Treatment Strategies for Children With Smith-Magenis Syndrome

Launched by NATIONAL HUMAN GENOME RESEARCH INSTITUTE (NHGRI) · Jul 21, 2007

Keywords

ClinConnect Summary

Smith-Magenis syndrome (SMS) is a rare (1/25,000) clinically recognizable syndrome, characterized by the following features: a distinct pattern of minor craniofacial and skeletal anomalies, expressive speech/language delays, psychomotor and growth retardation, and a striking neurobehavioral phenotype. This phenotype includes stereotypies, self-injurious and aggressive behaviors, and a chronic sleep disorder associated with an inverted circadian melatonin rhythm. Sleep disturbances include daytime sleepiness, early sleep onset, and early morning awakening. Disturbed sleep is the strongest pr...

Gender

ALL

Eligibility criteria

• * INCLUSION CRITERIA:
• • SMS subjects enrolled in protocol 01-HG-0109 will be invited to participate in this study. Protocol 01-HG-0109 has approximately 90 SMS subjects.
• • SMS inpatient admissions for the dTR-MT trial will be deferred until the BL study completes 10 SMS subjects who demonstrate expected SMS inverted diurnal MT profiles at baseline (T0).
• SMS Subjects (N=12-15 per each treatment goal; 60 total enrollment):
• • Male and female, childhood (average 5-16 years old; under age 5 years on case-by-case basis), all ethnicities with confirmed diagnosis of SMS (del 17p11.2). In some cases, molecular cytogenetic FISH screening (RAI1 FISH probe) may be required to confirm the SMS diagnosis prior to enrollment.
• • Prepubertal (less than or equal to Tanner stage II).
• • No history of seizures
• • Priority will be given to subjects who are medication free and/or willing to discontinue sleep/behavioral medications during the study trial. We anticipate significant interest from families whose children are currently enrolled in the 01-HG-0109 protocol. We will also consider drug-free new referrals (self-referrals and/or via health care providers) eligible for enrollment.
• • Documented sleep disturbance (by sleep log diary and/or actigraphy).
• • Unaffected Healthy Control Subjects (N=15). The pharmacokinetics of melatonin release by the dTR tablet will be evaluated in unaffected healthy control subjects prior to use in the inpatient SMS trial.
• • Males and females of any ethnicity and between the ages 18-45 years.
• • Regular (11PM - 7AM) sleep schedule for at least 1 week prior to study.
• • Non-smokers, who have no history of seizures.
• • Willing to discontinue coffee consumption for a period of 1-2 weeks prior to trial.
• • BMI within normal limits (10-90 percentile).
• • Unaffected with SMS.
• EXCLUSION CRITERIA:
• SMS Subjects:
• • Inability to obtain informed consent.
• • Failure to confirm clinical diagnosis of SMS by standard molecular cytogenetic (FISH) methods and/or DNA-based mutation analysis of RAI1 gene.
• • Retinal diseases: macular degeneration, retinitis pigmentosa, diabetes, cataracts.
• • Skin disease: Lupus (lupus erythematosis), history of skin cancer, history of adverse reaction(s) to sun (rash, reddening).
• • Medications that are photosensitizing: Phenothiazines (Thorazine, Stelazine), Imipramine (AD), Porphyrins (antitumor), Chloroquine (antimalarial), Hydrocholorthiazine (antihypertensive, diuretic), Lithium (mood stabilizer) and/or antibiotics (Tetracycline).
• • SMS subjects with extensive medication use may be excluded, depending on medications used and whether or not discontinuing medications for the trial presents a significant health risk. These include medications that might affect daytime vigilance (e.g., some seratonin antagonists such as Trazadone, SSRIs) and/or MAOIs, and/or antipsychotics (Risperidone), and/or some SSRIs (e.g., fluvoxamine) that affect the metabolism of melatonin and/or are strong CYP1A2 inhibitors.
• Healthy Adult Controls:
• • Individuals who have been diagnosed with a sleep disorder (e.g, restless legs, sleep apnea) known to impact sleep may be excluded at the discretion of the PI.
• • Not willing to discontinue caffeine consumption (chocolate, coffee, tea) during study period.
• • Persons with extensive medication use may be excluded, depending on medications used and whether or not discontinuing medications for the trial presents a significant health risk. These include medications that might affect daytime vigilance (e.g., some seratonin antagonists such as Trazadone, SSRIs) and/or MAOIs, and/or antipsychotics (Risperidone), and/or some SSRIs (e.g., fluvoxamine) that affect the metabolism of melatonin and/or are strong CYP1A2 inhibitors.
• • Employed on a shift work schedule.
• • Transmeridian travel within the last 2 weeks.
• • Currently using melatonin.
• • Women currently taking oral contraceptives (BCPs)
• • Pregnant women and/or nursing mothers