Anti-LRP4 Myasthenia Gravis

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: In this newly described myasthenia syndrome, an autoantibody against a novel receptor protein is described and clinical features elucidated.

Source: Zouvelou V, et al. Double seronegative myasthenia gravis with anti-LRP4 antibodies. Neuromuscul Disord 2013;23:568-570.

Among patients with Myasthenia Gravis (MG), approximately 80% have serum autoantibodies directed against the nicotinic acetylcholine receptor, 5-10% have autoantibodies directed against the tyrosine kinase muscle-specific kinase (MuSK), and, in the remainder, the autoimmune target is unknown. Recently, antibodies to low-density lipoprotein receptor-related protein 4 (LRP4) have been reported in otherwise seronegative MG patients. What are the clinical characteristics of these patients?

Presenting symptoms and signs of two double seronegative MG patients from Greece, one male and one female, both aged 52 years, with anti-LRP4 antibodies are reported. Dropped head syndrome due to isolated neck extensor weakness of 1 month’s duration was the presenting symptom in the former, whereas 3 months of fluctuating diplopia and neck pain, nasal speech, neck extensor weakness (MRC 4/5), fatigue-induced diplopia and ptosis on examination were the presenting findings in the latter. Both patients improved with rest and worsened with fatigue. Both presented with mild symptoms, and neither had a family history of myasthenia. Repetitive nerve stimulation was positive in the former, and single-fiber electromyography of the deltoid and orbicularis oculi, respectively, was positive in both. Pyridostigmine produced improvement in both, and the latter underwent thymectomy for residual thymic tissue found on CT of the mediastinum, revealing follicular hyperplasia. LRP4 antibodies may describe a new subgroup of MG patients. Larger groups of such patients will be required to clarify this and other LRP4-MG related questions.

Commentary

Neuromuscular synapse formation is a complex, multistep process between motor nerves and muscle fibers, resulting in the high concentration of acetylcholine receptors perfectly arrayed opposite active zones of the presynaptic nerve terminal. Agrin, a motor neuron-derived ligand, and MuSK, a receptor tyrosine kinase expressed in skeletal muscle, are central to this process. Synapses do not form in their absence, but they do not directly interact. LRP4 has been identified as a receptor for agrin, and its binding of agrin is required to stimulate MuSK phosphorylation, a necessary step for pre- and post-synaptic differentiation, including the aggregation of acetylcholine receptors in the junctional plasma membrane. Evidence suggests that LRP4 self-associates with MuSK, and that this complex is then conformationally altered by agrin, reorienting adjacent MuSK molecules, stimulating MuSK phosphorylation. LRP4, agrin, and MuSK are also expressed in the central nervous system where they may have a role analogous to that at the neuromuscular synapse. It remains to be determined whether LRP4 antibodies play a pathogenic role in otherwise seronegative MG patients, or whether they are merely biological markers of the disease. It is also unclear how LRP4 autoantibodies would impair neuromuscular transmission and cause muscle weakness in MG patients. Meanwhile, efforts to develop a convenient assay appropriate for the routine diagnosis of LRP4-MG are in progress.