Dysautonomia as the Presenting Symptom in Anti-Muscle-Specific Kinase Antibody Myasthenia Gravis.

In an minority of Myasthenia Gravis (MG) patients, the autoantibodies bind to muscle-specific kinase (MUSK). These MuSK antibody-mediated MG (MuSK MG) patients are not only immunologically distinct, but also have different characteristic clinical features. Dysautonomia in MG is rarely reported. We present a MuSK MG patient who suffered from life-threatening autonomic dysfunction. MuSK MG should be considered in the differential diagnosis in cases of unclarified dysautonomia, given the potential for treatment in those cases.

Congenital myasthenic syndrome due to mutations in MUSK suggests that the level of MuSK phosphorylation is crucial for governing synaptic structure.

MUSK encodes the muscle-specific receptor tyrosine kinase (MuSK), a key component of the agrin-LRP4-MuSK-DOK7 signaling pathway, which is essential for the formation and maintenance of highly specialized synapses between motor neurons and muscle fibers. We report a patient with severe early-onset congenital myasthenic syndrome and two novel missense mutations in MUSK (p.C317R and p.A617V). Functional studies show that MUSK p.C317R, located at the frizzled-like cysteine-rich domain of MuSK, disrupts an integral part of MuSK architecture resulting in ablated MuSK phosphorylation and acetylcholine receptor (AChR) cluster formation. MUSK p.A617V, located at the kinase domain of MuSK, enhances MuSK phosphorylation resulting in anomalous AChR cluster formation. The identification and evidence for pathogenicity of MUSK mutations supported the initiation of treatment with ß2-adrenergic agonists with a dramatic improvement of muscle strength in the patient. This work suggests uncharacterized mechanisms in which control of the precise level of MuSK phosphorylation is crucial in governing synaptic structure.

Excellent response to therapeutic plasma exchange in myasthenia gravis patients irrespective of antibody status.

INTRODUCTION: The primary objective of this study was to assess response to plasma exchange (PLEX) in myasthenia gravis (MG) patients with and without autoantibodies (Ab) to acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). Analysis was also done to determine if correlation existed between sex, early or late onset MG, thymoma, or thymectomy and response to PLEX. MATERIALS AND METHODS: Data was analyzed on 58 consecutive MG patients treated with PLEX. Responses were categorized as complete response, clinical improvement requiring maintenance PLEX, or no/minimal response to PLEX. RESULTS: Eighty-eight percent (51/58) of patients were Ab-positive; 44 had AChR and 7 had MuSK Ab. Complete response was seen in 26 patients (24 Ab+), 24 remain on maintenance PLEX (19 Ab+), and 2 had no/minimal response (both AChR Ab+). Ab status (P = 0.43), AChR Ab (P = 0.10), MuSK Ab (P = 0.45), early onset MG (P = 0.63), thymoma (P = 0.46), and thymectomy (P = 0.16) were not significantly associated with outcome. Patient sex did show significant association with outcome (P = 0.01), with men more likely to have complete response and women more likely to require maintenance. Late onset MG is significantly associated with higher likelihood of complete response (P = 0.03). Antibody titers declined after PLEX in 83% of patients with complete response, in whom pre- and post-PLEX titers were available (n = 6). CONCLUSIONS: In conclusion, our study showed 96% response rate to PLEX in MG; however, only patient gender and late onset MG were significantly associated with treatment response.

Thymectomy may not be associated with clinical improvement in MuSK myasthenia gravis.

INTRODUCTION: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG. METHODS: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. RESULTS: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19). DISCUSSION: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019.