1. Myasthenia gravis
By: Nikki Young

2. Overview I: Epidemiology II: Risk Factors III: Symptoms of MG
IV: Types of MG
V: Pathophysiology and Mechanisms of MG
VI: Treatment of MG
VII: References and Study Questions

3. Gender and ethnicity are linked to rate of MG prevalence
20 per 100,000 US
Incidence
1.7 to 10.4 per 1 million
Gender
< 40 women
> 50 men
Ethnic origin
Low in Europe, North America
High in China
Earlier onset

4. HLA association is a known risk factor of MG
Common HLA Association
HLA-DR3, B8, DR9 early onset
HLA-DR2, B7 late onset
DR14, DQ5 (Anti-MuSK)
Mostly unknown causes
Possible risks: genetic link, other AI disease, thymoma

5. Main symptoms of MG include muscle weakness and fatigue
Eyes/Face
Ptsosis, diplopia
Facial muscle weakness (eyelid closure, drooling)
Bulbar
Dysphagia, Dysarthria, Dysphonia
Jaw fatigue
Head/neck
Head droop
Limbs
Arms > legs (waddling)
Respiratory
Dyspnea
Respiratory failure (myasthenic crisis)

6. MG is not just an autoimmune disease
Autoimmune MG
Ocular (oMG)
~10%
Generalized (gMG)
w/in 2 years
Neonatal MG
Maternal Abs
Congenital Myasthenia
Genetic mutations

7. Two known types of autoimmune MG
Anti-AChR (acetylcholine receptor)
Focus: ~80-90%, known mechanisms
Anti-MuSK (muscle specific kinase)
Differences, 30-40% remaining cases
Unsure of pathophysiology
Others
seronegative

8. What are the three mechanisms of Anti-AChR MG?
1) Complement Activation
IgG 1 and 3
MAC
Flattened membrane
2) Antigenic Modulation
Crosslinking Abs
Endocytosis, degradation
3) AChR Block
Bind Ach binding site
Block neuromuscular transmission

9. Mechanisms of Anti-MuSK MG are still being researched
MuSK important for AChR clustering and membrane stability
Complement activation unlikely
IgG4 Abs

10. Differences between Anti-AChR and Anti-MuSK MG
AChR-MG
MuSK-MG
Age of onset
Bimodal: <40 & >50
4th decade
Gender
Female <40, Male >50
85% female
Pattern of weakness
Predominant ocular involvement
Bulbar and limb weakness
Neck, shoulder, bulbar and respiratory weakness
Distinctive features
Initially ocular, later becomes generalized
Cranial and bulbar atrophy, triple furrowing of the tongue
HLA association
DR3, B8, DR9 early onset
DR2, B7 late onset
DR14, DQ5

11. What role to Th cells play in MG?
Anti-AChR MG Anti-Musk MG
Th1 cells Th2 cells
Increased MHC-II expression B-cells to produce IgG4
Complement activation

12. Cholinesterase Inhibitors
Treatments for MG
Cholinesterase Inhibitors
Longer ACh activity
Immune Therapies
Short-term
Plasma Exchange
IV Ig
Long-term
Corticosteroids
Immunosuppressant drugs
Thymectomy

13. References
Meriggioli, M. N., & Sanders, D. B. (2009). Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. The Lancet Neurology, 8(5),
Conti-Fine, B. M., Milani, M., & Kaminski, H. J. (2006). Myasthenia gravis: past, present, and future. The Journal of clinical investigation, 116(11),
Hurst, R. L., & Gooch, C. L. (2016). Muscle-Specific Receptor Tyrosine Kinase (MuSK) Myasthenia Gravis. Current Neurology and Neuroscience Reports, 16(7), 1-4. doi: /S Z
Verschuuren, J., Huijbers, M., Plomp, J., Niks, E., Molenaar, P., Martinez-Martinez, P., Losen, M. (2013). Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmunity Reviews, 12(9), doi: /J.AUTREV
Symptoms Image:
Koneczny, I., Cossins, J. and Vincent, A. (2014), The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J. Anat., 224: 29–35. doi: /joa.12034

14. Study Questions
1) Which is not an immunological mechanism of Anti-AChR MG?
Complement binding and activation
Inhibition of acetylcholine release
AChR block
Antigenic modulation
2) Which is not a role of Th cells in MG?
Complement activation
IgG4 production by plasma cells
Decreased ACh production
Increased MHC-II expression in muscle cells

15. 3) What is not a current treatment for MG?
Cholinesterase inhibitors
Complement inhibition
Thymectomy
Corticosteroids
4) The most common symptoms of MG include:
Muscle weakness
Fatigue
Myasthenic crisis
Both A and B

16. Short Answer:
What is the difference in the target of Anti-AChR and Anti-MuSK Abs, and what is a possible difference in the clinical presentation of these two types of MG?