Exome sequencing identifies targets in the treatment-resistant ophthalmoplegic subphenotype of myasthenia gravis

Myasthenic ophthalmoparesis: Time To resolution after initiating immune therapies

“…Although the mechanisms of action of prednisone at the myasthenic EOM end plate is unknown, a study in 15 patients with MG assessing the metabolomic response in sera to treatment with low doses of prednisone (∼0.29 mg/kg/day) in the first 12 weeks showed an upregulation of membrane‐associated glycerophospholipids and downregulation of proinflammatory pathways . This is interesting because we have reported that the pathogenetic mechanisms underlying the ophthalmoplegic treatment‐resistant MG subphenotype may, in part, be due to aberrant muscle end plate membrane repair and stability, and specifically gangliosphingolipid metabolism …”

A unique subphenotype of myasthenia gravis

“…Focusing on this group alone in a multicenter study, we showed that, of those with juvenile MG followed on treatment for at least 2 years, treatment‐resistant ophthalmoplegia was only observed among children with African genetic ancestry . Moreover, there was a trend toward the complete OP‐MG subphenotype of MG, in which all 12 EOMs are at least 50% affected, to develop in younger children manifesting with MG compared with patients with postpubertal onset of MG symptoms …”

“…Subsequently, in an audit of hospital‐based clinic records attending to myasthenics younger than 20 years of age, across several South African centers, up to 20% of juvenile MG cases developed treatment‐resistant ophthalmoplegia irrespective of whether the MG was generalized or remained confined to the extraocular muscles (EOMs) . Also, younger children with African genetic ancestry developing MG appear to be at greater risk of developing the most severe manifestation of the OP‐MG subphenotype (see below) …”

“…This racial bias of EOM treatment resistance was evident despite no differences in the immune therapies used or compliance with treatment . Although the timing of treatment initiation was no different among the racial subpopulations and therefore cannot account for OP‐MG's observed racial bias, a subanalysis considering only those with African genetic ancestry showed a significant delay in time to treatment between those who developed OP‐MG and those in whom the ocular manifestations responded to standard treatment . Concomitant thyroid ophthalmopathy was excluded biochemically, with appropriate orbital imaging and unrestricted orbital forced duction testing, and common mitochondrial DNA deletions were excluded using long‐range PCR .…”

On the double: Early immunotherapy speeds recovery of ocular myasthenic weakness

“…Extraocular muscles have fewer prominent synaptic folds and/or lower expressions of complement regulators and may be particularly susceptible to antibody‐mediated injury . Potentially functional gene variants in gangliosphingolipid and myogenesis pathways may also contribute to the ophthalmoplegic subphenotype of selected individuals . These factors represent some of the immunological and genetic reasons why ocular weakness in MG can be refractory and persist after successful treatment of other skeletal muscle weakness.…”