Duchenne Muscular Dystrophy (DMD)

Diagnosis

In diagnosing any form of muscular dystrophy, a doctor usually begins by taking a patient and family history and performing a physical examination. Doctors may find pseudohypertrophy, lumbar spine deviation, gait abnormalities, and several grades of diminished muscle reflexes.

Much can be learned from these observations, including the pattern of weakness. A patient’s history and physical go a long way toward making a diagnosis, even before any complicated diagnostic tests are done.

Cardiomyopathy in patients with DMD may be associated with conduction abnormalities as well. A doctor may observe characteristic changes in an electrocardiogram. Also, structural changes in the heart, as valvular heart disease (specially affecting the mitral valve when it occurs) can be detected by echocardiography. Therefore, electrocardiogram, noninvasive imaging with echocardiography, or cardiac MRI are essential, along with consultation with a cardiologist. 

CK and other enzyme levels

Early in the diagnostic process, doctors often order a blood test called a CK level. CK stands for creatine kinase, an enzyme that leaks out of damaged muscle. When elevated CK levels are found in a blood sample, it usually means muscle is being disintegrated by some abnormal process, such as a muscular dystrophy or inflammation. A very high CK level suggests that the muscles themselves (and not the nerves that control them) are the likely cause of the weakness, although it does not indicate exactly what type of muscle disorder might be occurring. High levels of CK may be found before the onset of symptoms, even in newborns affected by DMD.

The CK level peaks (at 10 to 20 times the upper limit value) by age 2, then progressively falls at a rate of 25% per year, eventually returning to normal level when a considerable amount of muscle tissue has been replaced by fat and scar/fibrotic tissue.

Genetic testing

Genetic testing involves analyzing the DNA of any cells (usually blood cells are used) to see whether there is a mutation in the dystrophin gene, and if so, exactly where it occurs. Such DNA testing for dystrophin mutations is widely available in the United States. Your MDA Care Center physician or genetic counselor can give you more information on testing options. And, for more on getting a definitive genetic diagnosis, see The Genie's Out of the Bottle: Genetic testing in the 21st century.

Usually genetic diagnosis is indicated for patients with elevated serum CK levels and clinical findings of dystrophinopathy. Diagnosis is confirmed if a mutation of the DMD gene is identified. The genetic analysis is first directed to find large deletion/duplication mutations (70% to 80% of cases present these kinds of mutations). If initial genetic analysis is negative, the analysis of small and micro deletion/duplication gene mutations is next.

Female relatives of men and boys with DMD can undergo DNA testing to see if they are carriers of the disease. Women who are DMD carriers can pass on the disease to their sons and their carrier status to their daughters. In a minority of cases, girls and women who are DMD carriers may themselves show symptoms of DMD, such as muscle weakness and heart problems. These symptoms may not appear until adulthood (see Causes/Inheritance).

Several experimental drugs currently in development to treat DMD require knowledge of a person's precise genetic mutation, so genetic testing has become important not only for diagnosis but possibly for future treatments.

Muscle biopsy

To obtain more information, a doctor may order a muscle biopsy, the surgical removal of a small sample of muscle from the patient. By examining this sample, doctors can tell a great deal about what’s actually happening inside the muscles. However, muscle biopsy is seldom needed in the modern era because nearly all patients are diagnosed with genetic testing.

Modern techniques can use the biopsy to distinguish muscular dystrophies from inflammatory and other disorders, and to distinguish among different forms of muscular dystrophy. For instance, the amount of functional dystrophin protein found in a muscle biopsy sample sheds light on whether the disease course is likely to be DMD, with no dystrophin present, or the milder Becker muscular dystrophy (BMD), with some partially functional dystrophin present.

Histologic (tissue-related) evidence of a myopathy may be observed from birth among male children with DMD. Although not typically performed, endomyocardial (inner cell layer of the heart) biopsy shows a variable distribution of dystrophin in cardiomyocyte (heart muscle cells).

Compared to DMD, BMD usually has a later age of onset (from 5 to 60 years of age). The clinical involvement tends to be milder, with some grade of retained strength.¹ Patients with BMD remain ambulatory at least until age 16 and in some cases well into adult age. Contractures and cognitive disorders are less common and severe in BMD patients compared with DMD patients. CK levels are usually elevated five times or more in BMD patients. Cardiac involvement in BMD is often predominant. Patients with BMD typically live beyond age 30. 

If the suspicion of DMD remains high despite negative genetic analysis, dystrophin detection by western blot technique or staining with selective antibodies is carried out in the tissue derived from a muscle biopsy. The western blot is useful to predict the severity of the disease as the quantity of dystrophin present in the analysis is related to the clinical presentation. Less than 5% of the normal quantity of dystrophin is related to DMD, a level 5% to 20% of normal is related to the intermediate disease, and more than 20% of normal level is related to BMD.^2,3

References

1. Bradley, W. G., Jones, M. Z., Mussini, J. -M & Fawcett, P. R. W. Becker-type muscular dystrophy. Muscle Nerve (1978). doi:10.1002/mus.880010204
2. Hoffman, E. P. et al. Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne’s or Becker’s muscular dystrophy. N. Engl. J. Med. (1988). doi:10.1056/NEJM198805263182104
3. Hoffman, E. P. et al. Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology (2012). doi:10.1212/wnl.39.8.1011