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Flashcards in Muscle Deseases Deck (17):
1

Describe the genetic defect for spinal muscular atrophy.

-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.

2

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

Both are x-linked.

DMD and BMD are caused by mutations of an X-linked gene (Xp21 region) that encodes for a protein named dystrophin. Dystrophin is located in the cytoplasm adjacent to the sarcolemmal membrane, and dystrophin and the dystrophin associated protein complex form an interface between the intracellular contractile apparatus and the extracellular connective tissue matrix, transferring 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.

3

Becker muscular dystrophy.

Patients with BMD have a later onset with milder symptoms, and can survive well into the 40’s and beyond.

Muscle biopsy in both conditions show variation in muscle fiber size, increased endomysial connective tissue, degeneration and necrosis of muscle fibers, and muscle fiber regeneration. Eventually, the muscles become almost completely replaced by fat and connective tissue.

Treatment is with immunosupressives; one promising line of research involves cell therapy by transplanting stem cells into the muscle of affected mice.

Female carriers can demonstrate increased creatine kinase levels, and can be at risk for cardiomyopathy.

4

Duchenne muscular dystrophy.

Incidence of DMD is 1:3500 live male births; two thirds of cases are familial, one third represent new mutations.

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.

Creatine kinase is increased early in the disease, even before symptoms appear; electromyogram shows a myopathic pattern.

Muscle biopsy can be used to establish the diagnosis (western (protein) immunoblot for dystrophin); genetic tests are also available.

5

Describe the genetic defect for myotonic dystrophy.

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).

Patients often present in late childhood with abnormalities of gait, which eventually progresses to weakness of the hand and wrist; facial muscle atrophy leads to a typical facial appearance with a sagging face, ptosis, and open mouth; other abnormalities include cataracts, frontal balding, gonadal atrophy, abnormal glucose tolerance, and cardiomyopathy.

Muscle biopsy can show selective atrophy of type 1 fibers as well as ring fibers (both not specific); patients will also have elevated creatine kinase.

6

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

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.

7

List the three subgroups of inflammatory myopathies.

Infectious: (e.g., trichinosis, necrotizing fasciitis and myositis due to group A streptococcus, clostridial gas gangrene).

Associated with systemic inflammatory disease: (e.g. systemic lupus erythematosis (SLE), polyarteritis nodosa, rheumatoid arthritis, sarcoidosis).

Noninfectious inflammatory disease:

Dermatomyositis
Polymyositis
Inclusion Body Myositis

8

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

a

9

dermatomyositis

-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.
-Treat with immunosuppressive agents.

10

polymyositis

-Muscle and systemic involvement is similar to that seen in dermatomyositis, except for the lack of skin involvement. This disorder is also mainly seen in adults.
-Pathogenesis may be caused by T-cell mediated injury of myocytes. Muscle biopsy shows lymphocytic inflammation surrounding and invading muscle fibers, without the perifascicular atrophy seen in dermatomyositis. Necrotic and regenerating muscle fibers are found throughout the fascicle. No vascular injury is seen.
-Treat with immunosuppressive agents.

11

inclusion body myositis

-Begins with the involvement of distal muscles, in contrast to dermatomyositis and polymyositis.
-Muscle involvement may be asymmetric.
-Typically affects individuals over the age of 50.
-Pathogenesis is uncertain, but muscle biopsy shows rimmed vacuoles (not specific), along with lymphocytic inflammatory infiltrate. As with all forms of inflammatory myopathy, increased creatine kinase is present.
-There is no beneficial effect with immunosuppressive agents

12

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

a

13

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%.

Muscle weakness may be generalized, or localized to the extraocular muscles (ptosis).

Diagnosis rests on detection of the above antibodies in the appropriate clinical setting; electrophysiologic studies can also be helpful, as well as bed-side tests in those patients with ptosis (ice pack test, edrophonium test).

Treatment is with anticholinesterase drugs, immunosuppressive agents, plasmapheresis in acute cases, and thymectomy in those with tumors.

14

Lambert-Eaton myasthenia syndrome

Pathogenesis of Lambert-Eaton myasthenia syndrome is believed to be due to autoantibodies directed against calcium channels; this condition is often seen as a paraneoplastic syndrome, with malignancy present in 60% of cases (often small cell lung carcinoma).

Patients may have detectable “voltage gated calcium channel antibodies” and show no improvement with anticholinesterase agents; electrophysiologic studies can also help distinquish this entity from myasthenia gravis, along with the presence of non-thymic malignancies.

15

List the causes of elevated creatine kinase.

Acute myocardial infarct or other myocardial injury (e.g. myocarditis)
Skeletal muscle diseases such as inflammatory myopathies, muscular dystrophies, rhabdomyolysis, skeletal muscle trauma
Cerebrovascular accidents, head injury

CK-MB isoenzyme is used primarily for the diagnosis of acute myocardial infarct, along with cardiac troponin I; while cardiac troponin I is specific for cardiac muscle, CK-MB is not. As such, cardiac troponin I is the preferred enzyme to measure for detection of myocardial injury.

Total CK is helpful in the assessment of skeletal muscle injury, in the absence of cardiac disease or other conditions that may cause increased CK

16

define muscular dystrophy

The term muscular dystrophies refers to a heterogeneous group of inherited disorders which result in muscle weakness and eventually muscle atrophy and wasting, with muscle replaced by fibrofatty tissue.

17

creatine kinase

Creatine kinase is cytosolic enzyme which converts creatine to phoshocreatine; in the process ATP is converted to ADP.

Creatine kinase exists as three isoenzymes: CK-BB, CK-MB, and CK-MM (B = brain, M = muscle) .

Skeletal muscle primarily expresses CK-MM (98%) with very low levels of CK-MB; however, as skeletal muscle is damaged and regeneration occurs, skeletal muscle can exhibit increased CK-MB expression. Cardiac muscle expresses CK-MM (70%) and CK-MB (20-25%). CK-BB is expressed at low levels in many tissues.

Creatine kinase is released into the interstitial space and blood when cells are damaged.