Alteration of eye movement due to muscle weakness is not uncommon among patients with myasthenia gravis (MG). But now researchers at University of Cape Town (UCT) have identified the main characteristics of patients with juvenile-onset MG and of African genetic ancestry who present ocular manifestations associated with MG and do not respond to available therapies.
In the study titled “A unique subphenotype of myasthenia gravis,” published recently at Annals of the New York Academy of Sciences, Jeannine M. Heckmann, associate professor in neurology at UCT, and Melissa Nel, clinical researcher at division of neurology at UCT, reviewed the clinical characteristics and management of treatment-resistant ophthalmoplegic MG (OP-MG).
According to hospital-based clinic records across several South African centers, up to 20 percent of juvenile MG cases present with treatment-resistant paralysis or weakness (ophthalmoplegia) of the muscles that control the eyes.
Presence of antibodies for acetylcholine receptor (AChR) has been reported previously to mediate the development to ophthalmoplegia. Following this observation, the majority of OP-MG cases had detectable levels of AChR antibodies, although this aggressive ocular manifestation also was found in patients positive for muscle-specific tyrosine kinase (MuSK) antibodies, and in patients negative for AChR, MuSK, and LDL receptor related protein 4 (LRP4) antibodies. These observations suggest that the underlying mechanism of OP-MG is complex and not confined to autoimmune-mediated damage that commonly characterizes the disease, the researchers wrote.
OP-MG has been reported mainly among Africans in the south of the continent, with only one report giving notice of similar treatment-resistant ophthalmoplegia in a subset of Korean children with ocular MG. This restricted incidence may indicate that OP-MG may be associated with genetic risk factors.
Ocular motility in OP-MG varies among patients. Some may show involuntary, brief movements of the eye before it stops at its endpoint, others may show only slow moments through a limited trajectory. In a few patients no clinically detectable dynamic eye movements at all can be detected.
In contrast with other ocular manifestations of MG, OP-MG patients fail to respond to immunotherapy in terms of ocular movement improvement. Patients may initially show some improvements. However, they end up developing delayed severe ophthalmoplegia from which they cannot recover upon a few rounds of therapy. It is still unclear what triggers the non-responsiveness to treatment.
To add knowledge on OP-MG the researchers conducted an unbiased genetic analysis of patients with OP-MG, and compared their genetic profiles with those of patients with MG, but no ophthalmoplegia.
They identified four genetic mutations that were associated with OP-MG. These were affecting genes involved in signaling pathways of muscular tissue formation and gangliosphingolipid biosynthesis, both related to ocular muscle function and stability.
OP-MG can cause substantial visual disability. Surgical elevation of the upper eyelid can help patients, but also may lead to complications such as inability to close and protect the eye against drying and abrasions. Still, such treatment strategy can be applied only in cases of MG remission.
“The management of OP-MG is an unmet need,” the researchers wrote. “To enable the discovery of new treatment approaches in the management of OP-MG, it is critical to understand the pathogenic mechanisms underlying the OP-MG subphenotype.”