Recent clinical, neuroimaging, sleep, and molecular cytogenetic studies have provided new insights into the mechanisms leading to the Smith-Magenis phenotype and are summarized in this review.
Cross sectional studies of patients with Smith-Magenis syndrome have found evidence for central and peripheral nervous system abnormalities, neurobehavioral disturbances, and an inverted pattern of melatonin secretion leading to circadian rhythm disturbance. A common chromosome 17p11.2 deletion interval spanning approximately 3.5 Mb is identified in about 70% of individuals with chromosome deletion. Recently heterozygous point mutations in the RAI1 gene within the Smith-Magenis syndrome critical region have been reported in Smith-Magenis syndrome patients without detectable deletion by fluorescent in-situ hybridization. Patients with intragenic mutations in RAI1 as well as those with deletions share most but not all aspects of the phenotype.
Findings from molecular cytogenetic analysis suggest that other genes or genetic background may play a role in altering the functional availability of RAI1 for downstream effects. Further research into additional genes in the Smith-Magenis syndrome critical region will help define the role they play in modifying features or severity of the Smith-Magenis syndrome phenotype. More research is needed to translate advances in clinical research into new treatment options to address the sleep and neurobehavioral problems in this disorder.
aDepartment of Neurology, Children's National Medical Center and the George Washington University of the Health Sciences, Washington, DC, USA
bMedical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
cDepartments of Pediatrics and Human Genetics, Virginia Commonwealth University, Richmond, Virginia
dMood and Anxiety Disorders Program, National Institute of Mental Health, NIH, Bethesda, Maryland, USA
eDepartment of Oncology, Georgetown University, Washington, DC, USA
Correspondence to Andrea L. Gropman, MD, FAAP, FACMG, Department of Neurology, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, USA Tel: +1 202 884 3511; fax: +1 202 884 5226; e-mail: firstname.lastname@example.org