Genetics - Muscular Dystrophy

Question 1

Definition

Answer 1

Muscular dystrophy = term for group of inherited diseases that causes progressive weakness and loss of muscle mass.

Question 2

Types of muscular dystrophy

Answer 2

Duchenne muscular dystrophy (DMD):
- Frameshift or nonsense mutations -> no dystrophin protein
- More severe S+S
- Presents from ages 2-3

Becker muscular dystrophy (BMD)
- Missense mutations result in misshapen dystrophin protein
- Milder S+S
- Presents from age 10-20

DMD-associated dilated cardiomyopathy
- Similar pathophysiology to DMD
- Cardiac muscle involvement only

Myotonic dystrophy
Facioscapulohumeral dystrophy

Question 3

Epidemiology

Answer 3

Male sex: X-linked inheritance
Family history: 2/3 of cases are inherited whilst the remaining 1/3 sporadic

Question 4

Aetiology

Answer 4

In all cases = genetic mutation is the underlying cause
- Dystrophinopathies = caused by mutations in the dystrophin gene
- Other examples are linked to genes that encode proteins that interact with dystrophin

Question 5

Pathophysiology

Answer 5

The dystrophin gene is located on the X-chromosome and due to its large size (79 exons) = vulnerable to deletions and duplications during meiosis, which can result in frameshift mutations or nonsense mutations (early STOP codon). The dystrophinopathies are inherited in an X-linked recessive manner.

The dystrophin gene encodes a protein which links intracellular actin to the cytoplasmic dystrophin-associated protein complex . In the absence of dystrophin, the muscular cell membrane (sarcolemma) becomes unstable and results in release of creatine kinase and muscle necrosis. In the short term there is muscle regeneration, however over time the muscle is infiltrated by fat and fibrotic tissue, resulting in weakness. This is particularly notable in the lower limbs.

Question 6

Signs

Answer 6

• Gower’s signs: child will stand up using their arms to push up due to weakness in lower limb
• Muscle wasting
• Calf pseudohypertrophy: visible enlarged calves due to fat and fibrotic tissues
• Waddling gait

Question 7

Symptoms

Answer 7

Muscle weakness:
- Proximal muscles first
- Distal muscles later
- Lower limbs before upper limbs
Delayed ability to sit stand or walk

Question 8

Investigations

Answer 8

• Creatine kinase: elevated creatine kinase occurs due to muscle necrosis but is a nonspecific test result
• Muscle biopsy: dystrophin abnormalities can be detected using immunohistochemical analysis, along with 11 other muscle protein abnormalities
• Genetic testing: specific testing for common mutations in dystrophin.

Question 9

Treatment

Answer 9

No cure
Treatment aids:
- Mobility assistance: exercise, physical aids and physiotherapy
Medical therapies: corticosteroids to improve muscle strength and ACE inhibitors/beta blockers for cardiomyopathy
Surgery: to correct postural deformities, such as scoliosis
Genetic counseling to parents: this will be offered to parents of children with dystrophinopathies

Question 10

Complications

Answer 10

Respiratory failure: due to weakness in the diaphragm as well as scoliosis
Inability to walk: as the disease progresses there is loss of function in the proximal muscles to the extent that most will require a wheelchair
Dilated cardiomyopathy: development of thin left ventricular wall and dilated ventricle occurs due to the role of dystrophin in cardiac muscle. This represents the most important life-limiting complication in DMD.
Arrhythmias: dystrophin gene also in heart muscle