Muscular Dystrophy and neuromuscular junction

Question 1

Duchenne’s and Becker’s Muscular Dystrophy

Answer 1

• A type of muscular dystrophy characterized by progressive skeletal and cardiac muscle degeneration

Question 2

Etiology of Duchennes and Beckers Muscular Dystrophy

Answer 2

• Due to mutations of dystrophin genes (dystrophinopathies)
• Results in muscle fiber degeneration
• X-linked recessive
  
  • Duchenne’s - 1/3 spontaneous; 2/3 inherited
• Due to defective gene on the X chromosome responsible for production of dystrophin
• Dystrophin - provides mechanical reinforment to sarcolemma and stabilizes glycoprotein complex, protection fro degradation. Without dystrophin, the glycoprotein complex is digested by proteases.

Question 3

Pathophysiology of Duchennes and Beckers

Answer 3

• Missing structural protein (dystrophin) → muscle fiber fragility → fibre breakdown → necrosis and regeneration

Question 4

Clinical Presentation of muscular dystrophy

Answer 4

Duchennes is associated with most severe clinical symptoms. Beckers has a similar presentation to Duchennes, but has a laterr onset and midler clinical course.

Question 5

Clinical Presentation Duchennes

Answer 5

• Weakness - tends to begin between 2-3 years of age, although they tend to be delayed in walking. Weakness affects proximal muscles first and lower extremities before upper extremities.
  
  • Difficulty running, jumping, and walking up stairs
  • Gower’s sign - use hands to push self up when arising from floor
  • Waddling gait, lumbar lordosis, calf enlargement
  • Children tend to be wheelchair bound by 12
• Elevated CK (50-100X) and transaminases
• Elevated AST and ALT
• Growth delay in first year resulting in short stature
• Cardiomypathy - specifically dilated cardiomyopathy and conduction abnormalities
• Fractures involving arms and legs
• Mild cognitive impairment or global development delay. However, some children will have average or above-average intellligence.

Question 6

Clinical Presentation Becker

Answer 6

• Later age of onset - 5-60 years
• Milder involvement
  
  • Retained strength allows you to distinquish between Beckers and Duchennes
  • Patients tend to remain ambulatory and intellectual disability is less common
• CK is elevated (5-10X normal)
• Cardiac involvement is a predominant feature

Question 7

Diagnosis of Beckers and Duchennes

Answer 7

• Should be suspected in the following situations
  
  • Evidence of delayed motor milestones in children with positive family history
  • No family history but child is not walking at 16-18 months, or presence of Gower’s sign, toe walking, or calf hypertrophy
  • Unexplained increases in transaminases - asparate transaminase and alanine transaminase
• Diagnosis - Elevated CK + Clinical Symptoms + Genetic Testing

Question 8

Treatment Duchennes and Beckers

Answer 8

• Glucocorticoids- Main treatment. Improve both motor and pulmonary function.
• Multidisciplinary core - PT to encourage mobility and reduce risk of contractures; nutrition; bone health; fracture and fall prevention; growth and endocrine management; routine immunization.
• Cardiac surveillance and administration of an ACEi or ARB starting at 10 for boys with Duchennes
• Respiratory surveillance - serial monitoring of vital capacity starting age age 5-6

Question 9

Prognosis Duchennes and Becker

Answer 9

• Duchennes - Most loose ambulation by 12 and require noninvasive ventilation by late teens. Survival beyond 3rd decade is uncommon.
• Becker - Remain ambulatiry beyond 16 and into adult life. Tend to survive beyond 30 and mean age of death is mid-40s. Most common cause of death is heart failure from cardiomyopathy.

Question 10

Steps of Muscular Contraction

Answer 10

1. Muscle activation - Motor nerve stimulates an action potential down to neuromuscular junction. This stimulates sacroplasmic reticulum to release Ca²⁺ into the muscle cell.
2. Muscle contraction - Calcium is released into the muscle and binds with troponin, allowing actin and myosin to bind forming cross bridges. During power stroke, myosin head bends and ADP + P are relased (power stroke - conformational change of myosin so that it pulls against the actin).
3. New molecule of ATP attaches to myosin head, causing cross-bridge to detach
4. ATP hydrolizes to ADP + P, returning myosin to re-oriented position.

Question 11

Muscular Structure

Answer 11

Question 12

Signs of Muscular Lesions

Answer 12

• Pure motor dysfunction - weakness and atrophy
• No sensory involvement
• Weakness is often diffuse but proximal

Question 13

Neuromuscular Junction

Answer 13

• Neuromuscular Junction - space between neuron and muscle + components within.

1. Action potential stimulates voltage gated Ca²⁺ channels to open inside axon terminal.
2. This makes the cell more positive, causing Ach vesicles to release Ach into the synaptic cleft/ neuromuscular junction.
3. Ach binds to Na⁺ gates channels on the muscles allowing Na⁺ to enter the muscles.
4. Once in the muscle, Na^{+<strong> </strong>}will stimualte an action potential within the cell. Next, Ach will detach from receptors.
5. Enzyme Acetylcholinesterase will break down Ach into choline and acetate.
   
   • Choline can combined with Acetyl CoA to make new Ach.

Question 14

The Action Potential

Answer 14

• Action Potential - large, brief reversal in polarity of an axon.
• The threshold potential is the voltage on a neural membrane at which an actional potential is triggered - it is all or nothing. The threshold potential is around -50mV
• Once ther thresold potential is met, voltage sensitive tions channels (Na⁺ and K⁺) will open.
  
  • Na⁺ channels open first, allowing sodium to rush in. This depolarizes the inside of the cell (makes more positive).
  • K⁺ channels open next, allowing potassium out of the cell. This repolarizes the cell (makes more negative).
• Absolute refractory period - state of axon in repolarizing period where a new action potential cannot be elicited because second gate of the Na⁺ channel, which is not not voltage-sensitive, is closed.
• Relative refractory period - state of an axon in the later phase of an action potential, where an increased electrical current is requried to produce an action potential. Potassium channels are still open.

Question 15

Myasthenia Gravis

Answer 15

• An acquried autoimmune disorder of the neuromuscular junction characterized by weakness and fatigability of skeletal muscles.

Question 16

Etiology/pathophysiology Myasthenia Gravis

Answer 16

• Due to development of autobodies the attack components of the neuromuscular junction, resulting in early saturation in the neuromuscular junction and inadequate muscle activation with increasing nerve stimulation.
• Majority who develop myasthenia gravis in adolescence or adulthood have autoantibodies that attack the acetylcholin receptors (AChR), fixing complement, and reducing numbers of AChRs over time.
• Other patients have autoantibodies directed against muscle-specific receptor tyrosine kinase (MuSK), which transmembrane component of the postsynaptic neuromuscular junction (stimulates clustering of AChRs).
• Seronegative/double seronegative myasthenia gravis - Seronegative (absence of AChR antibodies); double negative (absence of both AChR and MuSK antibodies). May have low affinity AChR antibodies or antibodies to other self-anitgens.
• Thymic abnormalities - Majority of AChR positive patients have thymic abnormalities:
  
  • Hyperplasia 60-70%
  • Thymoma 10-12% (tumour from thymus, can be benign or malignant).
  • Disease often improves after thymectomy. Indicates thymus may be the source of antigen that drives this autoimmune disease
• Genetic factors - certain genetic factors may contribute - HLA-B8, DRw3, and DQw2.

Question 17

Presentation myasthenia gravis

Answer 17

• Fluctuating skeletal muscle weakness
  
  • Commonly worse later in the day or after exercise
  • Fatigable, symmetric or asymmetric weakness without reflex changes, sensory changes, or coordination abnormalities
  • Occular (diplopia/ptosis), bulbar (dysarthria/dysphagia, fatigable chewing), and/or proximal limb weakness
  • Facial muscle weakness - dropped head syndrome, arms tend to be affected more than the legs
  • Respiratory muscle weakness may lead to respiratory failure
  • Symptoms may be exacerbated by infection, pregnancy, menses, and various drugs
• Myasthenic crisis - life threatening condition where weakness is severe enough to require intubation or to delay extubation after surgery
  
  • 10-20% of patients may experience this
• Cholinergic crisis - potential side effect of excessive anticholinesterase medication is weakness. Can be hard to distinquish from myasthenia gravis. It is very rare and usually not the cause of progressive weakness.

Question 18

Progression of Myasthenia Gravis

Answer 18

• Tends to peak within a few years of disease onset. There are 3 stages:
  
  • Active phase with most fluctuations and most severe symptoms that occur 5-7 years after onset.
  • Symptoms are stable but persistant
  • Remission may occur, either on immunotherapy or off → 30% have spontaneous remission.

Question 19

Investigations Myasthenia Gravis

Answer 19

• EMG
  
  • Repetitve stimulation - decremental response
  • Single fibre EmG shows increase jitter
• Spirometry - forced vital capacity to monitor respiratory effort
• anti-AChR antibody assay; anti-MuSK antibody
• CT/MRI to screen for thymoma/thymic hyperplasia

Question 20

Treatment Myasthenia Gravis

Answer 20

• Thymectomy - 85% show improvement or remission
• Acetylcholinesterase inhibitors (pyridostigmine) - does not control disease when used alone
• Immunosuppression
• Steriods 70-80% remission rate
  
  • Adjuncts or steriod sparing - azathioprine, cyclophosphamide, and mycophenolate
• Short-term immunodulation (for crises) - IVIg and plasmapheresis

Question 21

Signs of neuromucular junction lesion

Answer 21

• Pure motor dysfrunction
• No sensory involvement
• May see fatiguable weakness
• Most active muscles first be be involved