Myasthenia Gravis (MG) is a rare autoimmune neuromuscular disease, aimed at the neuromuscular junction. It is characterised by fluctuating muscle weakness and fatigability. It is a potentially life threatening condition when respiratory muscles are involved. In 85% of cases, autoantibodies directed against nicotinic acetylcholine receptors (AChR’s) in the postsynaptic membrane of the neuromuscular junction have been found. Autoantibodies directed against the Muscle Specific tyrosine Kinase (MuSK) also on the postsynaptic membrane have been found in 70% of cases. Together, autoantibodies to AChR and/or MuSK are present on over 90% of MG cases. Other autoantibodies are also often present.
The most frequent form of Myasthenia Gravis presents with thymus follicular hyperplasia and has an early onset. It has been shown to be associated with the ‘ancestral HLA haplotype’ A1 – B8 – Cw7 – DR17 – DQ2. The strong linkage disequilibrium had made it difficult to determine precisely which locus on this haplotype is most strongly associated. Early studies implicated HLA-B8 but this was later replaced with a stronger associated with HLA class II, specifically HLA-DR17. One consistent finding is that HLA-DR3 has a positive association with early onset Myasthenia Gravis and a negative association with late onset Myasthenia Gravis, whilst HLA-DR7 has the opposite, i.e. a negative association with early onset Myasthenia Gravis and a positive association with late onset Myasthenia Gravis. Another study using SNPs in a large group of patients found the strongest association to be with HLA-Cw7. The real disease association locus could even be another locus on the A1 – B8 – Cw7 – DR17 – DQ2 haplotype. One recent study has identified a region that overlaps the MHC class III and class I regions of the A1 – B8 – Cw7 – DR17 – DQ2 haplotype, which they termed MYAS1, that associates strongly with Myasthenia gravis.
Diagnosis of Myasthenia gravis does not depend on genetic testing. Tests to measure concentrations of serum autoantibodies are a more effective diagnostic tool. Genetic testing may however be an aid to diagnosis and is of value in providing insights into the mechanism of the disease, thereby potentially suggesting strategies for prevention and treatment.
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