What are the distinguishing characteristics of muscle‑specific kinase (MuSK)‑positive myasthenia gravis compared with acetylcholine‑receptor (AChR) antibody‑positive myasthenia gravis?

Distinguishing Characteristics of MuSK-Positive vs AChR-Positive Myasthenia Gravis

MuSK-positive myasthenia gravis presents with predominantly bulbar, facial, and neck muscle weakness in younger females with poor response to anticholinesterases, while AChR-positive MG shows more generalized limb weakness with better response to standard therapies including pyridostigmine and thymectomy. 1, 2, 3

Demographics and Disease Onset

• MuSK-MG occurs predominantly in females with disease onset typically in the third or fourth decade of life 2, 3, 4
• AChR-MG has a more balanced gender distribution and broader age range of onset, with bimodal peaks in young women and older men 1
• MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype, while AChR-MG associates with different HLA alleles 3

Clinical Presentation and Muscle Distribution

• MuSK-MG demonstrates focal muscle involvement affecting predominantly neck, shoulder, facial, and bulbar-innervated muscles with prominent cranial and bulbar weakness 2, 3, 4, 5
• MuSK-MG patients develop muscle wasting in the involved muscles, which is not a typical feature of AChR-MG 3
• AChR-MG presents with more generalized weakness that is typically more proximal than distal, with variable ocular and bulbar involvement 1
• MuSK-MG patients have a higher rate of myasthenic crises compared to AChR-positive patients 2, 4, 5
• Respiratory muscle involvement is more frequent and severe in MuSK-MG, with more frequent and severe myasthenic crises 5

Antibody Characteristics and Pathophysiology

• MuSK antibodies are predominantly IgG4 subclass, which are monovalent, cannot fix complement, and only weakly bind Fc-receptors 6, 3, 5
• AChR antibodies are predominantly IgG1 and IgG3 subclasses, which are complement-fixing and create different pathogenic mechanisms 6
• MuSK-IgG4 antibodies exert pathogenicity by blocking the MuSK-LRP4 interaction, preventing MuSK activation and leading to dispersal of AChR clusters 5
• AChR antibodies cause complement-mediated destruction of the postsynaptic membrane and receptor internalization 6

Diagnostic Testing Differences

• Repetitive nerve stimulation on conventional limb muscles has lower yield in MuSK-MG, but recording from facial-innervated muscles shows abnormalities in at least three-quarters of patients 2, 4
• Single-fiber EMG of distal limb muscles has lower abnormality rates in MuSK-MG compared to AChR-positive or seronegative MG, but proximal limb or cranial muscle testing shows increased jitter in nearly all MuSK-positive patients 2, 4
• Anti-MuSK antibodies should be tested when AChR antibodies are negative, as approximately one-third of seronegative patients will be MuSK-positive 1, 7
• MuSK antibodies are detected in approximately 40% of generalized AChR antibody-negative MG 2, 4

Treatment Response Differences

Anticholinesterase Agents

• MuSK-MG patients are more likely to display poor tolerance of or lack of improvement with anticholinesterase agents (pyridostigmine), which is not a feature of seronegative or AChR-positive myasthenia 2, 4
• AChR-MG patients typically respond well to pyridostigmine, with approximately 50% showing adequate symptom control 1

Corticosteroids

• Both MuSK-MG and AChR-MG respond to corticosteroids, but MuSK-MG often requires prolonged, high doses that are difficult to taper 6, 5
• AChR-MG shows 66-85% positive response rates to corticosteroids with more manageable tapering 1

Thymectomy

• Thymus involvement is not prominent in MuSK-MG, and evidence for favorable response to thymectomy is limited 2, 6, 3
• Thymectomy should be evaluated in appropriate AChR-positive patients and may substantially reduce symptoms, particularly when thymoma is present (10-20% of AChR-positive cases) 1

B-Cell Targeted Therapies

• MuSK-MG patients respond exceptionally well to rituximab and plasmapheresis with long-term remissions, reflecting the role of short-lived plasma cells in IgG4 autoantibody production 6, 3, 5
• Rituximab produces reduction of antibody titers that follows clinical efficacy in MuSK-MG 6
• AChR-MG patients may also respond to rituximab but this is not the preferred first-line immunosuppressive therapy 1

IVIG

• IVIG is usually less effective in MuSK-MG compared to AChR-MG 6
• IVIG (2 g/kg IV over 5 days) is recommended for Grade 3-4 AChR-positive MG 1

Novel Therapies

• Efgartigimod alfa-fcab is FDA-approved specifically for AChR-positive patients who are refractory to conventional therapy, not for MuSK-MG 1
• Novel therapies for MuSK-MG include FcRn antagonists and CAAR-T cells targeting antigen-specific B cells 6

Disease Course and Prognosis

• A higher proportion of MuSK-MG patients have a refractory course requiring more aggressive immunosuppression 2
• MuSK-MG patients are managed successfully with immunomodulatory therapies, but require more intensive treatment regimens 2
• Approximately 50-80% of AChR-positive patients with initial ocular symptoms develop generalized myasthenia within a few years 1

Critical Clinical Pitfalls

• Do not assume anticholinesterase failure rules out myasthenia gravis—this is characteristic of MuSK-MG and should prompt MuSK antibody testing 2, 4
• Do not perform thymectomy in MuSK-MG patients as thymus involvement is not prominent and evidence for benefit is limited 2, 6, 3
• Avoid testing only distal limb muscles with electrodiagnostic studies in suspected MuSK-MG—include cranial and proximal muscles for higher diagnostic yield 2, 4
• Both MuSK-MG and AChR-MG require avoidance of medications that worsen myasthenia, including β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics 1