Diagnosis of Duchenne Muscular Dystrophy

Crystal Proud, MD: Duchenne muscular dystrophy [DMD] unfortunately has a bit of a delay typically before children reach a diagnosis offered by a neurologist. There is on average somewhere around a 2- to 2½-year delay between the onset of symptoms and the ultimate confirmation by a neurologist of a diagnosis of Duchenne muscular dystrophy. Sometimes this is the result of a lack of awareness to consider the diagnosis of DMD. Other times the symptoms may be somewhat subtle and present only as mild motor delays. Ultimately the children usually will present to a general pediatrician or family medicine specialist first, and then we hope the referral will take place to the neurologist who can move forward with diagnostic testing and assessments.

The average age of diagnosis for a patient with Duchenne muscular dystrophy is usually around age 5 or so. This is a time when we start to see the impact of the diagnosis on the muscles as we notice that these boys have either difficulty or impossibility in achieving the ability to jump. They start standing out from their peers perhaps when they lag behind them in a group where other children are running. They may be noticed to have difficulties going up and down stairs or having some challenges with tripping or falling, and that ultimately leads to the confirmation of their diagnosis when they present with these symptoms.

When a child presents with weakness, difficulty going up and down stairs, tripping or falling, or a difference in the way they are maneuvering their body, that ultimately prompts them to be evaluated by a neurologist or a neuromuscular specialist. This typically leads to 1 test, which is a blood test looking at the muscle enzyme level CK [creatine kinase]. This is traditionally elevated in muscular dystrophies, whereby those muscles are structurally unstable. The muscles break down, releasing that product into the bloodstream, and it is measurably elevated.

For most of our boys with Duchenne muscular dystrophy, they have a phenotype that is readily visible to individuals who are familiar with the diagnosis, whereby the physician would evaluate that child and notice that they had these characteristic findings including things like enlarged calf muscles, difficulties with jumping, and difficulties rising from a seated position on the floor. This phenotype would allow them to be able to determine that in the case of a young boy with these findings. Duchenne muscular dystrophy would be the most common etiology.

We would proceed by getting the CK blood test, and it would likely be elevated profoundly. Usually our boys have elevations of CK into the multiple thousands. This would prompt molecular testing with genetic testing. That would be the examination of the DMD gene, whereby we would likely identity abnormalities within that DMD gene that ultimately leads to insufficient production of the dystrophin protein.

When we send testing on boys for whom we have a concern for a dystrophinopathy, we’re going to examine the DNA results. Typically we are evaluating various points within the dystrophin gene. There are several ways the dystrophin gene can demonstrate abnormalities that lead to lack of appropriate dystrophin protein production.

One way is a duplication of an exon that makes up that gene. Another way is a deletion of exons within a gene, and that’s quite common. The third way is a point mutation within a gene that can lead to abnormalities. We are able to potentially provide some prognostic indicators to the patients and family based on whether there is what’s called an in-frame or an out-of-frame mutation.

The exons within a dystrophin gene are like puzzle pieces. For example, if there is a deletion of 1 of those puzzle pieces, the remainder of the other puzzle pieces may still fit together. If that’s the case, a partially functional protein, or a small amount of functional protein, may be produced. This might lead to a milder phenotype. You refer to that phenotype as Becker muscular dystrophy.

In the event the puzzle pieces do not fit together appropriately, then protein production may be profoundly impacted, and that is the more typical Duchenne muscular dystrophy phenotype we see. For that diagnosis, there is a generally accepted trajectory of prognosis that we can discuss with the families. We know that our boys typically start to struggle with their ability to keep up with others in elementary school.

We see more of a difficulty with ambulation as they start getting between the ages of 7 to 10. Many of them lose the ability to walk by the age of 13. Subsequently we start to see a decline in pulmonary and cardiac function thereafter.