Children's Cardiomyopathy Foundation
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ABOUT THE DISEASE

CAUSES

Although pediatric cardiomyopathy is one of the leading causes of cardiac death in children, an explanation for why it occurs remains unknown. Most cases are familial conditions that are genetically transmitted, but the disease can also be acquired during childhood. The most common cause for acquired cardiomyopathy is myocarditis, a viral infection that weakens the heart muscle. Other causes for acquired cardiomyopathy include: 1) cardiovascular conditions (i.e. Kawasaki disease, congenital heart defect, hypertension, cardiac transplantation or surgery), 2) infectious or inflammatory diseases, 3) immunologic diseases (i.e. HIV), 4) obesity or dietary deficiencies, 5) toxin reactions (i.e. drug, alcohol, radiation exposure), 6) connective tissue and autoimmune diseases, 7) endocrine diseases and 8) pregnancy related complications. Persistent rhythm problems or problems of the coronary arteries, either congenital or acquired, can also lead to a weakening of the heart.

It is being increasingly recognized that certain genetic mutations are the primary cause for pediatric cardiomyopathy. Mutations are defects in the DNA spiral, the protein structure of many genes. The abnormalities in DNA involve a displacement in the sequence of one or more of the amino acids that make up a gene protein. The disease is either inherited through one parent who is a carrier (autosomal dominant transmission with a 50% chance of recurrence) or through both parents who each contribute a defective gene (autosomal recessive transmission with a 25% chance of recurrence). Cardiomyopathy can also be inherited by maternal transmission (X-linked). Research continues to focus on identifying the specific genes that cause cardiomyopathy and better understanding how these genetic abnormalities contribute to the disease. However, it is a complex process with multiple diverse genes producing extremely variable outcomes.

The American Heart Association site provides more details in an "Overview of Inheritance for Cardiomyopathies." The Genetic Alliance site also provides a downloadable "Guide to Understanding Genetics for Patients and Professionals," which presents basic genetic concepts.

Many children with hypertrophic cardiomyopathy (50-60%) and to a lesser degree with dilated cardiomyopathy (20-30%) have a family history of the disease. Recent advancements in genetic research show that hypertrophic cardiomyopathy involves defects in the sarcomere genes and can be inherited in an autosomal dominant manner. Dilated cardiomyopathy involves defects in the cytoskeleton genes and can be inherited autosomal dominant, autosomal recessive or X-linked. In some cases, cardiomyopathy can be related to another inherited metabolic or congenital muscle disorder such as Noonan syndrome, Pompe disease, fatty acid oxidation defect or Barth syndrome. Most often, symptoms of these disorders present early in life.

Although there is a long list of possible causes for cardiomyopathy, few of them are directly treatable and most therapy is aimed at treating the secondary effects on the heart. According to the Pediatric Cardiomyopathy Registry, cardiomyopathies can be grouped into five categories based on the specific genetic cause of the disease: 1) myocarditis and other viral infections (27%), 2) familial inherited cardiomyopathies (24%), 3) neuromuscular disorders associated with cardiomyopathy (22%), 4) metabolic disorders (16%), and 5) malformation syndromes associated with cardiomyopathy (10%).

Myocarditis & Other Viral Infections

This a leading cause in children with cardiomyopathy and is more commonly associated with DCM. It is caused by viral infections that cause the body's immune system to malfunction damaging/inflaming the heart muscle tissue while attacking the invading virus. At this point, it is unknown whether certain children have a certain genetic makeup that may make them more susceptible to contracting myocarditis.

Isolated Familial Cases

Isolated familial cardiomyopathy is considered when the child does not show features of metabolic or muscular disorders, and there is a known family history of cardiomyopathy. In affected families with HCM, ARVD, DCM, and RM, the condition is predominately inherited in an autosomal dominant manner where an affected parent has a 50% chance of passing the defective gene to his/her offspring. In rare cases, ARVC, DCM and HCM can be inherited through autosomal recessive or maternal transmission where unaffected parent(s) have a 25% chance of an affected child with each pregnancy.

Although the genetic defect is the same in all members of an individual family, there are variable outcomes and severity of the disease in different family members. The disease's manifestation can range from minimal abnormality and no symptoms to severe complications within the same family. In some families it may appear that the mutated gene skips a generation but in reality the defective gene may not have expressed itself fully in a particular family member, and therefore echocardiograms may appear normal.

Neuromuscular Cases

Neuromuscular diseases associated with cardiomyopathy include those that affect the nerve or skeletal muscles. These include muscular dystrophies (i.e. Duchenne and Becker), congenital myopathies, metabolic myopathies, and ataxias (i.e. Friedreich Ataxia). Common symptoms are decreased muscle tone, weakness beginning after infancy, loss of motor control, decreased muscle relaxation and decreased muscle bulk. Almost all of the neuromuscular diseases associated with cardiomyopathy have a genetic basis.

Metabolic Disorder Cases

Inborn errors of metabolism consist of numerous infiltrative storage diseases, abnormal energy production, biochemical deficiencies and disorders related to toxic substances accumulating in the heart. This category also includes mitochondrial abnormalities (i.e. MELAS, MERRF, respiratory chain diseases, mitochondrial myopathies), fatty acid oxidation defects (carnitine deficiency, VCHAD, LCHAD, LCAD, MCAD), Pompe disease and Barth syndrome. When the demand for energy exceeds what the body can supply (i.e. during illness, physical stress or decreased oral intake), patients with impaired energy metabolism are unable to maintain their body's biochemical stability. This may lead to low blood sugar, excessive acidity in the blood and/or high ammonia levels that put additional strain on the heart.

Metabolic disorders are inherited by autosomal recessive transmission (each parent contributes a defective gene) or X-linked transmission (mother contributes defective gene). Usually patients appear to be physically normal in early childhood but as the body's energy production continues to be impaired, toxic substances may accumulate throughout the body leading to multiple organ failure. Common symptoms include muscle weakness, decreased muscle tone, growth retardation, developmental delays, failure to thrive, constant vomiting and lethargy. In critical states, the child may exhibit stroke like symptoms, seizures, have low blood sugar, and be unable to use the body's fuel correctly.

In contrast, patients with storage diseases such as Pompe, Cori, and Andersen disease cannot break down glycogen, the storage form of sugar. These syndromes are characterized by problems with growth, brain dysfunction, decreased muscle tone, muscle weakness, and symptoms of heart failure.

Malformation Syndrome Cases

Malformation syndromes are characterized by minor and major physical abnormalities with distinctive facial features. It is caused by genetic mutations through autosomal dominant, autosomal recessive, or X-linked recessive inheritance. It can also be cause by a chromosomal defect where a specific chromosome is deleted or duplicated. Noonan syndrome is the most common form associated with pediatric cardiomyopathy. Common symptoms include short stature, webbed neck, wide set eyes, low set ears and extra skin folds.

Idiopathic Cases

With patients where there is no remarkable family history (considered a "sporadic case"), a specific cause of muscle damage is never known. Researchers are still trying to classify the remaining "unknown cases" to determine if there are common genetic abnormalities. At present, the process of gene identification is difficult and lengthy. It is hoped that in the future there will be a clinical method to identify carriers of the gene within affected families and assess the risk of cardiac death.

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