Smith-Magenis syndrome (SMS) is a
mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features, and congenital anomalies ascribed to an interstitial deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptive daytime behavior have been linked to an abnormal circadian rhythm of
melatonin with a diurnal instead of nocturnal secretion of this
hormone. SMS provides a demonstration of a
biological basis for
sleep disorder in a
genetic disease. Considering that clock genes mediate the generation of circadian rhythm, haploinsufficiency for a circadian system gene, mapping to chromosome 17p11.2, may cause the inversion of the
melatonin circadian rhythm in SMS. The disorder of circadian timing in SMS may also affect entrainment pathway (retinohypothalamic tract), pacemaker functions (suprachiasmatic nuclei), or synthesis and release of
melatonin by the pineal gland. Elucidating pathophysiological mechanisms of behavioral phenotypes in
genetic disease can provide an original therapeutic approach in SMS: blockade of endogenous
melatonin production during the day combined with exogenous
melatonin administration in the evening.