Clinical Information

Fatigable weakness due to impaired synaptic transmission at the neuromuscular junction is characteristic of myasthenia gravis (MG). The diagnosis is made by clinical and electromyographic criteria. Positive autoimmune serology must be interpreted in the clinical and electrophysiological context and response to anticholinesterase medication. Most cases are autoimmune and are caused by IgG autoantibodies binding to critical postsynaptic membrane molecules (nicotinic acetylcholine receptor or its interacting proteins, such as muscle-specific kinase: MuSK).(1) Autoantibody detection frequency is lowest in patients with weakness confined to extraocular muscles (71% muscle acetylcholine receptor: AChR binding). Mayo Clinic’s first-line serological evaluation detects muscle AChR antibody in 92% of nonimmunosuppressed patients with generalized weakness due to MG. In adults with MG there is at least a 20% occurrence of thymoma or other neoplasm. If acetylcholine receptor (AChR) modulating antibodies are ≥90% and striational antibodies are ≥1:120, then there is an increased risk of thymoma, and AChR ganglionic neuronal autoantibody, glutamic acid decarboxylase autoantibody, neuronal voltage-gated potassium channel autoantibody, and collapsin response-mediated response-5-IgG may also be detected in that paraneoplastic context.(2)

MuSK antibody is detectable in more than one-third of those seronegative for muscle AChR antibody (<4% of all patients).(3-4) Physiologically, MuSK is involved in integrating and stabilizing AChR clusters in the motor endplate. MuSK is activated when the nerve-derived proteoglycan agrin binds to its receptor, lipoprotein-related protein 4 (LRP4). Antibodies to LRP4 itself have been described in rare patients.(1) Females are generally affected by autoimmune MuSK MG more often than males. Onset can occur at any age (pediatric to elderly). Patients may derive limited benefit from anticholinesterase medication. The thymus is normal, and patients are generally not benefited by thymectomy. Antibody-lowering therapies are effective. Bulbar, facial, and respiratory weakness are prominent, and crises are common.(1,3,4)

Six percent of nonimmunosuppressed patients with generalized MG lack demonstrable AChR or MuSK antibodies (double seronegative). However, as in autoimmune AChR MG and MuSK MG, testing for common organ-specific and nonorgan-specific autoantibodies is a valuable ancillary investigation in evaluating seronegative acquired generalized MG. General serological testing, coupled with family or personal history, will disclose autoimmune phenomena in 77% of those cases.(5) These disorders may include thyroid disease, type 1 diabetes, vitiligo, premature greying, rheumatoid arthritis, or lupus. Objective improvement in strength following a therapeutic trial of plasmapheresis or intravenous immune globulin would justify consideration of long-term immunosuppression.