Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
Myasthenia gravis (MG) is a rare autoimmune neuromuscular disorder characterized by muscle weakness and fatigue that commonly affect the eyes, face, jaw, throat, neck, and limbs.1
In most patients with MG, the development of autoimmunity is idiopathic. Scientists theorize that viral or bacterial proteins mimic certain proteins produced by the body, such as the acetylcholine receptor (AChR), but they have not yet discovered the triggering antigen. The similarities cause the immune system to target and destroy the body’s proteins.2,3
Approximately 85% of individuals with a diagnosis of MG have anti-AChR autoantibodies in their blood. Antibodies are Y-shaped proteins that B cells of the immune system use to target foreign substances in the body; however, anti-AChR autoantibodies target and damage AChRs, which are the docking sites for the neurotransmitter acetylcholine (ACh) in muscle tissue. As a result, the signal that ACh carries from nerve to muscle is impaired, resulting in decreased muscle contraction, muscle weakness, and muscle fatigue following repeated contractions.3
Thymic dysfunction is frequently associated with MG. The thymus plays an integral role in immune system function by enabling white blood cells, or T cells, to differentiate self from non-self. A thymic tumor, or thymoma, develops in approximately 15% of individuals with MG. In another 75%, the thymus is enlarged by the increased proliferation of thymic epithelial cells (thymic hyperplasia). Thymic dysfunction prevents T cells from maturing properly, preventing them from distinguishing self from non-self and enabling attacks on the body’s healthy tissues.3-5
Approximately 5% to 8% of individuals with MG have muscle-specific tyrosine kinase (MuSK) MG, which affects primarily the facial and bulbar muscles and generally is not associated with significant thymus abnormalities.6 Muscle biopsy specimens taken from individuals with MuSK-positive MG demonstrate mitochondrial abnormalities, whereas neurogenic abnormalities and muscular atrophy are typically found in individuals who have MG with anti-AChR antibodies.2 Overall, the root cause of anti-MuSK antibody synthesis is not well understood, although thymic dysfunction does not appear to play a role.1
A small subset of patients with MG have anti-lipoprotein reception protein 4 (anti-LRP4) autoantibodies rather than anti-MuSK or anti-AChR autoantibodies, and the remaining 5% to 8% lack identifiable autoantibodies in their blood but have positive test results during other assessments for MG.1
A pregnant woman with MG may temporarily pass autoantibodies from her blood through the placenta to the fetus, causing transient neonatal MG. This resolves in 2 to 3 months after birth.1,5,7
Although MG is largely not an inherited condition, genetic predisposition and genetic factors play a role in pathogenesis. Specific human leukocyte antigens (HLAs), which are proteins on the surface of cells that regulate the immune system, have been linked to a genetic predisposition to autoimmune diseases, including idiopathic MG. HLAs linked to MG include HLA-A1, -A3, -B7, -B8, -DRw3, and -DQw2. Individuals with anti-MuSK antibody MG exhibit DR14, DR16, and DQ5 HLA class II haplotype inheritance.2,3,6,8,9
Between 3.8% and 7.1% of individuals with a diagnosis of MG report family members with MG or another autoimmune condition. Other autoimmune diseases, especially thyroid disorders, rheumatoid arthritis, and systemic lupus erythematosus, often co-occur in individuals with MG. The frequent presence of autoimmune comorbidities indicates a genetic predisposition to autoimmune disease. Often, an environmental trigger, such as stress, a viral or bacterial infection, physical trauma, hyperthyroidism, allergic reactions, surgeries especially thyroidectomy, pregnancy, or childbirth, is required for the manifestation of such diseases.1,10
Several studies have revealed that monozygotic twins are independently seropositive for anti-AChR autoantibodies, a finding that supports genetic influences in pathogenesis.11-13
Rarely, children born to a healthy mother have congenital myasthenic syndromes. Congenital myasthenia is caused by defective genes; these encode abnormal proteins that become embedded in the neuromuscular junction. The abnormal proteins produce symptoms that are similar to those of MG. Next-generation sequencing has identified more than 30 different genes that contribute to the development of congenital myasthenic syndromes, some of which (eg, CHAT, SLC18A3, PREPL, SNAP25B, SYT2, and SLC5A7) participate in the ACh recycling pathway.14
- Myasthenia gravis. National Organization for Rare Disorders. Accessed February 5, 2022.
- Jowkar AA. Myasthenia gravis: etiology. Medscape. Updated August 27, 2018. Accessed February 3, 2022.
- Causes/inheritance – myasthenia gravis- diseases. Muscular Dystrophy Association. Published December 18, 2015. Accessed February 5, 2022.
- Khan MA, Anjum F. Thymic hyperplasia. StatPearls [Internet]. Updated December 8, 2021. Accessed February 5, 2022.
- Myasthenia gravis fact sheet. National Institute of Neurological Disorders and Stroke. Accessed February 5, 2022.
- Rodolico C, Bonanno C, Toscano A, Vita G. MuSK-associated myasthenia gravis: clinical features and management. Front Neurol. 2020;11:660. doi:10.3389/fneur.2020.00660
- Myasthenia gravis. Johns Hopkins Medicine. Accessed February 5, 2022.
- Carlsson B, Wallin J, Pirskanen R, Matell G, Smith CI. Different HLA DR-DQ associations in subgroups of idiopathic myasthenia gravis. Immunogenetics. 1990;31(5-6):285-290. doi:10.1007/BF02115001
- Niks EH, Kuks JBM, Roep BO, et al. Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5. Neurology. 2006;66(11):1772-1774. doi:10.1212/01.wnl.0000218159.79769.5c
- Bubuioc AM, Kudebayeva A, Turuspekova S, Lisnic V, Leone MA. The epidemiology of myasthenia gravis. J Med Life. 2021;14(1):7. doi:10.25122/jml-2020-0145
- Coppola R, Kay M, Dyess M. Myasthenia gravis in monozygotic twins (812). Neurology. 2020;94(15 Supplement).
- Ramanujam R, Pirskanen R, Ramanujam S, Hammarström L. Utilizing twins concordance rates to infer the predisposition to myasthenia gravis. Twin Res Hum Genet. 2011;14(2):129-136. doi:10.1375/twin.14.2.129
- Murphy J, Murphy SF. Myasthenia gravis in identical twins. Neurology. 1986;36(1):78-80. doi:10.1212/wnl.36.1.78
- Ramdas S, Beeson D. Congenital myasthenic syndromes: where do we go from here? Neuromuscul Disord. 2021;31(10):943-954. doi:10.1016/j.nmd.2021.07.400
Reviewed by Debjyoti Talukdar, MD, on 2/5/2022.