Did You Know…?

The month of June brings awareness to many disorders, such ALS, brain injuries, and aphasia to state a few. Myasthenia Gravis (MG), translated to “grave muscular weakness” in Greek and Latin, is an autoimmune disorder that this month brings our attention to. MG is primarily characterized by fluctuating muscle weakness, with stages of improvement and worsening. This relatively uncommon disorder is more prevalent in women between the ages of 20-40 (female:male ratio being 3:1). It more commonly affects males over the age of 50. MG is classified into six subtypes: 1) Early onset (<50 years of age) usually females, (2) late-onset (>50 years) common in males, (3) thymoma-associated, (4) MG with anti-MUSK antibodies, (5) ocular MG, and (6) MG with no detectable acetylcholine receptors (AChR) and muscle-specific tyrosine kinases (MUSK) antibodies. 

Neurotransmission at the neuromuscular junction (NMJ) results from acetylcholine, cholinergic neurotransmitter, which releases from the presynaptic neuron. Depolarization of the presynaptic neuron allows calcium to enter the neuron via voltage gated Ca2+ channels and engage with the SNARE complex of the vesicles so the neurotransmitter can be excreted out in the synaptic cleft. The neurotransmitter can then engage nicotinic (N1) receptors on the NMJ and trigger an end plate potential to cause depolarization of skeletal muscle and result in an action potential that allow muscle contraction to occur. Acetylcholine is degraded by acetylcholinesterase in the synaptic cleft to prevent sustained muscle contraction. 

MG, regardless of the subtypes, in general, results from the immune system producing antibodies against the AChR at the neuro-muscular junction. Antibodies against AChR can competitively bind to normal AChR preventing acetylcholine from acting on its receptor. AChR antibodies can also crosslink the receptors and make them more susceptible to be endocytosed and degraded. AchR can be also be rendered dysfunctional if a complement binds to the antibody-AChR complex and form a membrane-attack complex resulting in damaged junctional folds on the membrane, which effectively reduce the number of AChRs. In all, if antibodies are produced against the AChR, neurotransmission at the NMJ will not be effective in producing end-plate potential at the junction to trigger contraction of the muscle. MG characterized with antibodies against MuSK is relatively rare. Muscle-specific tyrosine kinase is another protein that is important for proper neurotransmission at NMJ. There is no clear explanation as to how anti-MuSK leads to MG pathogenesis. MuSK, when activated, promote clustering of AChRs, so it is hypothesized that anti-MuSK cause decreased density of AChRs, hence lowering efficiency of neurotransmission. 

Weakness of skeletal muscle primarily that worsens with repetitive activities or stress and improvement of the weakness with rest is the chief clinical feature of MG. Eye muscles are commonly affected, so the patient with MG would present with unilateral or bilateral ptosis and diplopia. Fatigability in muscles responsible for speech and swallowing, if affected by MG, make it more tiring to chew food with mouth closed. Patient was also present with dysphagia and dysarthria (difficulty forming and pronouncing words). 

Diagnosis for MG is fairly accessible and should be utilized as many grave cases of MG are due to lack of diagnosis and proper treatment thereafter. Antibodies against AChR are present in the blood and can be detected through a blood test in about 75% of cases. Edrophonium test is another available diagnostic tool. Edrophonium (tensilon) is an acetylcholinesterase inhibitor that temporarily relieves muscle weakness. For those who do not have MG, the chemical will not experience any change when administered. 

Anticholinesterase are fast acting medications prescribed to alleviate symptoms associated with MG. The medication prevents degradation of acetylcholine, keeping the neurotransmitter in the cleft longer to generate stronger muscle contraction. Pyridostigmine bromide (Mestinon), commonly, and Neostigmine are anticholinesterase prescribed to name a few. While the drugs are associated with only few side-effects, cramps and diarrhea are some undesirable effects of the drug. MG can also be treated with immunosuppressants to prevent production antibodies against AChRs. The immunosuppressants also prevent essential antibodies along with anti-AChRs, so the immunosuppressant medications are used with caution and is not permitted for individuals with a compromised immune system. Thymectomy is recommended for patients that present with MG due to thymoma to reduce the function of the immune system in producing antibodies. 

“Anti-AChR Antibodies: Mechanisms of Action.” Anti-AChR Antibody Mechanisms, neuromuscular.wustl.edu/mtime/modulation.htm.

Jayam Trouth, A., Dabi, A., Solieman, N., Kurukumbi, M., & Kalyanam, J. (2012). Myasthenia gravis: a review. Autoimmune diseases2012, 874680. https://doi.org/10.1155/2012/874680

Koneczny, I., Cossins, J., & Vincent, A. (2014). The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. Journal of anatomy224(1), 29–35. https://doi.org/10.1111/joa.12034

“Myasthenia Gravis (MG) Diagnosis and Tests.” Cleveland Clinic, my.clevelandclinic.org/health/diseases/17252-myasthenia-gravis-mg-/diagnosis-and-tests.

“MG Facts.” Myasthenia Gravis Foundation of America, myasthenia.org/What-is-MG/MG-Facts.

Omar A, Marwaha K, Bollu PC. Physiology, Neuromuscular Junction. [Updated 2020 May 24]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470413/

“What Are Treatment Options for Myasthenia Gravis (MG)?” Conquer Myasthenia Gravis, 15 Jan. 2019, http://www.myastheniagravis.org/about-mg/treatments/.

One thought on “Did You Know…?

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s