH7 (CMH1) and/or MYBPC3 (CMH4) genes. Hypertrophic cardiomyopathy has also been associated with mutation in the gene encoding cardiac myosin light-peptide kinase (MYLK2; see 606566.0001), which resides on chromosome 20q13.3; the gene encoding caveolin-3 (CAV3; see 601253.0013), which maps to chromosome 3p25; and with mutations in genes encoding mitochondrial tRNAs: see mitochondrial tRNA-glycine (MTTG; 590035) and mitochondrial tRNA-isoleucine (MTTI; 590045).
In the first demonstration of asymmetric hypertrophy of the heart in young adults, Teare (1958) reported the autopsy findings in 9 cases of sudden death in young subjects distributed in 6 families. This condition has been called muscular ... In the first demonstration of asymmetric hypertrophy of the heart in young adults, Teare (1958) reported the autopsy findings in 9 cases of sudden death in young subjects distributed in 6 families. This condition has been called muscular subaortic stenosis but more generalized ventricular hypertrophy is often an earlier and more impressive feature, and obstruction to outflow from the right ventricle can also occur. Study of the families of probands with the full-blown condition shows that an atrial heart sound ('presystolic gallop') and EKG changes of ventricular hypertrophy are the earliest signs. Sudden death occurs in some cases. Braunwald et al. (1964) reported in detail on 64 patients; multiple cases were observed in 11 families, which contained in all at least 41 definite or probable cases. As pointed out by Nasser et al. (1967), outflow obstruction may be absent in some affected members of families in which others do have outflow obstruction. Maron et al. (1974) studied 4 infants that died with ASH in the first 5 months of life, including 1 stillborn. ASH was demonstrated in one first-degree relative of each infant. Maron et al. (1976) analyzed the clinical picture of 46 children with ASH. On the basis of a study of an outpatient population, Spirito et al. (1989) suggested that the prognosis in hypertrophic cardiomyopathy may be less grave than has usually been considered on the basis of hospital-study patients. On morphologic grounds, 4 types of hypertrophic cardiomyopathy have been described: type 1 with hypertrophy confined to the anterior segment of the ventricular septum; type 2 with hypertrophy of both the anterior and the posterior segments of the ventricular septum; type 3 with involvement of both the ventricular septum and the free wall of the left ventricle and type 4 with involvement of the posterior segment of the septum, the anterolateral free wall, or the apical half of the septum (Maron et al., 1982; Ciro et al., 1983). Apical hypertrophic cardiomyopathy is, therefore, one form of type IV. It was first described by Yamaguchi et al. (1979) in Japan (where it appears to be more frequent than elsewhere) and later by Maron et al. (1982). The cases of apical hypertrophic cardiomyopathy described by Maron et al. (1982) belonged to families with different forms of hypertrophic cardiomyopathy. Malouf et al. (1985) reported apical hypertrophic cardiomyopathy in father and daughter of a Lebanese Christian family. The parents were not related; an only sib was normal on examination and echocardiogram as were 2 sisters of the father and their 6 children. In a metaanalysis of sudden death from cardiac causes in children and young adults, Liberthson (1996) found that hypertrophic cardiomyopathy was the most frequent cause of sudden death in young persons in association with strenuous physical exertion or sports.
In affected members of the large French Canadian kindred originally reported by Pare et al. (1961) and shown to have linkage to markers on the proximal portion of 14q, Geisterfer-Lowrance et al. (1990) identified heterozygosity for a missense ... In affected members of the large French Canadian kindred originally reported by Pare et al. (1961) and shown to have linkage to markers on the proximal portion of 14q, Geisterfer-Lowrance et al. (1990) identified heterozygosity for a missense mutation in the MYH7 gene (R403Q; 160760.0001). Ross and Knowlton (1992) reviewed this discovery beginning with the patients first seen by Pare in the 1950s. Using a ribonuclease protection assay, Watkins et al. (1992) screened the beta cardiac myosin heavy-chain genes of probands from 25 unrelated families with familial hypertrophic cardiomyopathy and identified 7 different missense mutations in 12 of the 25 families (see, e.g., 160760.0003-160760.0007). Atiga et al. (2000) studied 36 patients with CMH1 using beat-to-beat QT variability analysis. This technique quantifies the beat-to-beat fluctuations in ventricular repolarization reflected in the QT interval. Seven mutations were found in this group: 9 patients had the 'severe' arg403-to-gln mutation (160760.0001) and 8 had the more benign leu908-to-val mutation (160760.0010). Atiga et al. (2000) found higher QT variability indices in patients with CMH1 compared with controls, and the greatest abnormality was observed in patients with the arg403-to-gln mutation. CMH1 patients therefore exhibited labile ventricular repolarization and were considered to be at higher risk of sudden death from ventricular arrhythmias, particularly those with a 'severe' mutation. Blair et al. (2001) studied a family with familial hypertrophic cardiomyopathy in which 2 individuals suffered early sudden death and a third individual died suddenly at the age of 60 years with autopsy evidence of familial hypertrophic cardiomyopathy. A val606-to-met (V606M) mutation was observed in the MYH7 gene (160760.0005). This mutation had previously been proposed to give rise to a benign phenotype (see Abchee and Marian, (1997)). A second ala728-to-val (A728V) mutation (160760.0025) was found in cis with the V606M mutation. Blair et al. (2001) suggested that this second mutation in cis explained the more severe phenotype seen in this family. Arad et al. (2005) identified 2 different MYH7 missense mutations in 2 probands with apical hypertrophy from families in which the mutations also caused other CMH morphologies (see 160760.0038 and 160760.0039, respectively). Another MYH7 mutation (R243H; 160760.0040) was identified in a sporadic patient with apical hypertrophy; the same R243H mutation was later found by Klaassen et al. (2008) in a family segregating isolated left ventricular noncompaction (LVNC5; see 613426). In a Japanese proband with CMH (CMH17; 613873), Matsushita et al. (2007) identified heterozygosity for a missense mutation in the JPH2 gene (605267.0004); subsequent analysis of 15 known CMH-associated genes revealed that the proband also carried 2 mutations in MYH7 (see, e.g., 160760.0016). The authors suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband. In a 32-year-old African American woman with severe hypertrophic cardiomyopathy (see CMH7, 613690) and a family history of CMH and sudden cardiac death, Frazier et al. (2008) identified a heterozygous mutation in the TNNI3 gene (P82S; 191044.0003) and a heterozygous mutation in the MYH7 gene (R453S; 160760.0043). Frazier et al. (2008) suggested that the P82S variant, which they found in 3% of healthy African Americans, is a disease-modifying mutation in severely affected individuals, and that carriers of the variant might be at increased risk of late-onset cardiac hypertrophy. - Skeletal Muscle Involvement Fananapazir et al. (1993) demonstrated by biopsy of the soleus muscle the presence of central core disease of skeletal muscle (117000) in association with hypertrophic cardiomyopathy due to any of 4 different mutations in the MYH7 gene. Soleus muscle samples from patients in 4 kindreds in which hypertrophic cardiomyopathy was not linked to the MYH7 locus showed no myopathy or central core disease. In 1 family with the leu908-to-val mutation of the MYH7 gene (160760.0010), central core disease was demonstrated on soleus muscle biopsy, although cardiac hypertrophy was absent on echocardiogram in 2 adults and 3 children. Almost all patients had no significant muscle weakness, despite the histologic changes. The histologic hallmark of CCD was the absence of mitochondria in the center of many type I fibers as revealed by light microscopic examination of NADH-stained fresh-frozen skeletal muscle sections. McKenna (1993), who stated that he had never seen clinical evidence of skeletal myopathy in CMH1, doubted the significance of the findings. In a 44-year-old male with hypertrophic cardiomyopathy and respiratory failure, born of second-cousin British parents, Tajsharghi et al. (2007) identified homozygosity for a missense mutation in the MYH7 gene (E1883K; 160760.0035). The proband had 2 similarly affected sibs, a sister who had died at 57 years of age in cardiorespiratory failure and a brother who died at age 32 years from cardiac failure. Muscle biopsies from all 3 sibs showed findings typical for myosin storage myopathy (608358) with hyaline bodies seen in type 1 fibers. The sister had progressive muscle weakness and was wheelchair dependent by age 45, whereas the 2 brothers had milder proximal muscle weakness. The unaffected parents were presumed heterozygous carriers of the mutation, and another sib was unaffected. There was no family history of muscle weakness. In a mother with myosin storage myopathy, who later developed CMH, and in her daughter, who had early-symptomatic left ventricular noncompaction (LVNC5; see 613426), Uro-Coste et al. (2009) identified heterozygosity for the L1793P mutation in MYH7 (160760.0037). The mother presented at age 30 years with proximal muscle weakness, which progressed to the point of her being wheelchair-bound by 48 years of age. At age 51, CMH was diagnosed; echocardiography revealed no atrial or ventricular dilatation, and no abnormal appearance of the ventricular walls. Skeletal muscle biopsy at 53 years of age showed subsarcolemmal accumulation of hyaline material in type 1 fibers. Her 24-year-old daughter presented with heart failure at 3 months of age and was diagnosed with early-onset cardiomyopathy. Angiography revealed a less-contractile, irregular 'spongiotic' wall in the inferior left ventricle, and echocardiography confirmed the diagnosis of LVNC. The daughter did not complain of muscle weakness, but clinical examination revealed bilateral wasting of the distal leg anterior compartment and she had some difficulty with heel-walking.
In a discussion of hypertrophic cardiomyopathy, Maron et al. (1987) stated that approximately 45% of cases are sporadic. New mutations cannot be the explanation for all of the sporadic cases; hence, there may be other etiologically distinct disorders ... In a discussion of hypertrophic cardiomyopathy, Maron et al. (1987) stated that approximately 45% of cases are sporadic. New mutations cannot be the explanation for all of the sporadic cases; hence, there may be other etiologically distinct disorders represented in the group of hypertrophic cardiomyopathies. Systematic echocardiographic surveys of families of patients with hypertrophic cardiomyopathy have identified relatives older than 50 years of age with mild and localized left ventricular hypertrophy. Thus, the true proportion of sporadic cases may not be as high as 45%.