Melatonin Levels in Smith Magenis Syndrome (SMS)

Unique provision in the American Recovery and Reinvestment Act prevented approval of second year no-cost-extension in which completion of analyses were planned.

The goal of this pilot project is to determine whether melatonin levels are disordered in patients with Smith-Magenis Syndrome (SMS) and whether melatonin treatment can correct abnormal circadian rhythms in SMS patients. In addition, the study investigates the effects of bright light in an elderly control population that exhibits low melatonin secretion.

Participation involves 5 stages for SMS patients. First, Subjects will complete 4 sessions of 25-hour salivary or plasma sampling, with the last sampling occurring in front of a bright light box. Second, subjects will enroll in the melatonin treatment phase, involving a daily dose (up to 3 mg) for up to one year, with frequent (every 2-4 weeks) of 25-hour salivary or plasma sampling. During this stage, the subject and/or caregiver may also be asked to wear an activity wrist monitor, complete a daily sleep diary and behavioral questionnaires. Third, the subject may be asked to complete up to 3 25-hour sampling periods and take a melatonin pill on the same day to test how their body metabolizes the hormone, melatonin. The fourth stage is for subjects who are found to have an abnormal body rhythm. Subjects will complete a 25-hour plasma sampling period under bedrest to test for a hormone, Cortisol. The fifth stage is an optional 12-hour sleep analysis (polysomnography) to test for sleep disorders. Control participants will complete an abbreviated protocol of the 3 baseline 25-hour sampling periods and 1 involving bright light exposure.

Subjects will sit in front of a fluorescent bright light box while completing plasma samples to test for melatonin suppression in blood. This will be completed by both the SMS patient group and the control group of elderly individuals.

Subjects will take up to 3 mg of melatonin daily and will complete frequent (every 2-4 weeks) of saliva and/or plasma sampling to test for a change in the timing of the body clock in response to the melatonin.

Subjects will sit in front of an artificial, fluorescent light box (10,000 lux) while completing 25-hours of hourly plasma samples. The light lux level will be well below that identified as safe by the FDA.

Inclusion Criteria: Control participants: 30 individuals: ages 55-85, healthy without significant active medical problems. SMS patients: 20 individuals: ages 3-50, with a clinical diagnosis of Smith-Magenis Syndrome by a qualified Medical Geneticist, confirmed by cytogenetic analysis documenting deletion of chromosome band 17p11.2. Exclusion Criteria: Control participants: A current Axis I psychiatric or substance abuse disorder according to the DSM-IV Manual, abnormal heart, liver or kidney function, diagnoses of neurodegenerative or cerebrovascular disease (Alzheimer's disease, Parkinson's disease, stroke, etc.), cognitive impairment (Mini-Mental State Score < 23) but without a formal diagnosis of dementia, active symptoms of depression (Geriatric Depression Scale: 30 pt. version > 10), current diagnosis of cataracts, macular degeneration or retinopathy based on eye exam by an optometrist or ophthalmologist within the past year.

De Leersnyder H. Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment. Trends Endocrinol Metab. 2006 Sep;17(7):291-8. doi: 10.1016/j.tem.2006.07.007. Epub 2006 Aug 4.

Potocki L, Glaze D, Tan DX, Park SS, Kashork CD, Shaffer LG, Reiter RJ, Lupski JR. Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J Med Genet. 2000 Jun;37(6):428-33. doi: 10.1136/jmg.37.6.428.