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Inherited syndromes associated with cardiac disease

Inherited syndromes associated with cardiac disease
Literature review current through: Jan 2024.
This topic last updated: Dec 06, 2021.

INTRODUCTION — A number of inherited syndromes involve defects that produce systemic and 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 "Fabry disease: Cardiovascular disease".)

Hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies are inherited heart muscle disorders in which disease-causing genes are identifiable in the majority of patients (table 1). (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing" and "Genetics of dilated cardiomyopathy" and "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics" and "Definition and classification of the cardiomyopathies".)

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 "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

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 V5-6 (waveform 1) [1]. As the cardiac disease progresses, fibrosis can spread to the lateral free wall of the left ventricle. The extent and severity of fibrosis can be assessed by examining the distribution of late gadolinium enhancement with cardiac magnetic resonance (CMR). Significant mitral regurgitation is often present due to involvement of the posteromedial 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 "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis", 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 "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

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 and/or cardiac magnetic resonance (CMR) 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 "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

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'.)

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 DUX4 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".)

Friedreich ataxia — Friedreich ataxia is the most common hereditary ataxia in White populations. 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, particularly atrial fibrillation and other supraventricular arrhythmias, as well as ventricular arrhythmias, which are a frequent cause of death. (See "Friedreich ataxia".)

Barth syndrome — Barth 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 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 in adults: Clinical manifestations and diagnosis".)

METABOLIC DISORDERS

Fabry disease — Fabry disease is an X-linked genetic multisystem disorder resulting from a deficiency of the lysosomal enzyme alpha galactosidase; cardiac manifestations may be the predominant clinical features and usually include ventricular hypertrophy. This condition is discussed separately. (See "Fabry disease: Cardiovascular disease".)

Glycogen storage disease — Mutations in the PRKAG2 gene cause an autosomal dominant disorder, usually manifesting in adolescents and young adults with progressive left ventricular hypertrophy and a mild skeletal myopathy. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'PRKAG2 and LAMP2 genes'.)

Danon disease — Danon disease is an X-linked disorder caused by mutations in the LAMP2 gene associated with severe, progressive hypertrophic cardiomyopathy in male children and adolescents, and is also associated with skeletal myopathy and cognitive disabilities.

OTHER DISORDERS

Iron overload — Cardiac disease due to iron deposition within the myocardium can be seen in patients with iron overload resulting from hereditary hemochromatosis, secondary iron overload (eg, iron-loading anemias), or other causes. (See "Approach to the patient with suspected iron overload".)

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 "HFE and other hemochromatosis genes".)

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 sinus node dysfunction. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Cardiac iron overload'.)

Treatment with phlebotomy has been associated with reversal of the left ventricular dysfunction, but irreversible myocardial dysfunction can occur with advanced disease. (See "Management and prognosis 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 "Sideroblastic anemias: Diagnosis and management" and "Diagnosis of thalassemia (adults and children)".)

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 [9,10]. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

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 [11,12]. Granulofilamentous and cytoplasmic inclusions result from abnormal forms of desmin [12]. 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 [13]. Atrioventricular block and mild or subclinical myopathy may be present. Other desmin mutations may produce an idiopathic dilated cardiomyopathy without skeletal muscle involvement [14]. (See "Genetics of dilated cardiomyopathy", section on 'Desminopathy'.)

Cardiocutaneous syndromes

Naxos disease and Carvajal syndrome — The cosegregation of hyperkeratosis of palms and soles with woolly hair and the development of a life-threatening cardiomyopathy led to the identification of desmosomal mutations as the cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) [15,16]. Clinical genetic studies suggest that at least 60 percent of ARVC cases are familial with autosomal dominant inheritance. The cutaneous manifestations seen in the recessive families with Naxos disease and Carvajal syndrome are clinically obvious, but are not present in families with autosomal dominant inheritance, with the possible exception of mild, usually subclinical cutaneous manifestations in patients with desmoplakin mutations [17,18]. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics", 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 primary bilateral macronodular adrenal hyperplasia".)

Amyloid cardiomyopathy — Cardiac disease due to the deposition of amyloid fibrils is seen in familial AC and TTR amyloidosis, as well as in non-genetic disease (eg, senile TTR amyloidosis). These conditions are discussed separately.

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 keyword(s) of interest.)

Basics topic (see "Patient education: 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 "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing" and "Genetics of dilated cardiomyopathy" and "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics" 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.

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References

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