Case 6 - myasthenia gravis

Question 1

epidemiology

Answer 1

• Prevalence ranges from 150 to 200 cases per million.
• Incidence increases steadily in men while there are peaks around 30 and 50 for women
• Female male ratio 3:1
• Late and early onset type

Question 2

AChR - function

Answer 2

• Nicotinic AChR is a heteropentamer consisting of two α-subunits and 4 others which are organized around a central pore  creating the transmembrane protein responsible for transducing neuronal signals into muscle contractions

Question 3

AChR-MG - pathophysiology

Answer 3

• Antibodies against the AChR are found in approximately 80% of MG patients. At least half of the AChR autoantibodies are directed at the AChR α-subunits (main immunogenic region)
• AChR antibodies are predominantly of the IgG1 and IgG3 subclasses
• Both able to bind to C1q  classical complement pathway
• Activate immune cells

Question 4

AChR-MG pathomechanism

Answer 4

• The predominant mechanism is the binding of the antibody and activation of the complement cascade, leading to the formation of the membrane attack complex (MAC), which causes damage of the postsynaptic membrane, calcium influx, depolarization and destruction of synaptic folds which contain AChRs and associated proteins
• Other mechanisms of pathogenicity include:
• Antigenic modulation by the binding and crosslinking of AChRs, leading to increased endocytosis and degradation
• The impairment of AChR function, either by the blocking of ACh binding to the receptor or the prevention of channel opening (rare)
• Antibody-dependant cellular cytotoxicity (ADCC) –> NK cells kill

Question 5

MuSK - function

Answer 5

• MuSK is a membrane protein that is critical to the clustering of AChRs in the neuromuscular junction

Question 6

MuSK-MG

Answer 6

• Antibodies against MuSK are found in approximately 7–10% of all MG patients
• MuSK antibodies belong mainly to the IgG4 subclass.
• They do not fix complement and are not strong activators of cell-mediated cytotoxicity
• IgG4 undergo Fab arm exchange, MuSK antibodies are functionally monovalent, and they cannot crosslink antigens of the same class.
• The mechanism by which MuSK antibodies exert their pathogenic effect on the neuromuscular junction is via binding to the Ig-like domain of the protein, preventing its phosphorylation, and subsequently disrupting the Agrin-Lrp4-MuSK-Dok-7 signalling pathway.

Question 7

Lrp4-MG

Answer 7

• Lrp4 is the postsynaptic receptor of nerve-derived agrin. The binding of agrin to Lrp4 activates MuSK and initiates a cascade of events leading to the aggregation of AChRs in the neuromuscular junction
• Many Lrp4-MG patients also have antibodies against agrin. Lrp4 antibodies are mostly of the IgG1/IgG2 subclass and are believed to be directly pathogenic by disrupting the activation of MuSK  leading to unclustering of AChR

Question 8

symptoms

Answer 8

• The spectrum of symptoms ranges from a purely ocular form to severe weakness of the limb, bulbar and respiratory muscles. The age of onset is variable from childhood to late adulthood with disease peaks in younger adult women and older men
• Symptoms normally start as bulbar weakness
• Generalised symptoms include muscle weakness and muscle fatigue –> might lead to respiratory crisis (ventilation prevents death)
• Achr MG –> general
• Musk –> bulbar

Question 9

genetics

Answer 9

HLA alleles can contribute to MG
also some others SNPs can contribute to increase odds

Question 10

diagnosis and biomarkers

Answer 10

• antibody testing –> radio immunotoxin assay
• EMG - lower force of contraction at least 10% lower each time
• CT/MRI to check for thymoma
• Physical examination (check for muscle weakness)
• QMG

Question 11

treatment

Answer 11

1. Acetylcholine esterase inhibitors –> increase Ach presence in synaptic cleft (NMU)
2. Corticosteroids –> immunosuppressive treatment (prednisone)
   * Used to treat myasthenic crisis
3. Azathioprine –> non-steroid immunosuppressant
4. Rituximab –> antibody directed against CD20
5. IVIG
6. Belimumab –> anti-BAFF look up
7. Competitor antibodies (non-pathogenic)
8. Proteasome inhibitors to kill plasma cells by increasing toxic protein buildup
9. Plasmapheresis / immunoabsorbance
10. Eculizumab –> anti-C5 antibody
11. Efgartigimod –> anti-recycling Igs
12. Thymectomy –> AcHR with or without thymoma

Question 12

Lamber eaton myasthenic syndrome

Answer 12

• In LEMS antibodies are against VGCC on the pre-synaptic membrane
• Synaptic vesicles are not released which leads to similar symptoms as in MG

Question 13

have look at complement

Answer 13

draw it and watch videos