Clinical features of LRP4/agrin‐antibody–positive myasthenia gravis: A multicenter study

Abstract

Introduction Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin‐antibody–positive double‐seronegative myasthenia gravis (DNMG). Methods DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. Results Of 181 DNMG patients, 27 (14.9%) were positive for either low‐density lipoprotein receptor–related protein 4 (LRP4) or agrin antibodies. Twenty‐three DNMG patients (12.7%) were positive for both antibodies. More antibody‐positive patients presented with generalized symptoms (69%) compared with antibody‐negative patients (43%) ( P ≤ .02). Antibody‐positive patients’ maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody‐negative patients ( P ≤ .005). Seventy percent of antibody‐positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody‐negative patients. Most LRP4‐ and agrin‐antibody–positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow‐up of 11 years. Discussion Antibody‐positive patients had more severe clinical disease than antibody‐negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations

“…The binding of agrin to Lrp4 activates MuSK and initiates a cascade of events leading to the aggregation of AChRs in the neuromuscular junction. Lrp4 antibodies are present in 2–50% of double seronegative MG cases [ 6 , 75 , 76 ]. Many Lrp4-MG patients also have antibodies against agrin.…”

“…Many Lrp4-MG patients also have antibodies against agrin. Lrp4 antibodies are mostly of the IgG1/IgG2 subclass and are believed to be directly pathogenic by disrupting the activation of MuSK [ 75 ]. In patients with congenital myasthenic syndromes due to gene mutations in agrin, neuromuscular junctions are less stable and AChRs are more dispersed and un-clustered.…”

“…Patients can present with ocular or generalized MG, but it is believed that symptom severity is overall milder in this subgroup. About 20% have only ocular symptoms after 2 years of disease [ 75 ]. However, patients with a combination of anti-Lrp4 and anti-agrin antibodies may have more severe symptoms [ 75 ].…”

Immunopathology of Autoimmune Myasthenia Gravis: Implications for Improved Testing Algorithms and Treatment Strategies

“…Moreover, high levels of agrinAbs are found among ALS patients ( 60 ), suggesting that the detection of agrinAbs are not specific from a diagnostics standpoint. Furthermore, in a recent study, although most agrin positive patients were presented with severe form of disease, they responded well to standard MG therapy ( 37 ).Thus the clinical utility of routine agrinAbs testing is currently not evident.…”

“…The disease is generally associated with late-onset age, and a milder phenotype with variable thymus pathology ( 35 , 36 ). However, a recent multicentric study demonstrated that LRP4 patients have a more severe presentation than quadruple seronegative MG (negative for AChR, MuSK, LRP4, and agrin) patients ( 37 ). The combination of antibodies to agrin and LRP4 produces more severe symptoms than LRP4 alone ( 37 ).…”