Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune condition that impacts components of the neuromuscular junction, causing signal transmission across the postsynaptic membrane to be disrupted. It is a clinically and biologically heterogeneous condition defined by the presence of specific autoantibodies that have a key role in its pathogenesis and diagnosis. At the effector stage, MG is well characterized, with 3 autoantigens that account for roughly 90% to 95% of clinical cases. The muscle acetylcholine receptor (AChR) is the major target in 80% to 85% of MG cases, while pathogenic autoantibodies directed against muscle-specific tyrosine kinase (MuSK) or low-density lipoprotein receptor-related protein 4 (LRP4) are present in the remaining patients.¹ 

Myasthenia gravis is not a disease that shows direct inheritance, and it is not contagious. A genetic susceptibility to autoimmune illness, on the other hand, can run in families. Rarely, MG can affect more than one member of the same family.²

Genetic Susceptibility

Specific Human Leukocyte Antigen Alleles Linked to Myasthenia Gravis Susceptibility

Genetic tests have identified specific human leukocyte antigen (HLA) alleles that are linked with susceptibility to MG, as with most autoimmune disorders.³ Some genes are associated with autoimmunity, but the HLADRB1*1501, HLADQ5, and CTLA4 polymorphisms have a more specific association with MG and MG subgroups. The risk of developing MG can be increased by genetic polymorphisms in the promoter region of CHRNA1, which encodes the AChR subunit. Many HLA alleles have been linked to a higher risk of MuSK MG, including HLADQB1*05, HLADRB1*14, and HLADRB1*16.⁴

Genome-Wide Association Studies of Early-Onset Myasthenia Gravis

A recent genome-wide association study (GWAS) involving over 600 patients from northern Europe discovered that tumor necrosis factor alpha-induced protein 3 (TNFAIP3)-interacting protein 1 (TNIP1) is linked to early-onset MG (EOMG), confirming previous findings that HLA-B08 and protein tyrosine phosphatase nonreceptor 22 (PTPN22) are linked to EOMG.³ GWASs discovered variants in the major histocompatibility complex (MHC) class II locus, PTPN22, and TNIP1 in 649 EOMG cases from Scandinavia, the United Kingdom, France, The Netherlands, Germany, and the United States. Based on candidate gene research, the cytotoxic T lymphocyte-associated protein 4 gene (CTLA4) has been reported as a susceptibility factor for MG. Patients with MG are also more likely to have a personal or family history of other autoimmune conditions, such as autoimmune thyroid disease, rheumatoid arthritis, and type 1 diabetes mellitus, though the genetic reason for this autoimmunity susceptibility is unknown. Finally, about 5% of patients have a family history of MG, which is frequently inherited in an autosomal dominant form.⁵ 

Non-HLA Genes Associated With Myasthenia Gravis

Non-HLA genes linked to MG include cathepsin L2 (CTSL2), PTPN22, cytotoxic T cell late antigen 4 (CTLA4), galectin-1 (LGALS1), forkhead/winged-helix transcription factor 3 (FOXP3), interleukin receptor 2b (IL2Rb), interferon-g (IFNG), interleukin-4 receptor a (IL4R), interleukin-10 (IL10), muscle nicotinic acetylcholine receptor a-subunit (CHRNA1), muscle nicotinic acetylcholine receptor d-subunits (CHRND), tumor necrosis factor alpha (TNF), and TNIP1.³ 

Myasthenia Gravis and Epigenetics

MicroRNAs have a role in post-transcriptional gene silencing and are found to be dysregulated in a number of autoimmune disorders. A decrease in microRNAs in the peripheral blood lymphocytes of MG patients was linked to a rise in proinflammatory cytokines. MiR-150-5p, miR-21-5p, and let-7 are examples of dysregulated microRNAs in MG, which are dependent on both the MG subgroup and chronic immunosuppression. The let-7 family is upregulated in MuSK MG, whereas miR-150-5p and miR-21-5p are increased in AChR antibody MG.³ 

Twin Studies in Myasthenia Gravis

The contribution of genetic determinants to disease risk has been estimated by comparing disease concordance between monozygotic (identical) and dizygotic (fraternal) twins. Based on a thorough literature search, MG concordance in monozygotic twins was 30% to 40%, compared to 4% to 5% in dizygotic twins.³ 

References

1. Zagoriti Z, Kambouris ME, Patrinos GP, Tzartos SJ, Poulas K. Recent advances in genetic predisposition of myasthenia gravis. Biomed Res Int. 2013;2013:404053. doi:10.1155/2013/404053
2. Myasthenia gravis: inheritance. Genetic and Rare Diseases Information Center (GARD). Updated April 3, 2018. Accessed February 7, 2022. 
3. Avidan N, Le Panse R, Berrih-Aknin S, Miller A. Genetic basis of myasthenia gravis – a comprehensive review. J Autoimmun. 2014;52:146-153. doi:10.1016/j.jaut.2013.12.001
4. Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. Nat Rev Dis Primers. 2019;5(1):30. doi:10.1038/s41572-019-0079-y
5. Renton AE, Pliner HA, Provenzano C, et al. A genome-wide association study of myasthenia gravis. JAMA Neurol. 2015;72(4):396-404. doi:10.1001/jamaneurol.2014.4103

Reviewed by Hasan Avcu, MD, on 2/10/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.