MG would seem to be due to a reduced number of acetylcholine receptors (AChR) at the postsynaptic muscle membrane due to circulating anti-AChR antibodies, or may be due to antibodies to muscle-specific tyrosine kinase (anti-MuSK), LRP4
, and agrin.
However, testing for antibodies against lowdensity lipoprotein receptor-related protein 4 (LRP4
) gave weakly positive results in a cell-based indirect immunofluorescence assay in an independent external laboratory (Medizinisches Versorgungszentrum Labor Volkmann Karlsruhe, Karlsruhe, Germany).
It will be placebo-controlled and will evaluate the efficacy of a 10 mg/kg dose of efgartigimod in gMG patients, including both acetylcholine receptor (AChR) autoantibody positive and AChR autoantibody negative patients whose disease is driven primarily by MuSK and LRP4
autoantibodies, over a period of 26 weeks.
More recently, Lrp4
, which resembles the Wnt coreceptors Lrp5/6 in structure, has been established as an important mediator of the effects of sclerostin.
Klooster et al., "MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4
," Proceedings of the National Academy of Sciences of the United States of America, vol.
Currently, gene defects that influence the development and maintenance of NMJ are assigned to a separate group of the CMS and rank second in the disease causes following defects of the acetylcholine receptors (AChRs).[sup] These genes include RAPSN , DOK7 , LRP4
, MUSK , and AGRN .[sup], Agrin, encoded by AGRN , is a cell-specific heparan sulfate proteoglycan generated by alternative splicing.
However, the seronegative MG is also an autoimmune condition, but lack of antibody positivity is presumed to be due to an insensitivity of the commercial assay to detect antibodies or presence of antibodies towards other antigen particles , in the neuromuscular junction, such as cortactin antibodies , low-density lipoprotein receptorrelated protein 4 (Lrp4
) , and anti-striated muscle antibodies (a-SM) not measured by the commercial assay.
Myasthenia gravis could be classified according to the antibody specificity [acetylcholine receptor (AChR), muscle-specific receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4
), and seronegative], age at onset (in children; aged less than or more than 50 years), type of course (ocular or generalized), and thymus histology (thymitis, thymoma, and atrophy) .
A total of 11.4% polymorphisms (25/220 SNPs) within the below listed 9 genes were found to have a statistically different distribution between cases and controls: NRC31, ANKH, VDR, ROR2, CALCR, IL6, COL1A2, CBG, and LRP4
. Seventeen genetic variants were associated with an increased SF risk (9 SNPs and 8 haplotypes) and eight variants--were associated with a decreased SF risk (7 SNP and 1 haplotype) as detailed in Table 2.
As a first step in laying down the junction, motor neurons release the protein agrin, which reaches out to LRP4
, a protein on the muscle cell surface.
Zelcer's team has shown that Idol does not affect protein concentrations of ABCA1, transferrin receptor, or some LDLR family proteins, i.e., lipoprotein receptor-related protein 4 (LRP4
), sorting protein-related receptor (SorLA), and apolipoprotein E receptor (ApoER).