Inherited syndromes associated with cardiac disease Author William J McKenna, MD Section Editor Bernard J Gersh, MB, ChB,

DPhil, FRCP, MACC Deputy Editor Susan B Yeon, MD, JD, FACC Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2013. | This topic last updated: May 1, 2013. INTRODUCTION Hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy are commonly inherited (table 1). (See "Genetics of hypertrophic cardiomyopathy" and "Genetics of dilated cardiomyopathy" and "Genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy" and "Definition and classification of the cardiomyopathies".) In addition, a number of inherited syndromes consist of defects that produce systemic as well as cardiac manifestations, most of which affect skeletal muscle. These disorders will be briefly reviewed here and are discussed in detail on the appropriate topic reviews. Amyloid cardiomyopathy and cardiac manifestations of Fabry disease are discussed in detail separately. (See "Clinical manifestations and diagnosis of amyloid cardiomyopathy" and "Cardiac manifestations of Fabry disease and screening in patients with left ventricular hypertrophy".) NEUROMUSCULAR DISORDERS Cardiomyopathy occurs in a variety of inherited neuromuscular disorders. The underlying neuromuscular disease is usually apparent at the onset of cardiac disease but some patients have no or only mild neurologic manifestations. Dystrophin disorders Mutations in the dystrophin gene on the X chromosome produce both Duchenne and Becker muscular dystrophy. In addition, deletions in the 5' muscle promoter of the dystrophin gene can cause a predominant cardiac phenotype that presents as a dilated cardiomyopathy. Skeletal muscle biopsies of individuals with X-linked dilated cardiomyopathy due to dystrophin deletions demonstrate the classic pathologic changes of Duchenne or Becker dystrophies, but the muscle manifestations may be subclinical. (See "Genetics of dilated cardiomyopathy", section on 'Dystrophin gene mutations'.) Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is caused by a defective gene located on the X chromosome that is responsible for the production of dystrophin, a high molecular weight protein that is localized to the sarcolemmal membrane of normal skeletal muscle. Patients with DMD have complete or almost complete absence of dystrophin in skeletal muscle. The clinical onset of weakness usually occurs between two and three years of age. (See "Clinical features and diagnosis of Duchenne and Becker muscular dystrophy".) DMD causes a primary cardiomyopathy with extensive fibrosis of the posterobasal left ventricular wall, resulting in the characteristic electrocardiographic changes of tall right precordial R waves with an increased R/S ratio and deep Q waves in leads I, aVL, and V56 (waveform 1) [1]. As the cardiac disease progresses, fibrosis can spread to the lateral free wall of the left ventricle. Significant mitral regurgitation is often present due to involvement of the posterior papillary muscle [2]. Cardiac involvement is also associated with conduction abnormalities, especially intraatrial and interatrial but also involving the AV node, and a variety of arrhythmias, primarily supraventricular [3]. (See "Clinical features and diagnosis of Duchenne and Becker muscular dystrophy", section on 'Cardiomyopathy'.) Becker muscular dystrophy Like DMD, Becker muscular dystrophy (BMD) is an X-linked disorder involving the dystrophin gene [4,5]. However, in contrast to the absence of dystrophin in skeletal muscle in DMD, most patients with BMD have an abnormal dystrophin protein. BMD is later in onset and slower in progression than DMD. The clinical manifestations are also less severe as affected patients typically remain ambulatory until at least age 15 and often into adult life. (See "Clinical features and diagnosis of Duchenne and Becker muscular dystrophy".) Although muscle involvement is less severe than in DMD, cardiac involvement in BMD can be more severe [6]. It has been suggested that, because patients with mild BMD are still able to perform strenuous exercise, the associated mechanical stress on the heart may be harmful for myocardial cells with abnormal dystrophin. Echocardiography reveals early right ventricular involvement with the later development of left ventricular dysfunction and heart failure that can be rapidly progressive and is usually the ultimate cause of death [6]. In addition, abnormalities of the AV node and infranodal conduction system can result in fascicular and bundle branch block and can progress to complete heart block. (See "Clinical features and diagnosis of Duchenne and Becker muscular dystrophy".) Emery-Dreifuss muscular dystrophy Emery-Dreifuss muscular dystrophy (EDMD), also known as humeroperoneal muscular dystrophy, can be inherited as an X-linked recessive, autosomal dominant, or autosomal recessive disorder involving the emerin or lamin A/C genes. The different forms of Emery-Dreifuss muscular dystrophy have identical symptoms, which usually begin in the

first or second decade of life. Muscle weakness and wasting has a humeroperoneal distribution and tend to be slowly progressive. Contractures are often the first manifestations of the disease. (See "Emery-Dreifuss muscular dystrophy".) A cardiomyopathy may be seen in EDMD. It is typically associated with AV conduction abnormalities; other common findings include atrial paralysis, atrial fibrillation, atrial flutter, and infranodal or AV conduction block with the development of slow junctional rhythms that often require pacemaker insertion. Sudden death can occur. Facioscapulohumeral muscular dystrophy Facioscapulohumeral dystrophy (FSHD) is the third most common hereditary muscle disorder after Duchenne muscular dystrophy and myotonic dystrophy. The classic form is inherited in an autosomal dominant fashion and the affected gene has been mapped to chromosome 4q35. FSHD is usually slowly progressive but there is variability in both age of onset and severity. The onset in the classic form is usually between the ages of 10 and 30 and progression is slow with an almost normal life span; however, the infantile form is rapidly progressive. The disease initially involves the face and the scapulae followed by the foot dorsiflexors and the hip girdles. Asymmetry of muscle involvement and sparing of bulbar, extraocular, and respiratory muscles are other typical features. Cardiac involvement can occur. The manifestations include P wave abnormalities, intraventricular conduction delay, and supraventricular arrhythmias. (See"Facioscapulohumeral muscular dystrophy".) Myotonic dystrophy Myotonic dystrophy (also called dystrophia myotonica [DM]) is a multisystem disease with autosomal dominant inheritance and variable penetrance and clinical anticipation, eg, increasingly severe disease with each successive generation. Two main forms have been identified: DM1, in which the genetic defect is a trinucleotide repeat in a gene encoding a protein kinase called myotonin; and, less commonly, DM2 (also known as proximal myotonic myopathy or PROMM), in which the disease locus is on chromosome 3q21. Clinical features include myotonia (delayed muscle relaxation after contraction), weakness and wasting affecting facial muscles and distal limb muscles, frontal balding in males, cataracts, multiple endocrinopathies, and low intelligence or dementia. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".) In the classic form, DM has its onset in adolescence or adulthood and disease severity may be mild (eg, isolated cataracts) to severe with marked skeletal muscle and cardiac and/or endocrine dysfunction. The congenital form occurs in children born to affected mothers with myotonic dystrophy. Cardiac manifestations include atrioventricular block and intraventricular conduction delay, with occasional progression to complete heart block, atrial fibrillation, ventricular tachyarrhythmias, and a cardiomyopathy characterized by a reduced left ventricular ejection fraction, wall motion abnormalities on echocardiography, and in less than 10 percent of patients, heart failure. Sudden death can result from conduction system disease or ventricular tachycardia, and cardiovascular causes are responsible for about 30 percent of deaths. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Cardiac abnormalities'.) Friedreich ataxia Friedreich ataxia is the most common hereditary ataxia in Caucasians. It is transmitted as an autosomal recessive trait and is caused by loss of function mutations in the frataxin gene. The major clinical manifestations are neurologic dysfunction (eg, progressive ataxia of all four limbs may be seen by age five or earlier), diabetes mellitus, and cardiac disease. Electrocardiographic and echocardiographic abnormalities are those of morphologically mild asymmetric septal hypertrophy with progressive impairment of systolic function. The main clinical manifestations are arrhythmic complications related to the cardiomyopathy which are a frequent cause of death. (See "Friedreich ataxia".) Barth's syndrome Barth's syndrome is an X-linked disorder characterized by skeletal myopathy, dilated cardiomyopathy, short stature, and neutropenia. Affected individuals often die at a young age from heart failure and its complications. Genetic mapping studies defined a locus that overlapped with the Emery-Dreifuss muscular dystrophy locus. Barth's syndrome is caused by mutations in a novel gene (G4.5) that codes for proteins called tafazzins [7,8]. Alternative splicing of this gene may account for the variations in tissue and disease expression. This genetic mutation is also responsible for isolated left ventricular noncompaction [8]. (See "Isolated left ventricular noncompaction".) OTHER DISORDERS Iron overload Cardiac disease due to iron deposition within the myocardium can be seen in hereditary hemochromatosis and hereditary sideroblastic anemias. The 2005 guidelines from the American College of Physicians proposed the following cutoff levels for identifying patients with iron overload: transferrin saturation (serum iron total iron binding capacity) greater than 55 percent and serum ferritin greater than 200 or 300 microg/L in women and men, respectively [9,10]. (See "Pathophysiology and diagnosis of iron overload syndromes".) Hemochromatosis Hereditary hemochromatosis is a common disorder with recessive inheritance that affects 1 in 400 individuals of northern European ancestry. It is characterized by increased iron absorption and deposition in parenchymal tissues, including the heart. This disorder is due to mutations in the HFE gene that lead to increased intestinal iron absorption. (See "Genetics of hereditary hemochromatosis".)

Diabetes mellitus, bronze skin changes, and/or evidence of hepatitis or cirrhosis should alert the clinician to the possible presence of hereditary hemochromatosis. However, the absence of these disorders does not exclude the diagnosis since, prior to the use of screening studies, heart disease was the presenting manifestation in up to 15 percent of patients. Iron deposition can lead to a dilated cardiomyopathy characterized by the development of heart failure and conduction disturbances such as the sick sinus syndrome. (See "Clinical manifestations of hereditary hemochromatosis", section on 'Heart disease'.) Treatment with phlebotomy has been associated with reversal of the left ventricular dysfunction, but irreversible myocardial dysfunction can occur with advanced disease. (See "Treatment of hereditary hemochromatosis".) Hereditary sideroblastic anemias and thalassemias Sideroblastic anemias and thalassemias are hereditary disorders that cause anemia of varying severity depending upon the specific genetic defect. Ineffective erythropoiesis leads to increased iron absorption; in addition, regular red blood cell transfusions are necessary in the management of most of these disorders. These processes ultimately lead to iron overload and deposition in various tissues, including the heart (picture 1). Iron deposition in the myocardium can result in arrhythmias and HF, which usually occur late in the course of the disease. (See "Clinical aspects, diagnosis, and treatment of the sideroblastic anemias" and "Clinical manifestations and diagnosis of the thalassemias".) Phlebotomy, which is effective in treating iron overload due to hereditary hemochromatosis, is not feasible in the sideroblastic anemias and thalassemias because of the underlying anemia. Iron chelation therapy, if initiated early, may prevent or reverse the cardiac abnormalities. Assessment of myocardial iron overload with cardiac magnetic resonance T2* imaging to guide chelation therapy has dramatically improved prognosis in thalassemia [11,12]. (See "Iron overload syndromes other than hereditary hemochromatosis", section on 'Chelation therapy'.) Desmin cardiomyopathy Desmin is a polypeptide that normally aggregates to form filaments of a diameter intermediate between myosin and actin in both skeletal and cardiac muscle [13,14]. Granulofilamentous and cytoplasmic inclusions result from abnormal forms of desmin [14]. Desminopathy is a skeletal and cardiac myopathy caused by mutations in desmin or alpha B crystallin, a chaperone for desmin. Desminopathy is usually inherited in an autosomal dominant pattern although some kindred demonstrate autosomal recessive transmission. In contrast to other forms of cardiomyopathy, it requires ultrastructural study for diagnosis. The failure of desmin to aggregate into intermediate filaments and the presence of granulofilamentous material leads to impairment in relaxation and contraction and clinical presentation resembling restrictive cardiomyopathy [15]. Atrioventricular block and mild or subclinical myopathy may be present. Other desmin mutations may produce an idiopathic dilated cardiomyopathy without skeletal muscle involvement [16]. (See "Genetics of dilated cardiomyopathy", section on 'Desminopathy'.) Naxos disease Clinical genetic studies suggest that at least 30 percent of ARVC cases are familial with autosomal dominant inheritance. Recessive disease with cutaneous manifestations include Naxos disease and Carvajal syndrome [17]. Affected individuals develop the arrhythmogenic cardiomyopathy accompanied by nonepidermolytic palmoplantar keratosis which causes hyperkeratosis of the palms and soles, and wooly hair. (See "Genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy", section on 'Autosomal recessive disease and Naxos disease'.) Carney complex Atrial myxomas are rarely inherited as part of the Carney complex, which is characterized by cardiac and mucocutaneous myxomas, lentiginosis, and endocrine dysfunction including bilateral adrenal micronodular hyperplasia that can lead to Cushing's syndrome. The cardiac tumors are often multicentric, rarely metastasize and are amenable to surgical resection. There at least three different genetic loci with two identified genes. (See"Cardiac tumors" and "Cushing's syndrome due to ACTHindependent macronodular adrenal hyperplasia".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the key word(s) of interest.)

Basics topic (see "Patient information: Friedreich ataxia (The Basics)")

SUMMARY AND RECOMMENDATIONS

A variety of cardiomyopathies are due to familial disease (table 1). Most are primarily associated with cardiac involvement and can lead to hypertrophic, dilated, arrhythmogenic, or restrictive cardiomyopathy. Other inherited

syndromes produce systemic manifestations (eg, skeletal muscle disease) as well as cardiac disease. (See "Genetics of hypertrophic cardiomyopathy" and "Genetics of dilated cardiomyopathy" and "Genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy" and "Definition and classification of the cardiomyopathies".) Cardiomyopathy occurs in a variety of inherited neuromuscular disorders. The underlying neuromuscular disease is usually but not always apparent at the onset of cardiac disease. (See 'Neuromuscular disorders' above.) Other inherited disorders with systemic manifestations as well as cardiomyopathy include disorders that cause iron overload (hemochromatosis and hereditary sideroblastic anemias and thalassemias), desmin cardiomyopathy, and cardiocutaneous syndromes, including Naxos disease. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Sanyal SK, Johnson WW, Thapar MK, Pitner SE. An ultrastructural basis for electrocardiographic alterations associated with Duchenne's progressive muscular dystrophy. Circulation 1978; 57:1122. Sanyal SK, Johnson WW, Dische MR, et al. Dystrophic degeneration of papillary muscle and ventricular myocardium. A basis for mitral valve prolapse in Duchenne's muscular dystrophy. Circulation 1980; 62:430. Perloff JK. Cardiac rhythm and conduction in Duchenne's muscular dystrophy: a prospective study of 20 patients. J Am Coll Cardiol 1984; 3:1263. Worton R. Muscular dystrophies: diseases of the dystrophin-glycoprotein complex. Science 1995; 270:755. Ervasti JM, Ohlendieck K, Kahl SD, et al. Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 1990; 345:315. Melacini P, Fanin M, Danieli GA, et al. Myocardial involvement is very frequent among patients affected with subclinical Becker's muscular dystrophy. Circulation 1996; 94:3168. Bione S, D'Adamo P, Maestrini E, et al. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet 1996; 12:385. Ichida F, Tsubata S, Bowles KR, et al. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 2001; 103:1256. Schmitt B, Golub RM, Green R. Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians. Ann Intern Med 2005; 143:522. Qaseem A, Aronson M, Fitterman N, et al. Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2005; 143:517. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet 2000; 355:2051. Modell B, Khan M, Darlison M, et al. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2008; 10:42. Fuchs E, Weber K. Intermediate filaments: structure, dynamics, function, and disease. Annu Rev Biochem 1994; 63:345. Goebel HH. Desmin-related neuromuscular disorders. Muscle Nerve 1995; 18:1306. Arbustini E, Morbini P, Grasso M, et al. Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desmin-immunoreactive material deposits. J Am Coll Cardiol 1998; 31:645. Li D, Tapscoft T, Gonzalez O, et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation 1999; 100:461. Kaplan SR, Gard JJ, Carvajal-Huerta L, et al. Structural and molecular pathology of the heart in Carvajal syndrome. Cardiovasc Pathol 2004; 13:26.

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