Myasthenia Gravis Support Group
Myasthenia gravis (MG) is a neuromuscular disease leading to fluctuating muscle weakness and fatiguability. The hallmark of myasthenia gravis is muscle weakness that increases during periods of activity and improves after periods of rest. Although myasthenia gravis may affect any voluntary muscle, muscles that control eye and eyelid movement, facial expression, and...
Below is some information for those individuals who are seronegative. I just came across this information while doing some research this morning.
I hope this is helpful for any of you still looking for diagnosis.
Bruce
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Journals@Ovid Full Text Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis.
Pevzner, Alexandra 1; Schoser, Benedikt 2; Peters, Katja 1; Cosma, Nicoleta-Carmen 1; Karakatsani, Andromachi 1; Schalke, Berthold 3; Melms, Arthur 4; Kroger, Stephan 1
Journal of Neurology. 259(3):427-435, March 2012.
[Article.][Original Communication: PDF Only]
AN: 00005068-201203000-00004.
AB : Myasthenia gravis (MG) is an autoimmune disorder characterized by a defect in synaptic transmission at the neuromuscular junction causing fluctuating muscle weakness with a decremental response to repetitive nerve stimulation or altered jitter in single-fiber electromyography (EMG). Approximately 80% of all myasthenia gravis patients have autoantibodies against the nicotinic acetylcholine receptor in their serum. Autoantibodies against the tyrosine kinase muscle-specific kinase (MuSK) are responsible for 5-10% of all myasthenia gravis cases. The autoimmune target in the remaining cases is unknown. Recently, low-density lipoprotein receptor-related protein 4 (LRP4) has been identified as the agrin receptor. LRP4 interacts with agrin, and the binding of agrin activates MuSK, which leads to the formation of most if not all postsynaptic specializations, including aggregates containing acetylcholine receptors (AChRs) in the junctional plasma membrane. In the present study we tested if autoantibodies against LRP4 are detectable in patients with myasthenia gravis. To this end we analyzed 13 sera from patients with generalized myasthenia gravis but without antibodies against AChR or MuSK. The results showed that 12 out of 13 antisera from double-seronegative MG patients bound to proteins concentrated at the neuromuscular junction of adult mouse skeletal muscle and that approximately 50% of the tested sera specifically bound to HEK293 cells transfected with human LRP4. Moreover, 4 out of these 13 sera inhibited agrin-induced aggregation of AChRs in cultured myotubes by more than 50%, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that LRP4 is a novel target for autoantibodies and is a diagnostic marker in seronegative MG patients. (C) 2012 Springer. Part of Springer Science Business Media
I hope this is helpful for any of you still looking for diagnosis.
Bruce
________________________________________________________
Journals@Ovid Full Text Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis.
Pevzner, Alexandra 1; Schoser, Benedikt 2; Peters, Katja 1; Cosma, Nicoleta-Carmen 1; Karakatsani, Andromachi 1; Schalke, Berthold 3; Melms, Arthur 4; Kroger, Stephan 1
Journal of Neurology. 259(3):427-435, March 2012.
[Article.][Original Communication: PDF Only]
AN: 00005068-201203000-00004.
AB : Myasthenia gravis (MG) is an autoimmune disorder characterized by a defect in synaptic transmission at the neuromuscular junction causing fluctuating muscle weakness with a decremental response to repetitive nerve stimulation or altered jitter in single-fiber electromyography (EMG). Approximately 80% of all myasthenia gravis patients have autoantibodies against the nicotinic acetylcholine receptor in their serum. Autoantibodies against the tyrosine kinase muscle-specific kinase (MuSK) are responsible for 5-10% of all myasthenia gravis cases. The autoimmune target in the remaining cases is unknown. Recently, low-density lipoprotein receptor-related protein 4 (LRP4) has been identified as the agrin receptor. LRP4 interacts with agrin, and the binding of agrin activates MuSK, which leads to the formation of most if not all postsynaptic specializations, including aggregates containing acetylcholine receptors (AChRs) in the junctional plasma membrane. In the present study we tested if autoantibodies against LRP4 are detectable in patients with myasthenia gravis. To this end we analyzed 13 sera from patients with generalized myasthenia gravis but without antibodies against AChR or MuSK. The results showed that 12 out of 13 antisera from double-seronegative MG patients bound to proteins concentrated at the neuromuscular junction of adult mouse skeletal muscle and that approximately 50% of the tested sera specifically bound to HEK293 cells transfected with human LRP4. Moreover, 4 out of these 13 sera inhibited agrin-induced aggregation of AChRs in cultured myotubes by more than 50%, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that LRP4 is a novel target for autoantibodies and is a diagnostic marker in seronegative MG patients. (C) 2012 Springer. Part of Springer Science Business Media
YEAH for future double negatives and YEAH for this test that will make getting treatment easier and faster for them!
Thank you Bruce!
(No matter the statistics, if you have it, it is 100%, no one was ever 3% pregnant.)
b.
There are blood tests for two types of autoantibodies that have been discovered to be associated with dysfunction (MG) at the neuromyojunction. The common one attaches to receptors on the muscle so the messenger, acetylcholine, can't get through.
MuSK is an important protien in forming those receptors to begin with and probably maintaining and repairing them, because if it is attacked the receptors look different under the electron microscope and people who have the antibodies to MuSK have MG.
LRP4 is a protien that takes things back another step. It attaches to another protien (agrin) and this activates MuSK so it can do its job.
So they checked for antibodies to this protein in people who were negative for the other two autoantibodies, but who were diagnosed with MG (how, would be described in the article) and found out that 12 of 13 had antibodies to LRP4.
The rest of the stuff describes the testing they did to show that antibodies to LRP4 could actually cause changes to the receptors and therefore be a cause of problems as well as a marker for MG.
I hope that is clear and accurate. b.
(And thank-you Beth, for the explanation!)
This is indeed good news.
Thanks to all of you - who track the technical journals!
Here's hoping, Cathi - a test will be developed soon!
- Ross
The following is a paper from the Japanese group who looked at about 300 non-AChR patients and found the LRP4 antibody turned up in patients with MusK antibodies as well as those those serogegative for both AChR and MusK antibodies. There is actually no evidence to suggest that the antibodies are not also present in a significant proportion of patients with AChR antibodies.
http://www.viverelamiastenia.it/file/Lrp4_JAP.pdf
The focus in Europe is rather diffrent in that they have been looking at these antibodies in congenital myasthenia and have been using diaminopyridine to try to treat the condition. I don't think that is available in the US for standard MG though.
It has been suggested that the mechanism by which the statins make MG a bit worst in about a quater of the patients taking one works though this pathway but I could not find any real evidence for this.
Maybe more will come out in the meetings, but do you know anything about why the large discrepancy between 12 out of 13 and 9 out of 300?
b?
It is possible that the study from March had a different method or assay...
http://archneur.ama-assn.org/cgi/content/abstract/69/4/445
debra
Thanks for sharing this additional information. It is good to know that research is being done for the seronegative MG patients.
Hopefully more information may be forthcoming from this week's MG conference.
Bruce