Miscellaneous Genetic Cardiomyopathies

Allen P. Burke, M.D.

Joseph J. Maleszewksi, M.D.

Infantile and Genetic Cardiomyopathy

A genetic basis underlies a majority of nonischemic cardiomyopathies (Chapters ). In most cases of cardiomyopathy in adults, there are multiple genes and mutations that are associated with a particular phenotype (i.e., dilated, hypertrophic, arrhythmogenic, or noncompaction). In many examples, however, specific mutations or genes are associated with cardiomyopathy that typically presents at an early age and has extracardiac manifestations.

Although there is an overlap between familial cardiomyopathy and those associated with specific syndromes, the current chapter focuses on diseases that have a genetic basis, that often have extracardiac manifestations, that often occur in infants and children, and that are known by the specific mutation or by a specific eponym. The practice of renaming cardiomyopathy after a new mutational finding (e.g., desminopathy, laminopathy) has been discouraged.¹ Cardiomyopathies that are not defined by the mutational status or clinical syndrome but rather by cardiac clinicopathologic features are discussed in previous chapters.

Noonan Syndrome

Noonan syndrome is an autosomal dominant condition characterized by short stature, heart defects, pectus excavatum, webbed neck, learning problems, cryptorchidism, and facial dysmorphism.² It occurs in up to 1 in 1,000 live births.³ Cardiovascular manifestations occur in 20% of patients and include cardiac hypertrophy (hypertrophic cardiomyopathy [HCM]-like phenotype), valvular dysplasias, atrial septal defect, ventricular septal defect, and patent ductus arteriosus (see Chapter 3).

Noonan syndrome and related conditions are caused by the dysregulation of the RAS-MAPK signaling pathway. Overall, mutations are found only in a subset of patients and include variants in PTPN11 (about 50% of identified mutations), SOS1 (13%), RAF1 (5% to 15%), and RIT1 (9%). Mutations of KRAS, NRAS, SHOC2, BRAF, MEK1, and CBL have also been reported.²^,³

Pulmonary valve stenosis is the most common cardiovascular manifestation. The rate of HCM-like phenotype is as high as 70% in mutation-positive individuals and is frequently associated with pulmonary valve dysplasia with stenosis. There may be associated atrial and ventricular septal defects and mitral valve disease in up to one-third of these patients.³

The pathologic cardiac manifestations include generalized left ventricular hypertrophy and dome-shaped dysplastic pulmonic valves. Autopsy studies are few, and the pathologic features of the cardiomyopathy have not been studied.⁴

Myofiber disarray can occur in association with fibrosis (Fig. 160.1), but classic whorled appearance of sarcomeric HCM is not generally
seen. Magnetic resonance imaging has demonstrated a subset of patients with myocardial bridges and left ventricular diverticula, crypts, and crevices.⁵

FIGURE 160.1 ▲ Noonan syndrome. There is myocyte hypertrophy and fibrosis, with mild disarray of myofibers. The histologic appearance is nonspecific. The diagnosis rests of constellation of clinical findings, including valve disorders, especially pulmonary stenosis (not shown) in addition to cardiomyopathy.

Friedreich Ataxia

Friedreich ataxia is the most common cause of inherited childhoodonset ataxia. It is an autosomal recessive disease caused by mutations in the human frataxin gene, FXN. Frataxin functions as a mitochondrial iron chaperone protein. Mutations result in abnormal accumulation of intramitochondrial iron, mitochondrial dysfunction, and oxidative damage.⁶^,⁷

Cardiac manifestations of Friedreich ataxia occur at an older age than do the neurologic symptoms, generally in early adulthood. Up to 90% of patients will demonstrate cardiac abnormalities on echocardiography. Approximately 20% of patients will develop a hypokinetic dilated cardiomyopathy phenotype that may be fatal. Earlier phases of the cardiomyopathy are characterized by cardiac hypertrophy, which may be asymmetric or concentric.

The severity of left ventricular hypertrophy is related to the number of GAA repeats in the first intron of FXN. Pathologically, the heart is dilated and hypertrophied.⁶ Histologically, there is diffuse interstitial fibrosis, patchy chronic inflammation, and endocardial fibrosis.⁶ Small-vessel disease of intramural coronary arteries has also been described.⁸

Cardiomyopathy in patients with Friedreich ataxia may be exacerbated by diabetic ketoacidosis and Graves disease.⁹ Sudden death has been reported as the initial manifestation of cardiac symptoms with diagnosis made by postmortem molecular testing.⁶

Myotonic Dystrophy

Myotonic dystrophy is an autosomal recessive disease involving facial, neck, and distal limb muscles. There are two types with differing genetic etiologies. Type 1 (Steinert disease) is caused by mutations in DMPK. Type 2 (proximal myotonic myopathy) is a milder form of the disease caused by mutations in ZNF9.

Cardiac involvement manifests most commonly as conduction defects, which may occur in the absence of severe skeletal disease and occur in the majority of patients. First-degree heart block is the most common abnormality, followed by ventricular tachycardia. Rarely, the progression of the disease can lead to sudden, unpredictable death. Conduction electrophysiologic studies are generally performed to guide implantation of defibrillators.¹⁰

Histologic findings are nonspecific. There is typically fibrosis of the bundle of His and proximal bundle branches.¹¹ Myocytes show nonspecific hypertrophy with occasional vacuoles and disarray.¹¹ Electron microscopic findings include prominent I bands and myofibrillar degeneration.¹²

X-Lined Muscular Dystrophy

Duchenne and the milder Becker muscular dystrophies are caused by mutations in the dystrophin gene DMD, located at Xp21. Dystrophin is a cytoskeletal protein that provides structural support to the myocyte and links the sarcomeric contractile apparatus to the sarcolemma and extracellular matrix.

Duchenne muscular dystrophy (DMD) is most commonly caused by deletion of one or more exons, with duplications, single nucleotide variant, and splicing variants causing a lower percentage of total cases. In patients that survive past the age of 18, development of cardiomyopathy (dilated phenotype) is the rule. In fact, with improvements in treatment for respiratory and other complications, the cardiomyopathy is thought to account for most deaths in DMD (either heart failure or arrhythmia). Pathologically, there is myocardial fibrosis that is typically interstitial, although transmural scars may occur. The changes are most marked in the posterobasal region and adjacent lateral wall of the left ventricle.¹³

In ˜6% of men with idiopathic dilated cardiomyopathy without skeletal myopathy, defects in the dystrophin gene may be identified.¹⁴ Overall, X-linked inheritance accounts for between 2% and 5% of familial cases of dilated cardiomyopathy that manifests in young men with rapidly progressive heart failure.¹⁵

The presence of increased serum creatine phosphokinase (SCPK) is suggestive of the disease in men with a history of X-linked cardiomyopathy. Mutational analysis for pathogenic mutations in the dystrophic gene DMD is diagnostic, and immunohistochemical staining for dystrophin may also be helpful (Fig. 160.2).

Female carriers develop a milder form of cardiomyopathy, usually in their 50s. Immunohistochemical stains for dystrophin reveal a patchy loss of dystrophin, with scattered myocytes showing no staining in a mosaic pattern.¹⁶ Cardiac findings are similar to those in males, with biventricular dilation and diffuse fibrous replacement. 16 The right ventricular free wall may become thin and replaced by fibrofatty tissue, mimicking arrhythmogenic right ventricular cardiomyopathy.¹⁶

Becker dystrophy is also the result of mutations in the DMD gene, but unlike DMD, some protein is produced. These individuals usually manifest a milder phenotype, but most (70%) will also develop cardiomyopathy, which, like DMD, is a common cause of mortality.¹⁷

Cardiac Involvement in Emery-Dreifuss and Myofibrillar Myopathies/Muscular Dystrophies

Emery-Dreifuss muscular dystrophy is a myopathy that causes cardiac dysrhythmias, late-onset heart failure, and progressive skeletal myopathy characterized by contractures of the neck, elbows, and ankles. It was generally considered an X-linked disease, although autosomal dominant forms have been more recently described. It is an example of a nuclear “envelopathy,” or “laminopathy” caused by mutations of genes that encode proteins of the nuclear envelope. Mutations in the EMD gene, encoding emerin, cause the X-linked form, while LMNA gene mutations are responsible for autosomal forms, which manifest as a dilated phenotype (see Chapter 19).¹⁸

Mutations in LMNA also cause a related condition, limb girdle myotonic dystrophy type 1B.¹⁹ Endomyocardial biopsy specimens show only nonspecific findings.²⁰

FIGURE 160.2 ▲ Duchenne cardiomyopathy. A. Immunohistochemical staining showing normal cytoplasmic dystrophin reactivity. B. Decreased expression is seen in male with sporadic cardiomyopathy in whom cardiac symptoms predated skeletal muscle disease. (Reproduced Arbustini E, Narula N, Dec GW, et al. The MOGE(S) classification for a phenotype-genotype nomenclature of cardiomyopathy: endorsed by the World Heart Federation. J Am Coll Cardiol. 2013;62:2046-2072, with permission.)

The “myofibrillar myopathies” (see Chapter 27) are characterized by myofibrillar disorganization of the Z-disk progressing to myofibrillar degradation in the adjacent sarcomere.²¹ The pathologic diagnosis of myofibrillar myopathy is established by skeletal muscle biopsy in which hyaline deposits are present that may be congophilic. Cardiac involvement is most frequent in myofibrillar myopathies caused by mutations in desmin and zaspin (so-called desminopathy and zaspopathy, respectively).

Barth Syndrome

X-linked dilated cardiomyopathy in male infants is most frequently caused by Barth syndrome (dilated cardiomyopathy, skeletal myopathy, growth retardation, and neutropenia).²² Male neonates or young infants present with congestive heart failure, neutropenia, and 3-methylglutaconic aciduria. Children die in infancy from progressive heart failure, sudden death, or sepsis. The pathologic findings are nonspecific, but imaging studies demonstrate that at least one-half of patients have left ventricular noncompaction.²³

Barth syndrome is caused by mutations in the tafazzin gene (TAZ) on chromosome Xq28. Heart failure is common as patients survive childhood and is caused by cardiomyopathy with both a dilated and noncompaction phenotype, as well as endocardial fibroelastosis (EFE).²⁴

TABLE 160.1 Cardiac Involvement in Glycogen Storage Diseases^a

Inborn Error	Cardiac Involvement	Dominant Involvement	Diagnostic Tests
Type IIa (Pompe), lysosomal acid α-glucosidase (GAA)	Cardiomyopathy, infantile	Skeletal myopathy, hypotonia, macroglossia	Glycogen vacuoles in myocytes Decreased enzyme activity in skin fibroblasts/genetic testing
Type IIb (Danon) lysosomal membrane protein-2 (LAMP2)	Hypertrophic cardiomyopathy	Similar to Pompe, degree dependent on residual enzyme activity	Decreased enzyme activity in muscle/genetic testing Ultrastructural lysosomal vacuoles in heart muscle
Over 10 entities, including McArdle, Andersen, von Gierke, Hers (type VI), Forbes disease	None/minimal	Hypoglycemia, myopathy, various others	Decrease enzyme activity in liver (types I, III, VI, VIII/IX), muscle (III, VII, VIII/IX), skin fibroblasts (IV), RBCs (VII), lack of increased venous lactate with forearm ischemia (V, VII)
PRKAG2 mutation	Cardiomyopathy Conduction defect	Skeletal myopathy	Glycogen vacuoles in heart muscle Genetic testing
^aThere is no significant cardiac involvement in other carbohydrate metabolism disorders, such as galactosemia, fructose disorders, and pyruvate carboxylase/dehydrogenase deficiency.

Inborn Errors of Carbohydrate Metabolism (Tables 160.1, 160.2, 160.3, 160.4)

Pompe Disease

Pompe disease is an autosomal recessive glycogen storage disease (infantile type IIa) caused by α-1,4 glycosidase (acid maltase) deficiency. Of the glycogen storage diseases, types II to IV may cause cardiac dysfunction in infants and young children. Type V glycogen storage disease (McArdle disease) rarely involves the heart.³⁵ Affected infants have profound cardiac dysfunction, with large accumulations of glycogen in cardiac myocytes. There is massive cardiomegaly and typically biventricular dilatation (Fig. 160.3). Diagnosis is made by accumulation of PAS-positive (diastase-labile) vacuoles diffusely throughout myocytes (Fig. 160.4) and, at autopsy, in other affected organs (skeletal muscles, liver, and nervous system).

Danon Cardiomyopathy

Defects in lysosome-associated membrane protein 2 (LAMP-2) cause the X-linked cardiomyopathy “Danon disease” (type IIb). Clinical manifestations are limited largely to the heart, usually with massive degrees of LV hypertrophy and ventricular preexcitation.³⁶ Skeletal myopathy occurs in about 20% of patients.³⁷

TABLE 160.2 Cardiac Involvement in Inborn Errors of Metabolism: Fatty Acid Oxidation and Glycerol Metabolism Disorders

Inborn Error	Cardiac Involvement	Dominant Involvement	Diagnostic Tests
Fatty acid (β-oxidation cycle)
Medium-chain acyl dehydrogenase	Minimal	Neonatal vomiting, lethargy, acidosis, SIDS like; episodic	Plasma/urine medium-chain fatty acid conjugates of carnitine; enzyme deficiency in cultured fibroblasts Genetic testing
Long-chain hydroxyacyl-CoA dehydrogenase	Cardiomyopathy	Myopathy with exertion; HELLP in mothers of affected fetuses	Plasma acylcarnitine and acylglycine profile; enzyme study in skin fibroblasts
Very long-chain hydroxyacyl-CoA dehydrogenase	Cardiomyopathy dominant	Myopathy	Acylcarnitine profile in serum or blood; enzyme activity in skin fibroblasts
Glycerol metabolism
Glycerol kinase	Association with Duchenne muscular dystrophy	Acidosis, hypoglycemia	Elevated blood and urine glycerol