Multi-disciplinary study of Smith-Magenis syndrome
Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation (MCA/MR) syndrome associated with deletion of chromosome 17 band p11.2. As part of a multi-disciplinary clinical, cytogenetic, and molecular approach to SMS, detailed clinical studies including radiographic, neurologic, developmental, ophthalmologic, otolaryngologic, and audiologic evaluations were performed on 27 SMS patients. Significant findings include otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65%, brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal anomalies (especially duplication of the collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20-78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. The frequency of these many abnormalities in SMS suggests that patients should be evaluated thoroughly for associated complications both at the time of diagnosis and at least annually thereafter.
[Show description] [Hide description] DESCRIPTION: Duplication of 17(p11.2p11.2) in a Male Child With Autism and Severe Language Delay
- "the majority mediated by non-allelic homologous recombination between flanking lowcopy repeat sequences termed proximal and distal SMS-REPs [Bi et al., 2003 and Fig. 1]. The SMS neurobehavioral phenotype is variable but consistently includes language delay, hyperactivity, mild to moderate mental retardation (MR), a severe sleep disturbance, self-hugging, and self-injurious beha- vior [Finucane et al., 1994; Greenberg et al., 1996; This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http:Dykens et al., 1997; Madduri et al., 2006]. On the other hand, patients with chromosome 17(p11.2p11.2) duplications corresponding to the SMS deletion interval do not exhibit self-injurious behavior, or self-hugging, but do exhibit expressive language delay and symptoms of autism, obsessive-compulsive disorder, and attention deficits [Kozma et al., 1991; Brown et al., 1996; Potocki et al., 2000; Moog et al., 2004]. "
[Show abstract] [Hide abstract] ABSTRACT: A quantitative long-term fluid consumption and fluid-licking assay was performed in two mouse models with either an ∼2 Mb genomic deletion, Df(11)17, or the reciprocal duplication copy number variation (CNV), Dp(11)17, analogous to the human genomic rearrangements causing either Smith-Magenis syndrome [SMS; OMIM #182290] or Potocki-Lupski syndrome [PTLS; OMIM #610883], respectively. Both mouse strains display distinct quantitative alterations in fluid consumption compared to their wild-type littermates; several of these changes are diametrically opposing between the two chromosome engineered mouse models. Mice with duplication versus deletion showed longer versus shorter intervals between visits to the waterspout, generated more versus less licks per visit and had higher versus lower variability in the number of licks per lick-burst as compared to their respective wild-type littermates. These findings suggest that copy number variation can affect long-term fluid consumption behavior in mice. Other behavioral differences were unique for either the duplication or deletion mutants; the deletion CNV resulted in increased variability of the licking rhythm, and the duplication CNV resulted in a significant slowing of the licking rhythm. Our findings document a readily quantitated complex behavioral response that can be directly and reciprocally influenced by a gene dosage effect. © 2012 Wiley Periodicals, Inc.
- "Diagnostic neuroimaging revealed potential neuroanatomic anomalies in SMS patients, including a reduced volume of the cerebellar vermis [Greenberg et al., 1996]. No neuroimaging data of PTLS patients has been reported. "
[Show abstract] [Hide abstract] ABSTRACT: Smith-Magenis Syndrome (SMS) is a complex genomic disorder mostly caused by the haploinsufficiency of the Retinoic Acid Induced 1 gene (RAI1), located in the chromosomal region 17p11.2. In a subset of SMS patients, heterozygous mutations in RAI1 are found. Here we investigate the molecular properties of these mutated forms and their relationship with the resulting phenotype. We compared the clinical phenotype of SMS patients carrying a mutation in RAI1 coding region either in the N-terminal or the C-terminal half of the protein and no significant differences were found. In order to study the molecular mechanism related to these two groups of RAI1 mutations first we analyzed those mutations that result in the truncated protein corresponding to the N-terminal half of RAI1 finding that they have cytoplasmic localization (in contrast to full length RAI1) and no ability to activate the transcription through an endogenous target: the BDNF enhancer. Similar results were found in lymphoblastoid cells derived from a SMS patient carrying RAI1 c.3103insC, where both mutant and wild type products of RAI1 were detected. The wild type form of RAI1 was found in the chromatin bound and nuclear matrix subcellular fractions while the mutant product was mainly cytoplasmic. In addition, missense mutations at the C-terminal half of RAI1 presented a correct nuclear localization but no activation of the endogenous target. Our results showed for the first time a correlation between RAI1 mutations and abnormal protein function plus they suggest that a reduction of total RAI1 transcription factor activity is at the heart of the SMS clinical presentation.
- "Smith-Magenis syndrome (SMS, OMIM #182290) is a genomic disorder associated with a microdeletion at chromosome 17 band p11.2 with an estimated prevalence of 1∶15,000–1∶25,000 live births , . The clinical characteristics include behavioral problems, sleep abnormalities, intellectual disability, speech delay, growth retardation, brachycephaly, midface hypoplasia, prognathism and hoarse voice, among others , . "