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Published on: October 25, 2018
Seronegative myasthenia gravis
Angela Vincent1, John McConville, Maria Elena Farrugia
1Department of Clinical Neurology, University of Oxford, Oxford, United Kingdom.
Abstract:
Some myasthenia gravis (MG) patients do not have detectable acetylcholine receptor (AChR) antibodies and have been termed "seronegative" (SNMG) in many previous studies. A high proportion of patients with purely ocular symptoms, ocular MG, are seronegative; this may be because the sensitivity of the assay is insufficient to detect low levels of circulating AChR antibodies and because of intrinsic differences in the ocular muscles that make them more susceptible to circulating factors. Seronegative generalized myasthenia is proving to be heterogeneous both clinically and immunologically. Plasma from SNMG patients often contains a factor, probably an immunoglobulin M antibody, that alters AChR function in in vitro assays, but its target is not yet clear. A variable proportion of SNMG patients have antibodies to the muscle-specific tyrosine kinase (MuSK). These antibodies are directed against the extracellular domain of MuSK and inhibit agrin-induced AChR clustering in muscle myotubes. Although the role of these antibodies in causing myasthenic symptoms in vivo has not been elucidated, MuSK antibodies appear to define a group of patients who are often female with bulbar weakness, contrasting with MuSK antibody-negative SNMG patients who are more likely to have generalized weakness. MuSK antibody-positive patients may also differ in the distribution of their electrophysiological abnormalities and their responses to treatments.
Insights
Seronegative myasthenia gravis (MG) is complex, with some patients lacking acetylcholine receptor (AChR) antibodies. Further research reveals distinct immunological and clinical subtypes within this group, including those with muscle-specific tyrosine kinase (MuSK) antibodies.
Area of Science:
- Neurology
- Immunology
- Autoimmune Diseases
Background:
- Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission.
- A subset of MG patients, termed seronegative myasthenia gravis (SNMG), lack detectable acetylcholine receptor (AChR) antibodies.
- Ocular MG frequently presents as seronegative, potentially due to assay sensitivity or ocular muscle susceptibility.
Purpose of the Study:
- To investigate the heterogeneity of seronegative myasthenia gravis (SNMG).
- To explore the immunological and clinical characteristics of SNMG patients.
- To identify potential targets and clinical implications of novel antibodies in SNMG.
Main Methods:
- Analysis of patient plasma for factors affecting AChR function in vitro.
- Detection of antibodies against muscle-specific tyrosine kinase (MuSK).
- Clinical and immunological characterization of distinct SNMG subgroups.
Main Results:
- SNMG plasma may contain immunoglobulin M (IgM) antibodies impacting AChR function, though the target is unclear.
- A subset of SNMG patients possess antibodies against MuSK, inhibiting AChR clustering.
- MuSK antibody-positive SNMG patients often exhibit bulbar weakness and differ clinically and electrophysiologically from MuSK antibody-negative SNMG patients.
Conclusions:
- Seronegative myasthenia gravis is immunologically and clinically heterogeneous.
- Muscle-specific tyrosine kinase (MuSK) antibodies define a distinct subgroup of SNMG with specific clinical features.
- Further research is needed to elucidate the in vivo role of MuSK antibodies and other factors in SNMG pathogenesis.
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