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7/28/2019 Inherited Syndromes Associated With Cardiac Disease
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Inherited syndromes associated with cardiac diseaseAuthorWilliam J McKenna, MDSection EditorBernard J Gersh, MB, ChB, DPhil, FRCP, MACCDeputy EditorSusan B Yeon, MD, JD, FACCDisclosures
All topics are updated as new evidence becomes available and ourpeer review processis 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 neurologicmanifestations.
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 characteristicelectrocardiographic changes of tall right precordial R waves with an increased R/S ratio and deep Q waves in leads I, aVL, and V5-
6 (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
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first or second decade of li fe. 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), weaknessand 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 i ts 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".)
http://www.uptodate.com/contents/emery-dreifuss-muscular-dystrophy?source=see_linkhttp://www.uptodate.com/contents/emery-dreifuss-muscular-dystrophy?source=see_linkhttp://www.uptodate.com/contents/emery-dreifuss-muscular-dystrophy?source=see_linkhttp://www.uptodate.com/contents/facioscapulohumeral-muscular-dystrophy?source=see_linkhttp://www.uptodate.com/contents/facioscapulohumeral-muscular-dystrophy?source=see_linkhttp://www.uptodate.com/contents/facioscapulohumeral-muscular-dystrophy?source=see_linkhttp://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis?source=see_linkhttp://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis?source=see_linkhttp://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis?source=see_linkhttp://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis?source=see_link&anchor=H9#H9http://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis?source=see_link&anchor=H9#H9http://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis?source=see_link&anchor=H9#H9http://www.uptodate.com/contents/friedreich-ataxia?source=see_linkhttp://www.uptodate.com/contents/friedreich-ataxia?source=see_linkhttp://www.uptodate.com/contents/friedreich-ataxia?source=see_linkhttp://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/7,8http://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/7,8http://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/7,8http://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/8http://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/8http://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/8http://www.uptodate.com/contents/isolated-left-ventricular-noncompaction?source=see_linkhttp://www.uptodate.com/contents/isolated-left-ventricular-noncompaction?source=see_linkhttp://www.uptodate.com/contents/isolated-left-ventricular-noncompaction?source=see_linkhttp://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/9,10http://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/9,10http://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/9,10http://www.uptodate.com/contents/pathophysiology-and-diagnosis-of-iron-overload-syndromes?source=see_linkhttp://www.uptodate.com/contents/pathophysiology-and-diagnosis-of-iron-overload-syndromes?source=see_linkhttp://www.uptodate.com/contents/pathophysiology-and-diagnosis-of-iron-overload-syndromes?source=see_linkhttp://www.uptodate.com/contents/pathophysiology-and-diagnosis-of-iron-overload-syndromes?source=see_linkhttp://www.uptodate.com/contents/genetics-of-hereditary-hemochromatosis?source=see_linkhttp://www.uptodate.com/contents/genetics-of-hereditary-hemochromatosis?source=see_linkhttp://www.uptodate.com/contents/genetics-of-hereditary-hemochromatosis?source=see_linkhttp://www.uptodate.com/contents/genetics-of-hereditary-hemochromatosis?source=see_linkhttp://www.uptodate.com/contents/pathophysiology-and-diagnosis-of-iron-overload-syndromes?source=see_linkhttp://www.uptodate.com/contents/pathophysiology-and-diagnosis-of-iron-overload-syndromes?source=see_linkhttp://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/9,10http://www.uptodate.com/contents/isolated-left-ventricular-noncompaction?source=see_linkhttp://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/8http://www.uptodate.com/contents/inherited-syndromes-associated-with-cardiac-disease/abstract/7,8http://www.uptodate.com/contents/friedreich-ataxia?source=see_linkhttp://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis?source=see_link&anchor=H9#H9http://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis?source=see_linkhttp://www.uptodate.com/contents/facioscapulohumeral-muscular-dystrophy?source=see_linkhttp://www.uptodate.com/contents/emery-dreifuss-muscular-dystrophy?source=see_link -
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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 ACTH-
independent 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
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and more detailed. These articles are written at the 10th
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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 cardiacinvolvement and can lead to hypertrophic, dilated, arrhythmogenic, or restrictive cardiomyopathy. Other inherited
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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 isusually 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, andcardiocutaneous syndromes, including Naxos disease.
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