Becker Muscular Dystrophy: analysis of diversity in disease severity

Duchenne and Becker muscular dystrophy are X-linked inherited diseases caused
by a mutation in the DMD gene, which codes for dystrophin. The dystrophin
protein has an important stabilizing function in muscle tissue. Absence, as in
Duchenne muscular dystrophy (DMD), or abnormal functioning of dystrophin, as in
Becker muscular dystrophy (BMD), leads to muscle damage, resulting in
progressive muscle weakness, fibrosis and replacement of muscle tissue with
fat.

DMD has a quite uniform disease course, with patients becoming wheelchair
dependant around the age of ten to twelve and needing mechanical ventilation
around the age of seventeen. BMD, on the other hand, is characterized by a
disease course with a wide range of severity. Our recent study shows a
variability of age of loss of ambulation between nine and sixty years, while
some patients stay ambulatory throughout their entire life (unpublished data)

The factors responsible for this diversity in the clinical course of BMD are
still unknown, although the amount of dystrophin expression in heart or
skeletal muscle could be involved. It is likely that several additional factors
play a role in determining the severity of the disease. BMD, with its wide
range in clinical severity, gives an excellent opportunity to study these
parameters. Identification of these molecules or pathways could help to develop
supportive treatments for patients with BMD as well as DMD.

1. To investigate the possible relationship between amount of dystrophin
expression and clinical severity of BMD

2. To investigate the relationship between specific BMD-gene mutations and
clinical severity of BMD

3. To investigate possible other factors involved in BMD diversity, like
inflammation, a role for myofibrillar components, or muscle repair genes.

4. Search for biomarkers correlating to disease severity

5. MRI-analysis of muscle as a parameter for disease severity

6. To study the relationship between muscle weakness and severity of
cardiomyopathy in BMD patients.

Cross sectional observational study. Patient data will be gathered in the
course of one year. Analysis will be performed in the second year of the study.

During the stduy two invasive procedures are performed: one venapuncture to
obtain blood and a conchotome muscle biopsy of the tibial muscle of the lower
leg. Both are routinely performed during a diagnostic process for muscle
disease as part of our regular outpatient clinic. The risk of venapuncture is
some shortlasing local pain and possible bruising.
The semi-open biopsy technique with the conchotome involves a small incision of
1-1,5 cm and biopsy taking of the muscle under local anaesthesia. The risk
involves local pain during and after the procedure. There is a minimal risk for
local hemorrhage, infection or blistering under the adhesive plaster used for
wound closure. In over 200 of these biopsies in the LUMC the last years no
hemorrhage or infection was encountered. Three patients developed a
traction-related blister under the adhesive plaster, which disappeared after
removel of the plaster. Pain was reported minimal to moderate, lasting a
maximum of three days. Less than 1% of the patients used any analgesic drugs,
like paracetamol.