Clinical Features of LRP4/agrin-antibody-positive Myasthenia Gravis: A Multicenter Study

Overview

Journal Muscle Nerve

Date 2020 Jun 3

PMID 32483837

Citations 27

Authors

Michael H Rivner

Brandy M Quarles

Jin-Xiu Pan

Zheng Yu

James F Howard Jr

Andrea Corse

Mazen M Dimachkie

Carlayne Jackson

Tuan Vu

George Small

Robert P Lisak

Jerry Belsh

Ikjae Lee

Richard J Nowak

Vanessa Baute

Stephen Scelsa

J Americo Fernandes

Zachary Simmons

Andrea Swenson

Richard Barohn

R Bhavaraju Sanka

Clifton Gooch

Eroboghene Ubogu

James Caress

Mamatha Pasnoor

Hongyan Xu

Lin Mei

Affiliations

Soon will be listed here.

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.

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References

Zisimopoulou P, Evangelakou P, Tzartos J, Lazaridis K, Zouvelou V, Mantegazza R . A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun. 2013; 52:139-45. DOI: 10.1016/j.jaut.2013.12.004. View

Higuchi O, Hamuro J, Motomura M, Yamanashi Y . Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol. 2011; 69(2):418-22. DOI: 10.1002/ana.22312. View

Magill-Solc C, McMahan U . Motor neurons contain agrin-like molecules. J Cell Biol. 1988; 107(5):1825-33. PMC: 2115317. DOI: 10.1083/jcb.107.5.1825. View

Tzartos J, Zisimopoulou P, Rentzos M, Karandreas N, Zouvelou V, Evangelakou P . LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014; 1(2):80-7. PMC: 4212481. DOI: 10.1002/acn3.26. View

Beck G, Yabumoto T, Baba K, Sasaki T, Higuchi O, Matsuo H . Double Seronegative Myasthenia Gravis with Anti-LRP4 Antibodies Presenting with Dropped Head and Acute Respiratory Insufficiency. Intern Med. 2016; 55(22):3361-3363. PMC: 5173509. DOI: 10.2169/internalmedicine.55.7030. View

Ohkawara B, Cabrera-Serrano M, Nakata T, Milone M, Asai N, Ito K . LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner. Hum Mol Genet. 2013; 23(7):1856-68. PMC: 3943522. DOI: 10.1093/hmg/ddt578. View

Sanders D, El-Salem K, Massey J, McConville J, Vincent A . Clinical aspects of MuSK antibody positive seronegative MG. Neurology. 2003; 60(12):1978-80. DOI: 10.1212/01.wnl.0000065882.63904.53. View

Kim N, Stiegler A, Cameron T, Hallock P, Gomez A, Huang J . Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell. 2008; 135(2):334-42. PMC: 2933840. DOI: 10.1016/j.cell.2008.10.002. View

Conti-Fine B, Milani M, Kaminski H . Myasthenia gravis: past, present, and future. J Clin Invest. 2006; 116(11):2843-54. PMC: 1626141. DOI: 10.1172/JCI29894. View

10.

Jaretzki 3rd A, Barohn R, Ernstoff R, Kaminski H, KEESEY J, Penn A . Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000; 55(1):16-23. DOI: 10.1212/wnl.55.1.16. View

11.

Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A . Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med. 2001; 7(3):365-8. DOI: 10.1038/85520. View

12.

Karakaya M, Ceyhan-Birsoy O, Beggs A, Topaloglu H . A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop. J Clin Neuromuscul Dis. 2017; 18(3):147-151. PMC: 5436270. DOI: 10.1097/CND.0000000000000132. View

13.

Rodriguez Cruz P, Huda S, Lopez-Ruiz P, Vincent A . Use of cell-based assays in myasthenia gravis and other antibody-mediated diseases. Exp Neurol. 2015; 270:66-71. DOI: 10.1016/j.expneurol.2015.01.011. View

14.

Zhang B, Luo S, Wang Q, Suzuki T, Xiong W, Mei L . LRP4 serves as a coreceptor of agrin. Neuron. 2008; 60(2):285-97. PMC: 2743173. DOI: 10.1016/j.neuron.2008.10.006. View

15.

Nicole S, Chaouch A, Torbergsen T, Bauche S, De Bruyckere E, Fontenille M . Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. Brain. 2014; 137(Pt 9):2429-43. DOI: 10.1093/brain/awu160. View

16.

Yan M, Liu Z, Fei E, Chen W, Lai X, Luo B . Induction of Anti-agrin Antibodies Causes Myasthenia Gravis in Mice. Neuroscience. 2018; 373:113-121. PMC: 5942223. DOI: 10.1016/j.neuroscience.2018.01.015. View

17.

Zouvelou V, Zisimopoulou P, Rentzos M, Karandreas N, Evangelakou P, Stamboulis E . Double seronegative myasthenia gravis with anti-LRP 4 antibodies. Neuromuscul Disord. 2013; 23(7):568-70. DOI: 10.1016/j.nmd.2013.03.013. View

18.

Shen C, Lu Y, Zhang B, Figueiredo D, Bean J, Jung J . Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest. 2013; 123(12):5190-202. PMC: 3859418. DOI: 10.1172/JCI66039. View

19.

Huze C, Bauche S, Richard P, Chevessier F, Goillot E, Gaudon K . Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet. 2009; 85(2):155-67. PMC: 2725239. DOI: 10.1016/j.ajhg.2009.06.015. View

20.

Howard Jr J, Utsugisawa K, Benatar M, Murai H, Barohn R, Illa I . Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017; 16(12):976-986. DOI: 10.1016/S1474-4422(17)30369-1. View