Muscle Diseases

Question 1

Describe the genetic defect for spinal muscular atrophy.

Answer 1

• Distinctive group of autosomal recessive motor neuron diseases that present in childhood or adolescence.
• All forms of SMA are associated with mutations affecting survival motor neuron 1 (SMN1), a gene on chromosome 5 that is required for motor neuron survival.
• The most common form of SMA is known as Werdnig-Hoffmann disease.

Question 2

Compare and contrast the pathogenesis and clinical outcome of Duchenne and Becker muscular dystrophy.

Answer 2

• Both caused by mutations of an X-linked gene encoding for dystrophin, which transfers contractile force to the connective tissue
• Patients with DMD have little or no dystrophin; patients with BMD have decreased amounts of dystrophin or a defective, abnormal form of dystrophin.

-Patients with DMD usually develop symptoms by age 5, with weakness in the pelvic girdle, followed by the shoulder girdle. Patients may have a waddling “duck-like” gait and place hands on knees to assist in standing (Gower’s maneuver); may also see “pseudohypertrophy” of the calf muscles; patients are often wheel chair dependant by 10-12 years; complications include respiratory insufficiency with infections and cardiomyopthy, with median survival approximately 35 years.

Question 3

Describe the genetic defect for myotonic dystrophy.

Answer 3

Myotonic dystrophy can occur in adults and children, and is the most common adult muscular dystrophy. Myotonia refers to the sustained involuntary contraction of a group of muscles.

This is an autosomal dominant disorder, with increased CTG trinucleotide repeat sequences on chromosome 19 (trinucelotide repeat disorder), which affects the mRNA for dystrophia myotonia protein kinase (DMPK).

Question 4

Describe the genetic defect and clinical presentation of malignant hyperpyrexia (malignant hyperthermia).

Answer 4

Malignant hyperpyrexia (malignant hyperthermia) is a rare clinical syndrome characterized by a marked hypermetabolic state (tachycardia, tachypnea, muscle spasms, and later hyperpyrexia) triggered by certain inhalational anesthetics. This condition is associated with several mutations that encode proteins that control levels of cytosolic calcium. Upon exposure to an anesthetic, the abnormal calcium channels allow uncontrolled release of calcium from skeletal muscle cells. This acute medical emergency leads to tetany, increased muscle metabolism, and excessive heat production.

Question 5

List the three subgroups of inflammatory myopathies.

Answer 5

1. Infectious
2. Myopathies associated with systemic inflammatory disease (e.g. systemic lupus erythematosus)
3. Noninfectious inflammatory disease

Question 6

Compare and contrast the pathogenesis, clinical presentation, and pathologic findings of dermatomyositis, polymyositis, and inclusion body myositis.

Answer 6

Dermatomyositis (skin and skeletal muscle) :
-Inflammatory disorder of skin and skeletal muscle.
-Classic rash is violaceous discoloration of upper eyelids associated with periorbital edema, accompanied by scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees.
-Muscle weakness typically affects proximal muscles first and is symmetric, often accompanied by myalgias.
-Extramuscular manifestations may be present such as interstitial lung disease, vasculitis, and myocarditis; 20-25% of patients with dermatomyositis have an underlying malignancy!
-Juvenile form of the disease exists, more often is accompanied by abdominal pain and involvement of the gastrointestinal tract.
-Pathogenesis is thought to be related to immunologic injury to small blood vessels and capillaries in the skeletal muscle. Muscle biopsy shows lymphocytic inflammation around small blood vessels and in the perimysial connective tissue, along with perifascicular myocyte atrophy. Necrotic muscle fibers with regeneration is also seen.

Question 7

Compare and contrast the pathogenesis and key clinical associations of myasthenia gravis and Lambert-Eaton myasthenia syndrome.

Answer 7

Myasthenia gravis:
-Myasthenia gravis is an autoimmune disease caused by immune mediated loss of acetylcholine receptor (AChR). AChR antibodies can be detected in most patients. Some patients have antibodies directed against a related receptor, muscle specific tyrosine kinase (MuSK).
-Myasthenia gravis is often associated with thymic abnormalities, with thymic hyperplasia in 65% and thymoma in 15%.

Question 8

List the causes of elevated creatine kinase.

Answer 8

• Acute myocardial infarct or other myocardial injury (e.g. myocarditis)…cardiac troponin I now gold standard in AMI.
• Skeletal muscle diseases such as inflammatory myopathies, muscular dystrophies, rhabdomyolysis, skeletal muscle trauma
• Cerebrovascular accidents, head injury
• Total CK helpful in assessing skeletal muscle injury

Question 9

Define muscular dystrophy.

Answer 9

A heterogeneous group of inherited disorders which result in muscle weakness and eventually muscle atrophy and wasting, with muscle replaced by fibrofatty tissue.