Multi-disciplinary study of Smith-Magenis syndrome
ABSTRACT 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.
- SourceAvailable from: Paulina Carmona-Mora
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- "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 , . "
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.PLoS ONE 09/2012; 7(9):e45155. DOI:10.1371/journal.pone.0045155 · 3.23 Impact Factor
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- "The level of his verbal abilities is relatively high. He demonstrates particular Smith–Magenis syndrome-like spectrum of behavioral abnormalities with hyperactivity, abnormal interpersonal relations, aggressiveness, self-destructive behavior, including onychotillomania and trichotillomania, and polyembolokoilomania [Greenberg et al., 1996]. Sleep disturbances with anxiety and nocturnal cry were noted from early childhood. "
ABSTRACT: The development of midbrain dopamine (DA) neurons is regulated by several transcription factors, including Nurr1, Wnt1, Lmx1a/1b, En1, En2, Foxa1, Foxa2, and Pitx3. PITX3 is an upstream co-activator of the TH (tyrosine hydroxylase) promoter. Pitx3(-/-) mice have a selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to the significantly reduced DA levels in the nigrostriatal pathway and in the dorsal striatum and manifest anomalous striatum-dependent cognitive impairment and neurobehavioral activity. Treatment with L-DOPA, dopamine, or dopamine receptor agonists in these mice reversed several of their sensorimotor impairments. Heterozygous missense mutations in PITX3 have been reported in patients with autosomal dominant congenital cataract and anterior segment (ocular) mesenchymal dysgenesis (ASMD) whereas homozygous missense mutations have been found in patients with microphthalmia and neurological impairment. Using a clinical oligonucleotide array comparative genomic hybridization (aCGH), we have identified an ∼317 kb hemizygous deletion in 10q24.32, involving PITX3 in a 17-year-old male with a Smith-Magenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior. Interestingly, no eye anomalies were found in our patient. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of our patient has led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2012; 159B(2):236-42. DOI:10.1002/ajmg.b.32020 · 3.42 Impact Factor
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- "The phenotype is characterized by distinctive craniofacial and skeletal features [Tomona et al., 2006]. The involvement of central nervous system is expressed by hypotonia, cognitive and mental retardation, stereotypes, behavioral problems , and sleep disorders [Greenberg et al., 1996; Girirajan et al., 2006; Gropman et al., 2007]. Almost 100% of patients with SMS present sleep disorders, which consist in abnormalities of the circadian sleep–wake rhythm and in disruption of REM sleep [Gropman et al., 2007; Elsea and Girirajan, 2008]. "
ABSTRACT: We describe a 2-year-old baby affected by Smith-Magenis syndrome (SMS), due to 17p11.2 deletion, who presented repeated episodes of hemoglobin desaturation during REM sleep. The boy, aged 14 months, presented a phenotype characterized by psychomotor delay, right posterior plagiocephaly, telecanthus, strabismus, upslanting palpebral fissures, broad hypoplastic nasal bridge, short philtrum, deep ring shaped skin creases around the limbs, proximal syndactyly, bilateral hypoacusia. Polysomnographic (PSG) recording showed episodes of REM-related hypoventilation (hemoglobin desaturations without apneas or hypopneas). Sleep disorders are present in almost all the cases of SMS, but very few reports describe the sleep-related respiratory patterns. The finding of REM hypoventilation in SMS does not allow an unequivocal interpretation. It could reflect a subclinical restrictive respiratory impairment or, alternatively, an impairment of central respiratory control during REM sleep. In SMS children, respiratory abnormalities during sleep, and in particular during REM sleep, may cause sleep disruption, reduction of time spent in REM sleep, and daytime sleepiness. We therefore suggest that some sleep abnormalities described in SMS could be consequent to Sleep Disordered Breathing, and in particular to REM hypoventilation. Sleep studies in SMS should include the recording of respiratory parameters.American Journal of Medical Genetics Part A 03/2010; 152A(3):708-12. DOI:10.1002/ajmg.a.32700 · 2.16 Impact Factor