Smith-Magenis Syndrome patients show reduced melanopsin response in the pupillary light reflex

Abstract

Purpose : Smith-Magenis Syndrome (SMS) is a rare disease caused by a deletion (or a point mutation < 10% of the patients) in the gene RAI1 of chromosome 17. This gene plays an important role during the development of the brain. SMS patients show a disrupted sleep pattern caused by an alteration in daily profile of melatonin production that unusually peaks during the day. Here we used pupillometry in order to investigate the sustained component of the pupillary light response (PLR). This component reveals melanopsin activity since it is mediated by melanopsin expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). Among several functions, the ipRGCs contribute to photopic regulation of melatonin and therefore to the regulation of circadian rhythms of sleep.

Methods : PLRs were recorded monocularly (both eyes) in five SMS patients and three controls. A dark adaptation period of 10 minutes preceded PLR recordings in response to 1 second light flashes of different wavelengths: a 640 nm red light, which falls outside the absorption spectrum of melanopsin (no direct activation of the ipRGCs), followed by a 470 nm blue light, which is close to the peak absorption of melanopsin (direct activation of the ipRGCs) at 100 cd/m². A 2 minutes interval between flashes was observed. We analyzed the median amplitude of the sustained component between 5 and 7 seconds after flash presentation. All subjects underwent complete ophthalmological examination. Tests were performed with the RETIport system (Roland Consult, Brandenburg, Germany).

Results : All subjects showed normal fundus. The median amplitude of the sustained component did not differ between patients and controls for the 640 nm red light (relative amplitude of controls = 0.88 ± 0.04 and SMS patients = 0.87 ± 0.05). However, for the 470-nm blue light (with direct activation of the ipRGCs) the sustained component differed between patients and controls (relative amplitude of controls = 0.51 ± 0.04 and SMS patients = 0.64 ± 0.03; p = 0.0002 t-test).

Conclusions : The faster recovery of the pupil diameter after a 470-nm blue light stimulation in SMS patients points to decreased ipRGCs activation. This might be related to lack of photo-inhibition leading to production of melatonin during the day in these patients. Further studies are required to compare the melatonin level during the day and the alteration in the pupillary light response in this population.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.