The natural history study of Becker muscular dystrophy

Becker muscular dystrophy (BMD), like Duchenne muscular dystrophy (DMD), is an
X-linked inherited disorder (locus Xp21.2) caused by mutations in the
dystrophin gene (DMD gene), coding for the protein Dystrophin.

Dystrophin protein plays an important role in stabilising the muscle fibre
membrane. It is localized to the inner surface of the sarcolemma of muscle
fibres where it interacts with other integral membrane proteins (dystroglycans,
sarcoglycans, syntrohpin and dystrobrevin) of the dystrophin-associated
glycoprotein complex (DAG complex) forming a bridge across the sarcolemma and
thereby connecting the inner cytoskeleton to the extracellular matrix
protecting the muscle fibres against contraction-induced damage. In the absence
of dystrophin, as in DMD, or in the case of reduced amounts and/or abnormal
functioning dystrophin, as in BMD, muscle fibres become susceptible to damage
resulting in fibrosis and replacement of muscle fibres by fat.

Although BMD and DMD are caused by mutations in the same gene, BMD is
characterized by a milder phenotype. A well accepted theory for this
phenotypical difference lies in the reading frame theory. Mutations disrupting
the reading frame (*out-of-frame*) prevent the production of dystrophin leading
to a severe DMD phenotype. These patients develop muscle weakness in the early
years of life and lose ambulation by their early teens and ,unless appropriate
respiratory and cardiac treatment is initiated, affected individuals typically
die before reaching their twenties. Mutations that do not disrupt the reading
frame (*in-frame*) lead to the translation of an internally deleted but still
partially functional dystrophin protein causing BMD phenotype. Clinical
phenotype in these patients is highly variable with some patients able to
experience a near normal life style and life span while others lose the ability
to walk in their late teens or early twenties. Causes for this disease
varibiability are not yet fully understood.

In this extensive follow-up study we want to further define the variability in
clinical characteristics, disease severity and disease course in a large group
of BMD patients and standardize muscle strength and functional tests for
clinical follow-up. We want to explore factors involved in disease variability
such as dystrophin quantity/quality and identify potential genetic modifiers.
Markers for disease variability, severity and prognosis will be explored in
collaboration with the department for human genetics and the radiology
department within the LUMC.

- To describe the variability in clinical characteristics and natural history
of BMD.
Secondary objective:
- To assess the role of genetic, biochemical and radiographic markers on
disease severity and variability of BMD.

A single centre prospective natural history study: duration 4 years

During each visit several of the following examinations will be performed:
-Questionnaire: Every year
-Physical and neurological examination: Every year
-Muscle strength testing: Every year
-Functional assessment: Every year
-ECG, echocardiogram and holter registration: Year 1 and 3
-Pulmonary function test (handheld spirometer): Every year
-Blood and urine analysis**: Every year
-Muscle biopsy**: Year 1
-Muscle MR-imaging Only when also participatiing in the study "quantitative
muscle MR-imaging of skeletal muscle in Duchenne and Becker muscular dystrophy:
Year 1 and 2.

**This study is limited to two invasive procedures:
1. A venepuncture for blood withdrawal and one or two muscle biopsies.
2. A muscle biopsy which is performed under local anaesthesia. It does not
require the patient to stay in the hospital after the procedure and does not
impair normal daily activities afterwards. The complication risk is low and
limited to a small possibility of development of a hematoma.