GENETICS OF CARDIOMYOPATHY

The etiology of cardiomyopathy in the pediatric population is extremely heterogeneous with different genes and multiple mutations in each gene that cause the disease. While some genetic mutations have been identified, researchers continue to work on discovering new genes, including "modifier genes," which may influence disease severity and progression.

It is unclear whether disease causing mutations in adults occur at the same frequency or manifest in the same way in children. Some studies suggest that double mutations may be a contributing factor in more severe forms of pediatric cardiomyopathy. For a list of genetic mutations that cause cardiomyopathy, download the Genes Associated with Cardiomyopathy sheet.

Research continues on identifying new genetic mutations. The National Center for Biotechnology Information (NCBI) maintains a Genetic Testing Registry with a list of available genetic tests offered by laboratories in the U.S. and abroad. Commercial testing labs are now offering different panel tests on known genetic mutations for cardiomyopathy. For current testing options, view the chart on Genetic Testing Companies.

Associated Genetic Disorders

Cardiomyopathy can be secondary to a genetic disorder that affects the entire body. Information on the incidence, cause, symptoms, and characteristics of cardiomyopathy-related disorders can be found on the Associated Genetic Disorder sheet.

According to the Pediatric Cardiomyopathy Registry, cardiomyopathies with a genetic origin can be classified into four main categories: 1) familial/inherited, 2) neuromuscular disorders, 3) metabolic disorders, and 4) malformation syndromes.

Familial or Inherited

This category includes primary cardiomyopathies where the disease is isolated to the heart and caused by a genetic mutation that is passed down from generation to generation. Familial forms exist for:

  • Dilated cardiomyopathy
  • Hypertrophic cardiomyopathy
  • Restrictive cardiomyopathy
  • Arrhythmogenic right ventricular cardiomyopathy

While family members may test positive for the same genetic mutation, symptoms and disease severity may vary considerably. Some family members may have no symptoms and a normal echocardiogram. In some patients with a genotype positive/phenotype negative result, the genetic mutation is present, but it is not known if and when cardiomyopathy may manifest.

Neuromuscular Disorders

Neuromuscular diseases include those affecting the nerve or skeletal muscles. Common symptoms are decreased muscle tone, loss of motor control, decreased muscle relaxation, and decreased muscle bulk. Neuromuscular associated cardiomyopathies include:

  • Muscular dystrophies (Duchenne and Becker)
  • Congenital myopathies
  • Metabolic myopathies
  • Ataxias (Friedreich Ataxia)

Metabolic Disorders

With inborn errors of metabolism, the body can not properly convert food into energy, which can cause an accumulation of toxic substances in the heart. Common symptoms include jaundice, vomiting, failure to thrive, low blood sugar, poor appetite, lethargy, developmental delays, and seizures.

Children with glycogen storage diseases, such as Pompe, Cori, and Andersen, cannot break down glycogen, a storage form of sugar in the body. These diseases are characterized by low blood sugar, an enlarged liver, slow growth, and muscle cramps. Other metabolic disorders associated with cardiomyopathy include:

  • Mitochondrial abnormalities (MELAS, MERRF, respiratory chain diseases, mitochondrial myopathies)
  • Fatty acid oxidation disorders (carnitine deficiency, VCHAD, LCHAD, LCAD, MCAD)
  • Gaucher’s disease
  • Barth syndrome

Malformation Syndrome

Malformation syndromes are characterized by minor and major physical abnormalities with distinctive facial features. Noonan syndrome is the most common form associated with hypertrophic cardiomyopathy. Common symptoms include short stature, webbed neck, wide-set eyes, low-set ears, and extra skin folds. Other malformation syndromes include:

  • Cardiofaciocutaneous (CFC) syndrome
  • Costello syndrome
  • Neurofibromatosis type 1