Inherited disorders: Duchenne muscular dystrophy

You are a genetic counselor seeing a 26 year old pregnant woman who was referred to your office by her OB/GYN. After talking with her, you find that she is particularly interested to know about the risk facing her unborn child with respect to a condition known as Duchenne muscular dystrophy (DMD). She explains that her eight year old nephew was recently diagnosed with the condition.

You explain that DMD is, indeed, a genetic condition, and that it is characterized by a mutation in the gene coding for the protein dystrophin. Dystrophin is an important structural protein found in skeletal (striated) muscle which connects the cytoskeleton of a muscle fiber to the extracellular matrix (ECM). It is a cytoplasmic protein, and links actin filaments to other structural proteins outside of the cell (Figure 1). Dystrophin is key in maintaining the mechanical stability of skeletal muscle; a lack of it causes these cells to be increasingly fragile and prone to damage. The result of this damage is a steady leak of calcium into the sarcolemma, disrupting signaling pathways and ultimately causing mitochondria to burst. Damaged muscle tissue is progressively replaced by scar tissue and fat.

Figure 1: The role of dystrophin in muscle structure and integrity.

You are curious if the patient is aware of other family members who have been affected by DMD, and you describe the signs and symptoms. DMD typically presents around the age of three, first presenting as pain and weakness affecting the muscles of the hips, thighs, and shoulders, then progressing to the arms, legs, and trunk. Other symptoms include awkward gait, frequent falls, fatigue, poor progression of motor skills, and enlargement of the tongue and calf muscles. The average life expectancy of these patients is 25 years.

The patient recalls an uncle who died before she was born, who had a “developmental disorder” which sounded like DMD. He died when he was 23. She also knows one of her mother’s cousins died at a young age. To help explain the risk to her child, you show the patient a typical pedigree, based on her family history, for DMD (Figure 2).

Figure 2: Patient’s family history and pedigree with respect to DMD.