A reformed "release hypothesis" for Marcus Gunn Syndrome, based on newer clinic observations and experimental...

Marcus Gunn Syndrome (MGS), mostly occurring in congenital ptosis patients, is characterized by jaw movement evoking ptotic eyelid retraction, followed by collapse. Inverted, bilateral and acquired MGS were also reported. Some cases manifest MGS only temporarily in life. These features suggest MGS may be due to multiple pathogeneses, which are still unclear. People also classify MGS as a kind of trigeminal oculomotor synkenesis (TOS), like Duane syndrome (DS), in which ocular adduction prompts eyelid moving or eyeball retraction. The most popular hypothesis for TOS is congenital miswiring, as evidence supporting this hypothesis is found in DS cases: hypoplasia abducens nerve fusing with a branch of oculomotor nerve is observed. Seven mutant genes have been identified associated with TOS and two of them are found among MGS cases. Accordingly, these mutant genes may dominate cranial nerve misconnection and generate TOS. However, unlike in DS case, evidence of miswiring is not encountered in most MGS cases. The fact is that two "MGS genes" are from congenital fibrosis of extraocular muscle (CFEOM) cases presenting with associated MGS. But most of MGS cases do not suffer CFEOM. Thus, mutant genes dominated congenital miswiring may not be the pathogenesis for the majority of MGS. As an alternate pathogenic pathway, a "release hypothesis" proposed that MGS is a primitive physiologic reflex that became suppressed during phylogenetic development but could be released under certain pathologic conditions. This hypothesis was and is overlooked because the hypothesized reflex arc has not been defined. Decades ago, a neural tract tracing study in Xenopus revealed a direct projection from masticator afferent mesencephalic trigeminal nucleus (Vme) neurons to oculomotor and trochlear nucleus (III/IV). In clinical studies, co-firing of pterygoid muscle and levator palpebrae was recorded by electromyography during onset of MGS, and stimulating pterygoid muscle nerve elicited eyelid retraction. Recently, retraction of the ipsilateral eyelid by stimulating the trigeminal motor root was even observed in cases without congenital ptosis and MGS, highlighting the existence of a latent pathway. In rats, recently we demonstrated projections from the Vme neurons to the III/IV, and to their premotor neurons in interstitial nucleus of Cajal by neural tract tracing and electrophysiologic studies. Fos expression in pre-oculomotor neurons was induced by repeated down stretching the lower jaw. Combining previous and our own studies, we assumed the Vme neurons is excited when jaw moves and in turn, some eyelid activity related III motoneurons are activated through projections of Vme to oculomotor system, like in Xenopus. Genetic factors may dominate to what extent this primitive reflex-arc is preserved, which consequently determines phenotype.