Melanopsin System Dysfunction in Smith-Magenis Syndrome Patients

Sao Paulo Research Foundation (FAPESP) [2014/26818-2, 2014/50457-0, 2016/04538-3, 2014/06457-5, 2015/22227-2, 2016/22007-5] National Council for Scientific and Technological Development (CNPq) [480428/2013-4, 470785/2014-4, 404239/2016-1] CAPES [3263/2013] Janos Bolyai Scholarship of the Hungarian Academy of Sciences PURPOSE: Smith-Magenis syndrome (SMS) causes sleep disturbance that is related to an abnormal melatonin profile. It is not clear how the genomic disorder leads to a disturbed synchronization of the sleep/wake rhythm in SMS patients. To evaluate the integrity of the intrinsically photosensitive retinal ganglion cell (ipRGC)/melanopsin system, the transducers of the light-inhibitory effect on pineal melatonin synthesis, we recorded pupillary light responses (PLR) in SMS patients. METHODS: Subjects were SMS patients (n = 5), with molecular diagnosis and melatonin levels measured for 24 hours and healthy controls (n = 4). Visual stimuli were 1-second red light flashes (640 nm insignificant direct ipRGC activation), followed by a 470-nm blue light, near the melanopsin peak absorption region (direct ipRGC activation). Blue flashes produce a sustained pupillary constriction (ipRGC driven) followed by baseline return, while red flashes produce faster recovery. RESULTS: Pupillary light responses to 640-nm red flash were normal in SMS patients. In response to 470-nm blue flash, SMS patients had altered sustained responses shown by faster recovery to baseline. SMS patients showed impairment in the expected melatonin production suppression during the day, confirming previous reports. CONCLUSIONS: SMS patients show dysfunction in the sustained component of the PLR to blue light. It could explain their well-known abnormal melatonin profile and elevated circulating melatonin levels during the day. Synchronization of daily melatonin profile and its photoinhibition are dependent on the activation of melanopsin. This retinal dysfunction might be related to a deficit in melanopsin-based photoreception, but a deficit in rod function is also possible. Univ Sao Paulo, Dept Expt Psychol, Inst Psychol, Sao Paulo, Brazil Semmelweis Univ, Dept Ophthalmol, Budapest, Hungary Univ Sao Paulo, Dept Neurol, Fac Med, Sao Paulo, Brazil Budapest Univ Technol & Econ, Dept Mechatron Opt & Engn Informat, Budapest, Hungary Univ Texas San Antonio, Dept Cellular & Struct Biol, San Antonio, TX USA Univ Fed Sao Paulo, Dept Physiol, Sao Paulo, Brazil Univ Sao Paulo, Dept Physiol & Biophys, Inst Biomed Sci, Av Lineu Prestes 1524, BR-05508000 Sao Paulo, SP, Brazil Univ Fed Sao Paulo, Dept Physiol, Sao Paulo, Brazil FAPESP [2014/26818-2, 2014/50457-0, 2016/04538-3, 2014/06457-5, 2015/22227-2, 2016/22007-5] CNPq [480428/2013-4, 470785/2014-4, 404239/2016-1] CAPES [3263/2013] Web of Science