72 Muscular Dystrophy

Muscular Dystrophy

Muscular Dystrophy (MD) varies in terms of severity depending on the type of genetic mutations that occur, but all forms are depicted by the progressive loss of motor function, muscle weakness and loss of muscle mass and tissue.  Typically, symptoms appear in infancy, childhood or adulthood, again depending on the type of MD.  There are over 30 forms of MD as there are various genetic mutations that can occur that affect proteins that play important roles in skeletal muscle cells.  Most often MD is caused when genetic mutations are inherited, though sometimes spontaneous mutation can occur.

Pathogenesis – Muscular Dystrophy

Dystrophin Gene Mutations:

The most common form of muscular dystrophy is Duchenne Muscular Dystrophy (DMD), accounting for 50% of all cases.  DMD occurs when mutations affect the dystrophin gene, which is located on the X chromosome.  Duchenne MD is therefore considered a X-linked recessive disease and most cases of DMD occur in young males.  Biological females are less likely to have Duchenne MD as both XX chromosomes would need to carry the mutations in order for the disease to be expressed.  Biological males (XY) are more at risk for Duchenne MD, as inheriting only one X chromosome with the mutated gene will give rise to the disease.  Female carriers of DMD have usually inherited a single X chromosome mutation and their offspring have a 50% chance of inheriting the affected allele. 

The dystrophin protein plays an important role in anchoring the contractile proteins of muscle cells to the sarcolemma (muscle cell plasma membrane), which allows for the whole skeletal muscle cell (myofiber) to shorten during contraction and generate tension (force).  Additionally, the loss of cellular stability can create leaks in the myofibers which leads to important enzymes such as creatine phosphokinase (CP’K) seeping out and entering the blood stream.  The dystrophin protein also play roles in smooth muscle, heart muscle and the brain.

Becker MD is also caused by mutations in the dystrophin gene on the X chromosome, and is also a X-linked recessive disease.  Becker MD usually results in milder symptoms that progress more slowly, in comparison to the symptoms experienced with DMD.  Becker MD is the second most common type of MD.

Other Gene Mutations:

Myotonic MD is caused by genetic mutations of other genes (e.g., DMPK on chromosome 19) that can affect skeletal muscle function (strength, durability, fatiguability) and is inherited in an autosomal dominant fashion.  Myotonic MD is characterized by the slow loss of function and deterioration of the muscles of the face (including eyes), hands.  Myotonic MD (and lack of DMPK gene) can also negative affect the heart, smooth muscle, endocrine system and nervous system progressively throughout an individual’s life.   A person’s lifespan may be shortened due to respiratory insufficiency and cardiac conduction abnormalities.  Cognitive and mobility impairments may present as well.

Facioscapulohumeral Dystrophy (FSHD) as the name suggests involve muscle weakness occurring in the face, shoulders, and upper arms.  The genes (e.g., D4Z4 on chromosome 4) affected can be inherited in an autosomal dominant.   Signs and symptoms develop as a teenager or even much later in life (e.g., 40yrs old).  The disease typically develops slowly with asymmetrical muscle weakness and doesn’t affect lifespan.

Limb-girdle MD (LGMD) as the name suggests involve muscle weakness occurring in the pectoral (shoulder) and pelvic (hip) girdles.  The genes (e.g., CApN3) affected are most often inherited in an autosomal recessive manner.   Signs and symptoms develop as a young adult (e.g., 20-30yrs old) and involve gait abnormalities.  The disease typically develops slowly and doesn’t affect lifespan.  Individuals usually don’t have cardiac or intellectual impairments though may experience scoliosis.

Signs and Symptoms – Duchenne Muscular Dystrophy

Signs and symptoms of DMD and Becker MD may not appear until an infant begins to walk. 

Signs and symptoms include: delayed motor skill milestones (e.g., sitting, standing, walking, stair climbing, running, jumping, handwriting, feeding oneself, speaking), clumsy, gait abnormalities, and cognitive disabilities.  Becker MD is less severe than DMD, as individuals with Becker MD usually have a higher levels of functioning dystrophin protein  

The Gower sign is the classic physical example of MD, in which a child needs to use their hands and arms to push upright from a sitting position.

With DMD, loss of ambulation usually occurs between 7-13 years of age, and premature death as a result of respiratory muscle failure may occur in the 30-50s, depending on the severity of the disease and the availability of supportive treatments in place.  Complications involve immobilization, which can lead to contractures, osteopenia, and osteoporosis.  Additional concerns involve the development of scoliosis and cardiopulmonary failure.

Diagnosis – Muscular Dystrophy

Physical Exams: can reveal signs of muscle weakness, delayed motor skill milestones, as well as pseudohypertrophy of calf muscles at 1-2 years of age.  This pseudohypertrophy is derived from the Latin words pseudo (false) and hypertrophy (growth or enlargement) and may seem strange, as the muscles appear large in size, even though they are weak in strength.  The enlarged sized is due to the accumulation of scar and fat tissue within abnormal (and atrophying) muscle tissue.

Blood Tests:  Serum creatinine phosphokinase levels are elevated in active forms of MD, rising as much as 50-300 times higher than normal levels.  Elevated serum CPK indicate skeletal muscle disease, as CPK is a cytoplasmic enzyme that only enters the blood stream if the skeletal muscle cells (myofibers) are damaged and leaky.

Genetic Testing:  Polymerase Chain Reaction (PCR) tests reveal mutations in the dystrophin gene (or other genes that may be involved) and are helpful in informing treatment.  Prenatal screening (chorionic villus and amniocentesis) testing is available.  DNA tests can be done to determine whether a female is a carrier.

Imaging: (e.g., x-rays) can reveal development of scoliosis

Electromyography (EMG): measures the muscle cells’ electrical response to neural stimulation.  The EMG results of individuals with DMD often show lower amplitudes than normal indicating a reduced ability to generate force.  Reduced time length of force is also noted (potentially indicating greater fatiguability of muscle).

Electrocardiography (ECG):  is used to monitor cardiac electrical activity, which is a good indicator of heart function and way to assess for signs of cardiac myopathies.

Muscle biopsies and histology can reveal changes in fiber size and signs of degeneration.

Treatment – Duchenne Muscular Dystrophy

Treatment often takes a multiprong approach, with medical therapy, surgical interventions, and management of any cognitive, cardiac, and mobility impairment.

Medical therapies can include steroid therapy which acts by reducing T cell (and other WBC) activity and slowing the progression of muscle strength loss.  However, steroid therapy puts an individual at risk for the development of osteopenia, osteoporosis and vertebral compression fractures.  As such bone density is often monitored through dual energy x-ray absorptiometry (DXA) and an individual may be prescribed supplements (e.g., calcium, Vitamin D, and bisphosphonates).

Surgery is often used to treat contractures and deformities (e.g., kyphoscoliosis) that can occur.  At times pace makers are required.

Antisense oligomers work by binding to exons within the dystrophin pre-mRNA resulting in exon skipping which can allow for production of a truncated, but functional form of dystrophin protein.  Several have been approved for use by the Food and Drug Administration (FDA) in the USA.

Gene Therapies have been approved by the FDA for DMD as trials have been successful.  Trials have involved delivering a dystrophin gene in adeno-associated virus vectors to 4-5 year old patients with DMD.  After 4 years of receiving gene therapy, the test subjects were found to have retained motor function, whereas control subjects were found to have had a significant decline in motor function over the same time period.  Some patients experienced some initial adverse effects (e.g., vomiting, nausea, elevated liver enzymes, fever, and thrombocytopenia) which resolved within 90 days.  That being said, the trial found that some patients with particular deletions in the dystrophin gene were susceptible to more acute side-effects (e.g., acute liver injury, myositis, and myocarditis).  Therefore, gene therapy is currently only recommended to individuals with specific dystrophin mutation.  The current cost of gene therapy is very high ($2-3 million USD).

Supportive care: can involve mobility aids, physiotherapy, speech therapy, massage, learning assistance, and ventilation if required.  Healthy diet and moderate exercise is usually prescribed.

Summary

• Muscular Dystrophy:
  • Genetic disorder affecting musculoskeletal system.
  • Duchenne MD is a X-linked recessive disease.
  • Early onset muscle weakness, rapid degeneration.
  • Signs/symptoms: muscle weakness, waddling gait, pseudo hypertrophy.
  • Diagnosis: genetic testing, creatine kinase levels, electromyography.
  • Treatment: supportive care, physiotherapy, genetic therapies.