Cardiomyopathy, Familial Hypertrophic, 6

A number sign (#) is used with this entry because familial hypertrophic cardiomyopathy-6 (CMH6) is caused by heterozygous mutation in the gene encoding the gamma-2 regulatory subunit of AMP-activated protein kinase (PRKAG2; 602743) on chromosome 7q36.

Mutation in the PRKAG2 gene also causes the Wolff-Parkinson-White preexcitation syndrome (194200) in isolation or in association with cardiac hypertrophy.

For a phenotypic general description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600).

Description

Mutations in the PRKAG2 gene (602743) give rise to a moderate, essentially heart-specific, nonlysosomal glycogenosis with clinical onset typically in late adolescence or in the third decade of life, ventricular pre-excitation predisposing to supraventricular arrhythmias, mild-to-severe cardiac hypertrophy, enhanced risk of sudden cardiac death in midlife, and autosomal dominant inheritance with full penetrance (summary by Burwinkel et al., 2005).

Clinical Features

Laforet et al. (2006) studied a 38-year-old man who presented after 4 episodes of 'faintness' after swimming and had a 15-year history of lasting muscle stiffness without weakness in the arms and legs after prolonged exercise. He had 2 sibs who were asymptomatic, but a paternal aunt died suddenly at 65 years of age. Electrocardiogram showed sinus bradycardia with high-degree atrioventricular block and left bundle branch block, and a pacemaker was implanted. Echocardiography revealed hypertrophic cardiomyopathy. Limb muscle bulk and strength were normal on clinical examination, but deltoid muscle biopsy revealed sarcolemmal vacuoles in 10% of muscle fibers with intense periodic acid-Schiff staining, and ultrastructural analysis confirmed the presence of nonlysosomal glycogen accumulation.

Mapping

In a large family with 25 surviving individuals affected by familial hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome (WPW; 194200), or both, MacRae et al. (1995) found close linkage to DNA markers on chromosome 7q3. Four other loci responsible for familial hypertrophic cardiomyopathy had previously been identified (on chromosomes 1, 11, 14, and 15), but no report of individuals with familial hypertrophic cardiomyopathy due to mutation at the previously mapped disease loci were reported to have WPW, although 5 to 10% of hypertrophic cardiomyopathy patients have ventricular preexcitation. An association between WPW and familial hypertrophic cardiomyopathy had been noted in earliest descriptions of the latter condition. Braunwald et al. (1960) proposed that abnormal ventricular activation might result in regional myocardial hypertrophy or that localized hypertrophy might disrupt normal cardiac electrical discontinuity at the atrial ventricular ring. MacRae et al. (1995) performed linkage studies in 2 additional families with typical FHC (without WPW) which did not map to any of the 4 known FHC loci and found that they also did not map to 7q3.

Molecular Genetics

Sinha et al. (2000) reported a family in which 12 persons had ventricular preexcitation, 6 of whom also had cardiac hypertrophy. Three patients underwent successful ablation of typical accessory atrioventricular bundles, with subsequent loss of preexcitation. Gollob et al. (2001) demonstrated the presence of an R302Q mutation in the PRKAG2 gene (602743.0001) in this kindred.

Blair et al. (2001) identified heterozygous mutations in the PRKAG2 gene in 2 families with severe hypertrophic cardiomyopathy associated with conduction and electrocardiographic abnormalities, including WPW ventricular preexcitation syndrome in 3 individuals. Both mutations, 1 missense (H142R; 602743.0002) and 1 in-frame single codon insertion (602743.0003), occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, Blair et al. (2001) proposed that energy compromise may provide a unifying pathogenic mechanism in all forms of CMH.

Reports that dominant mutations in PRKAG2, an enzyme that modulates glucose uptake and glycolysis, can cause hypertrophic cardiomyopathy challenged the hypothesis that hypertrophic cardiomyopathy is a disease of the sarcomere. In addition to cardiac hypertrophy, individuals with PRKAG2 mutations frequently manifest electrophysiologic abnormalities, particularly Wolff-Parkinson-White syndrome (Gollob et al., 2001), atrial fibrillation, and progressive development of atrioventricular conduction block. Although atrial fibrillation is common in CMH patients and becomes increasingly prevalent with disease duration, neither accessory pathway nor conduction system diseases are typical features of CMH. To understand the mechanisms by which PRKAG2 defects cause disease, Arad et al. (2002) defined additional, novel mutations, including T400N (602743.0004) in an isolated patient and N488I (602743.0005) in the large family with CMH mapping to 7q3 originally reported by MacRae et al. (1995). A previously unrecognized and unusual histopathology was identified in hearts with PRKAG2 defects, which prompted biochemical analyses of the functional consequences of human PRKAG2 mutations on Snf4, the yeast homolog of the gamma-2 protein kinase subunit. Arad et al. (2002) concluded their data indicated that PRKAG2 defects do not cause CMH, but rather a novel glycogen storage disease of the heart in which hypertrophy, ventricular preexcitation, and conduction system defects coexist. They found that although the cardiac pathology caused by the PRKAG2 mutations R302Q, T400N, and N488I included myocyte enlargement and minimal interstitial fibrosis, these mutations were not associated with myocyte and myofibrillar disarray, the pathognomonic features of hypertrophic cardiomyopathy caused by sarcomere protein mutations. Instead, PRKAG2 mutations caused pronounced vacuole formation within myocytes. Several lines of evidence indicated that these vacuoles are filled with glycogen-associated granules. Analyses of the effects of human PRKAG2 mutations on Snf1/Snf4 kinase function demonstrated constitutive activity, which could foster glycogen accumulation.

In 3 sporadic, unrelated patients with lethal congenital glycogen storage disease of the heart (261740), who died of hemodynamic and respiratory failure secondary to hypertrophic nonobstructive cardiomyopathy but also had Wolff-Parkinson-White-like conduction anomalies, Burwinkel et al. (2005) identified heterozygosity for an R531Q mutation in the PRKAG2 gene (602743.0007). They noted that the molecular abnormalities of the R531Q mutant protein are more pronounced than those of other PRKAG2 mutants, which likely accounts for the more severe phenotype.

Arad et al. (2005) analyzed the PRKAG2 gene in 35 patients with hypertrophic cardiomyopathy who were negative for mutations in known sarcomere-protein genes, and identified a heterozygous missense mutation (Y487H; 602743.0008) in 1 proband with moderate hypertrophy and an extremely short PR interval.

In a child with idiopathic cardiac hypertrophy and presumed sporadic cardiomyopathy, who was negative for mutations in 9 of the known CMH genes, Morita et al. (2008) identified heterozygosity for a missense mutation in the PRKAG2 gene (H530R; 602743.0009). (The parents were not studied.) The mutation was not found in unrelated individuals matched by ancestral origin or in more than 1,000 control chromosomes.

In a father, son, and daughter with hypertrophic cardiomyopathy, Kelly et al. (2009) identified heterozygosity for a missense mutation in the PRKAG2 gene (E506Q; 602743.0010). Kelly et al. (2009) stated that 8 affected members of a family reported by Bayrak et al. (2006) with a PRKAG2 mutation at the same codon (E506K) had ventricular preexcitation and mild left ventricular hypertrophy; endomyocardial biopsy of the adult proband showed profound intracellular vacuolization and marked interstitial fibrosis. In the family studied by Kelly et al. (2009), the father had undergone cardiac transplantation for cardiomyopathy at age 29 years. In the 6-year-old daughter, 'prominent forces' were noted on electrocardiography and subsequent 2-D echocardiography revealed left ventricular mass at the 90th percentile for body surface area. The son presented at 6 months of age with a heart murmur and was found to have significant left ventricular hypertrophy on electrocardiogram; 2-D echocardiography showed markedly asymmetric septal hypertrophy and subaortic outflow tract obstruction. Repeat echocardiogram 5 months later showed severely obstructive CMH with hyperdynamic left ventricular systolic function and near-obliteration of the left ventricular cavity, and electrocardiography showed biventricular hypertrophy with a short PR interval (80 ms) and ventricular preexcitation. Examination of endocardial biopsy tissue from the boy showed a normal amount of glycogen present in the myocytes by staining and electron microscopy; a mild increase interstitial connective tissue was thought to represent nonspecific hypertrophic changes in the myocardium. Noting that in the patients reported by Burwinkel et al. (2005), the approximately 4- to 6-fold increase in cardiac mass was associated with only a 3-fold increase in glycogen content and an absence of more organized cellular aggregations of glycogen, Kelly et al. (2009) concluded that CMH due to PRKAG2 mutations may have a degree of cardiac hypertrophy exceeding that expected from observed amounts of glycogen deposition.

In a 38-year-old man with hypertrophic cardiomyopathy, severe conduction system abnormalities, and mild skeletal muscle glycogenosis, who was negative for mutation in the LMNA gene (150330), Laforet et al. (2006) identified heterozygosity for mutation in the PRKAG2 gene (602743.0011).

Animal Model

Arad et al. (2003) constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation (602743.0005). The transgenic mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen, developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiologic testing demonstrated alternative atrioventricular conduction pathways consistent with Wolff-Parkinson-White syndrome. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. Arad et al. (2003) concluded that these data establish that PRKAG2 mutations cause a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiologic findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe (232300), Danon (300257), and other glycogen storage diseases.