Can a rare form of myasthenia gravis shed additional light on disease mechanisms?

A healthy 43-year-old physician developed gradually progressive and fluctuating fatigable muscle weakness involving ocular, limb, bulbar and respiratory muscles, with episodic acute respiratory failure, eventually necessitating intermittent non-invasive respiratory support (NIV). A mild short episode occurred 15 years earlier with complete resolution. Electromyography (EMG) studies and acetylcholine receptor (AchR) antibodies were repeatedly non-diagnostic. The diagnosis of myasthenia gravis (MG) was finally confirmed by direct measurement of diaphragmatic strength using magnetic nerve stimulation providing clear cut evidence of significant fatigable weakness and the demonstration of muscle-specific kinase (MuSK) serum antibodies using a novel cell-based assay. The cluster of several atypical features and lack of response to commonly used treatment modalities prompted a search for a unifying mechanism and better understanding of the underlying pathophysiology. Review of the literature suggested a possible impairment of excitation–contraction coupling with malfunction of a signaling protein downstream to the AchR, without an accompanying impairment of electrical transmission. This postulated mechanism, resulting in a disturbance of calcium signaling, explained the unusual features in this patient's illness and led to treatment with salbutamol and ephedrine and to significant symptomatic improvement not achieved by any other treatment.