Health Effects of Carrying a Dystrophin Mutation

This section includes information about health effects in asymptomatic carriers, manifesting carriers, and germline mosaic carriers, as well as cardiomyopathy in carriers.

Health Effects Quick Facts

  • Most carriers of Duchenne/Becker muscular dystrophy are asymptomatic because of the protective effect of having two X chromosomes.
  • Manifesting carriers may have musculoskeletal symptoms and/or cardiac manifestations, including cardiomyopathy.
  • All carriers should have a cardiac evaluation in their early adult years. The American Academy of Pediatrics recommends EKG and echo at least every 5 years, starting at age 25 or 30.

Asymptomatic carriers

Most carrier females (~80-90%) have no musculoskeletal symptoms. Such females usually do not know that they are carriers unless a family member is diagnosed with Duchenne or Becker muscular dystrophy and they have genetic carrier testing.

X-inactivation is part of the explanation for why most carrier females are asymptomatic.

  • Through X-inactivation, females “turn off” one of their two copies of the X-chromosome in every cell.
  • X-inactivation is usually random. When X-inactivation is random, there are generally no musculoskeletal symptoms in carriers because they have sufficient dystrophin production.
  • Because muscle cells have more than one nuclei, muscle cells in a carrier are likely to have some nuclei with X-chromosomes with dystrophin mutations, and some nuclei with X-chromosomes without dystrophin mutations. In carriers with random X-inactivation, the X-chromosomes without dystrophin mutations allow the cells to make sufficient dystrophin.
  • X-inactivation is only one step, but an important one, in a very complicated process that determines how much dystrophin protein will be available for a particular cell or group of cells.

Manifesting carriers

A manifesting carrier is a female who has symptoms that are caused by having insufficient functional dystrophin protein.

Manifesting carriers may have skeletal muscle, joint, or cardiac symptoms, which can range from minor to severe. Rarely, a carrier has symptoms that are as severe as or more severe than those of a male with muscular dystrophy.

  • Musculoskeletal symptoms include muscle weakness, muscle pain, fatigue, and cramping. The most specific symptoms indicating insufficient dystrophin are muscle weakness and significant muscle cramping. Some manifesting carriers have no musculoskeletal symptoms but have cardiomyopathy.
  • There is no known cure for symptoms in manifesting carriers. Usually, manifesting carriers do not have as severe a progression as males, and generally continue to walk through their lives. The disease course may wax and wane.

Skewed X-inactivation may cause the symptoms in manifesting carriers.

  • Recall that females “turn off” one of their two copies of the X-chromosome in every cell through X-inactivation, which is usually random.
  • When X-activation is skewed, more of the X chromosomes without mutations may be inactivated. If this happens, women are likely to have symptoms because they have insufficient dystrophin.
  • The proportion of muscle cells with sufficient dystrophin tends to increase as carrier females age (although this does not happen in all manifesting carriers). This occurs through a complex process, where nuclei that have inactivated the normal X chromosome die and are replaced. Over time, this process results in an increase in the number of nuclei producing adequate dystrophin.

Manifesting carriers may have strong feelings about the uncertainty around their own health. It is difficult to predict whether symptoms in a manifesting carrier may progress, and if so, at what rate. Manifesting carriers with affected sons often have the additional concerns about dealing with their own symptoms while caring for their sons. Healthcare providers should be supportive and honest about their predictive limitations. In some cases a referral to a mental health provider might be warranted.

Manifesting carriers and carriers without symptoms generally have the same risk to have affected children. X-inactivation is not permanent and, depending on the cause, skewed X-inactivation may not be passed to daughters.

Germline mosaic carriers

Women with germline mosaicism most likely have no increased chance for skeletal muscle symptoms or cardiomyopathy, though insufficient data exists to exclude the risk.

Cardiomyopathy

Carriers of Duchenne/Becker muscular dystrophy are at increased risk of developing cardiomyopathy. Clinically significant disease typically does not occur until teenage or adult years.

Recommendations for cardiac care in Duchenne and Becker muscular dystrophy carriers from the American Academy of Pediatrics Section on Cardiology and Cardiac Surgery (2005):

  • Carriers of DMD or BMD should be made aware of the risk of developing cardiomyopathy and educated about the signs and symptoms of heart failure.
  • Carriers of DMD or BMD should be referred for evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders. Patients should undergo initial complete cardiac evaluation in late adolescence or early adulthood or at the onset of cardiac signs and symptoms, if these signs or symptoms appear earlier.
  • Carriers should be screened with a complete cardiac evaluation at a minimum of every 5 years starting at 25 to 30 years of age.
  • Treatment of cardiac disease is similar to that outlined for boys with DMD or BMD [as defined by American Academy of Pediatrics 2005].

Cardiac involvement can range from asymptomatic to severe heart failure.

Several studies suggest that preclinical or clinically-evident myocardial involvement is common in carriers (Neuromuscul Disord 1999; JAMA 1996), though a study evaluating life expectancy and cardiovascular mortality in carriers did not find an association between carrier status and risk of cardiac death (Heart 2008). A recent survey of carriers for DMD/BMD found incomplete reporting of carrier status to healthcare providers, incomplete adherence with the American Academy of Pediatrics recommended screening, and incomplete awareness of risk for cardiomyopathy (Pediatrics 2009).

If a woman presents with cardiomyopathy and has a family history of DMD/BMD, she is very likely to be a carrier.  A positive genetic test would confirm that she is a carrier and would verify that a dystrophin mutation is the cause of the cardiomyopathy.

If a woman presents with isolated idiopathic cardiomyopathy and no family history of DMD/BMD or familial cardiomyopathy, providers may consider cardiology consultation for possible genetic etiologies and genetic testing to include DMD/BMD carrier testing as a possible cause of the cardiomyopathy.

References

Pediatrics 2005;116:1569-1573
Pediatrics 2009; 123: e471-475
JAMA 1996;275:1335-1338
Heart 2008; 94:633-636
Neuromuscul Disord 1999;9:347-51
Neuromuscul Disord 2003;13:129-132