LRP4 antibodies are frequent in serum and CSF from amyotrophic lateral sclerosis patients (S34.004)

OBJECTIVE: To search for LRP4 antibodies in amyotrophic lateral sclerosis (ALS) patients because of the critical role of LRP4 in motor neuron function. BACKGROUND: ALS and myasthenia gravis (MG) are caused, respectively, by motor neuron degeneration and neuromuscular junction dysfunction. LRP4 is crucial in the development and function of neuromuscular junctions and motor neurons. Recently LRP4 autoantibodies have being detected by us and others in ~8[percnt] of the MG sera. DESIGN/METHODS: We developed a sensitive cell-based assay for LRP4 antibodies by which we studied the sera from 191 ALS patients from 3 countries. RESULTS: LRP4 autoantibodies were detected in sera from 37/191 (19.4[percnt]) ALS patients from Greece (12/51), Italy (12/53) and Israel (13/87), whereas only in 5/138 (3.6[percnt]) sera from patients with other neurological diseases and 0/90 sera from healthy controls. The Greek and Italian ALS cohorts were studied further: LRP4 antibodies were persistent in 5/6 tested patients for >10 months. Cerebrospinal fluid from 6/7 tested LRP4 antibody-seropositive ALS patients was also positive. No autoantibodies to AChR and MuSK were detected in ALS patients. No differences in clinical pattern were seen between ALS patients with or without LRP4 antibodies. Differences were seen in the female/male ratio between LRP4-seropositive ALS and MG patients (~1/1 versus ~3/1, respectively) and in the LRP4-antibody IgG subclass (IgG1 in most ALS and IgG1/IgG2 in most MG samples). CONCLUSIONS: We infer that LRP4 autoantibodies are involved in neurological manifestations affecting LRP4-containing tissues and are found more frequently in ALS than in MG. LRP4 antibodies may have a direct pathogenic activity in ALS by participating in the denervation process. The identification of LRP4 autoantibodies in ALS offers a potentially useful biomarker for diagnostic purposes, but much work is needed to investigate the pathogenic potential of these antibodies. Study Supported by: Greek GSRT (program “Aristeia”) Disclosure: Dr. Tzartos has nothing to disclose. Dr. Zisimopoulou has nothing to disclose. Dr. Tsonis has nothing to disclose. Dr. Evangelakou has nothing to disclose. Dr. Rentzos has nothing to disclose. Dr. Karandreas has nothing to disclose. Dr. Zouvelou has nothing to disclose. Dr. Thomaidis has nothing to disclose. Dr. Lauria has nothing to disclose. Dr. Andreetta has nothing to disclose. Dr. Mantegazza has nothing to disclose. Dr. Brenner has nothing to disclose. Dr. Petrou has nothing to disclose. Dr. Karusis has nothing to disclose. Dr. Tzartos has nothing to disclose.