Myasthenia gravis (MG) is an incurable and chronic autoimmune disease that can cause varying degrees of skeletal muscle weakness.
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Historically, diagnosing the condition has frequently been delayed or missed, due to symptoms varying significantly between affected individuals and an overlap in symptoms with other disorders. In addition to this, each MG subtype requires serological detection of specific analytes for an accurate diagnosis.
However, a range of targeted immunoassays can now be utilized to detect and quantify the autoantibodies responsible for this debilitating condition.
This enables a diagnosis to be made earlier, followed by prompt treatment to aid the control of symptoms and improve the lives of the 700,000 individuals affected by the condition worldwide.1
Diagnosis of myasthenia gravis
MG typically causes weakness in the facial muscles at its onset, leading to slurred speech, eyelid drooping, or difficulty swallowing. However, it can spread to other body parts, impacting the respiratory muscles and limbs.
MG is caused by the production of antibodies that attack vital proteins at neuromuscular junctions.
The detection of acetylcholine receptor antibodies (ARAbs) in the blood can be utilized to diagnose most MG cases. ARAbs prevent acetylcholine – the main neurotransmitter of the parasympathetic nervous system – from binding to its receptor, blocking regular muscle contractions.
However, approximately 20 percent of patients with clinical symptoms display no detectable level of ARAbs in their system. This can contribute to the misdiagnosis of MG as Lambert-Eaton syndrome, multiple sclerosis, or other conditions that cause muscle weakness. 2,3
In addition, so-called seronegative patients often have a more severe form of the condition, with approximately 30 percent eventually needing respiratory support. An early and definitive diagnosis is therefore critical, since seronegative patients require more intensive therapy.
Fortunately, an alternative biomarker has been identified by researchers. Muscle-specific receptor tyrosine kinase antibodies (MuSK-Abs) have been found in approximately 70 percent of seronegative MG patients.4
Antibodies against other molecules that are involved in the function of neuromuscular junctions have been identified as potential biomarkers in the small percentage of patients who test negative for both MuSK-Abs and ARAbs.
For example, low-density lipoprotein receptor-related protein 4 (LRP4) antibodies have demonstrated great promise for diagnosing double-seronegative individuals.
For the remaining two to five percent of people with MG who display no detectable levels of the above antibodies – referred to as triple-seronegative patients – the identification of agrin antibodies is currently being studied as an effective method for diagnosis.5
Testing and treatment
Using specific, sensitive, and proven testing methods for detecting these autoantibodies is critical for early diagnosis and treatment. Fortunately, many high-quality commercially available assays on the market can aid the diagnosis of the most common subtypes of MG.
Radioreceptor assays (RRAs) are well-suited to the detection of ARAbs, due to their high specificity and sensitivity.
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For instance, the Tecan Acetylcholine Receptor-Ab (ARAb) RRA utilizes a radio-labeled alpha-bungarotoxin snake venom marker to bind to human acetylcholine receptors without blocking ARAbs.
Additionally, dedicated ELISAs can be used to detect MuSK-Abs in most seronegative patients, lowering the barrier to entry for smaller clinical labs by demanding less specialized equipment than RRA alternatives.
As well as being highly sensitive, these assays – such as Tecan’s MuSK-Ab ELISA – are also semi-quantitative. This enables clinicians to utilize the correlation between MuSK-Abs levels and disease severity – no equivalent ARAb relationship is currently known – to provide an early indication of disease remission or treatment failure through repeat testing.6
Assays that can diagnose MG in double- and triple-seronegative individuals are not yet commercially available, and must be developed in-house by clinical labs if needed.
The prompt diagnosis of patients who are showing clinical symptoms of MG is imperative to allow treatment to begin as soon as possible, particularly in the case of seronegative individuals, who typically suffer more severe symptoms and need particularly intensive treatment.
For most individuals, an accurate diagnosis can be reached via the detection of serological antibodies, with RRAs able to detect ARAbs with high specificity and sensitivity.
However, ELISAs are usually utilized to identify MuSK-Abs in seronegative patients, and the correlation between disease severity and antibody concentration enables clinicians to monitor the success of treatment, offering an early warning of a potential relapse.
For the small percentage of people affected by MG that test negative for both MuSK-Abs and ARAbs, ongoing research into novel biomarkers will likely result in new assays being developed in the near future, assisting the robust diagnosis of double- and triple-seronegative MG subtypes.
References and further reading
- Chen, J. et al. Incidence, mortality, and economic burden of myasthenia gravis in China: A nationwide population-based study, The Lancet Regional Health - Western Pacific, Volume 5, 2020, 100063, ISSN 2666-6065, https://doi.org/10.1016/j.lanwpc.2020.100063
- What is seronegative myasthenia gravis? myasthenia-gravis.com. https://myasthenia-gravis.com/seronegative. Accessed 07.08.23
- Myasthenia gravis. Rare Disease Advisor. https://www.rarediseaseadvisor.com/disease-info-pages/myasthenia-gravis-differential-diagnosis/ Accessed 15.09.23
- Rivner, M. H. et al. Muscle-specific tyrosine kinase and myasthenia gravis owing to other antibodies, Neurologic Clinics, Volume 36, Issue 2, 2018, Pages 293-310, ISSN 0733-8619, ISBN 9780323583688, https://doi.org/10.1016/j.ncl.2018.01.004
- Myasthenia gravis workup: Laboratory tests, radiography, CT, and MRI, electrodiagnostic studies. Medscape. https://emedicine.medscape.com/article/1171206-workup. Accessed 07.08.23
- Myasthenia gravis – MG. ARUP Laboratories. https://arupconsult.com/content/myasthenia-gravis. Accessed 07.08.23
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