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Genes Feb 2022Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical... (Review)
Review
Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions (90%), encompassing multiple genes and including the retinoic acid-induced 1 gene (), or by pathogenic variants in itself (10%). is a dosage-sensitive gene expressed in many tissues and acting as transcriptional regulator. The majority of individuals exhibit a mild-to-moderate range of intellectual disability. The behavioral phenotype includes significant sleep disturbance, stereotypes, maladaptive and self-injurious behaviors. In this review, we summarize current clinical knowledge and therapeutic approaches. We further discuss the common biological background shared with other conditions commonly retained in differential diagnosis.
Topics: Humans; Intellectual Disability; Smith-Magenis Syndrome; Trans-Activators; Transcription Factors
PubMed: 35205380
DOI: 10.3390/genes13020335 -
Handbook of Clinical Neurology 2013Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features, and congenital anomalies ascribed to an... (Review)
Review
Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features, and congenital anomalies ascribed to an interstitial deletion of chromosome 17p11.2. Severe sleep disturbances and maladaptive daytime behavior have been linked to an abnormal circadian rhythm of melatonin with a diurnal instead of nocturnal secretion of this hormone. SMS provides a demonstration of a biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate the generation of circadian rhythm, haploinsufficiency for a circadian system gene, mapping to chromosome 17p11.2, may cause the inversion of the melatonin circadian rhythm in SMS. The disorder of circadian timing in SMS may also affect entrainment pathway (retinohypothalamic tract), pacemaker functions (suprachiasmatic nuclei), or synthesis and release of melatonin by the pineal gland. Elucidating pathophysiological mechanisms of behavioral phenotypes in genetic disease can provide an original therapeutic approach in SMS: blockade of endogenous melatonin production during the day combined with exogenous melatonin administration in the evening.
Topics: Adult; Child; Humans; Male; Sleep Wake Disorders; Smith-Magenis Syndrome
PubMed: 23622179
DOI: 10.1016/B978-0-444-52891-9.00034-8 -
European Journal of Human Genetics :... Apr 2008Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder caused by haploinsufficiency of the retinoic acid-induced 1 (RAI1) gene on chromosome 17p11.2.... (Review)
Review
Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder caused by haploinsufficiency of the retinoic acid-induced 1 (RAI1) gene on chromosome 17p11.2. Diagnostic strategies include molecular identification of a 17p11.2 microdeletion encompassing RAI1 or a mutation in RAI1. G-banding and fluorescent in situ hybridization (FISH) are the classical methods used to detect the SMS deletions, while multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR are the newer, cost-effective, and high-throughput technologies. Most SMS features are due to RAI1 haploinsufficiency, while the variability and severity of the disorder are modified by other genes in the 17p11.2 region. The functional role for RAI1 is not completely understood, but it is likely involved in transcription, based on homology and preliminary studies. Management of SMS is primarily a multidisciplinary approach and involves treatment for sleep disturbance, speech and occupational therapies, minor medical interventions, and management of behaviors.
Topics: Abnormalities, Multiple; Chromosomes, Human, Pair 17; Craniofacial Abnormalities; Humans; Intellectual Disability; Syndrome; Trans-Activators; Transcription Factors
PubMed: 18231123
DOI: 10.1038/sj.ejhg.5202009 -
CNS Drugs Jul 2020Smith-Magenis syndrome is a genetic disorder caused by a microdeletion involving the retinoic acid-induced 1 (RAI1) gene that maps on the short arm of chromosome 17p11.2... (Review)
Review
Smith-Magenis syndrome is a genetic disorder caused by a microdeletion involving the retinoic acid-induced 1 (RAI1) gene that maps on the short arm of chromosome 17p11.2 or a pathogenic mutation of RAI1. Smith-Magenis syndrome affects patients through numerous congenital anomalies, intellectual disabilities, behavioral challenges, and sleep disturbances. The sleep abnormalities associated with Smith-Magenis syndrome can include frequent nocturnal arousals, early morning awakenings, and sleep attacks during the day. The sleep problems associated with Smith-Magenis syndrome are attributed to haploinsufficiency of the RAI1 gene. One consequence of reduced function of RAI1, and characteristic of Smith-Magenis syndrome, is an inversion of melatonin secretion resulting in a diurnal rather than nocturnal pattern. Treatment of sleep problems in people with Smith-Magenis syndrome generally involves a combination of sleep hygiene techniques, supplemental melatonin, and/or other medications, such as melatonin receptor agonists, β-adrenergic antagonists, and stimulant medications, to improve sleep outcomes. Improvement in sleep has been shown to improve behavioral outcomes, which in turn improves the quality of life for both patients and their caregivers.
Topics: Animals; Humans; Melatonin; Mutation; Quality of Life; Sleep; Sleep Wake Disorders; Smith-Magenis Syndrome
PubMed: 32495322
DOI: 10.1007/s40263-020-00733-5 -
International Journal of Molecular... Jul 2019Smith-Magenis syndrome (SMS), linked to () haploinsufficiency, is a unique model of the inversion of circadian melatonin secretion. In this regard, this model is a... (Review)
Review
Smith-Magenis syndrome (SMS), linked to () haploinsufficiency, is a unique model of the inversion of circadian melatonin secretion. In this regard, this model is a formidable approach to better understand circadian melatonin secretion cycle disorders and the role of the gene in this cycle. Sleep-wake cycle disorders in SMS include sleep maintenance disorders with a phase advance and intense sleepiness around noon. These disorders have been linked to a general disturbance of sleep-wake rhythm and coexist with inverted secretion of melatonin. The exact mechanism underlying the inversion of circadian melatonin secretion in SMS has rarely been discussed. We suggest three hypotheses that could account for the inversion of circadian melatonin secretion and discuss them. First, inversion of the circadian melatonin secretion rhythm could be linked to alterations in light signal transduction. Second, this inversion could imply global misalignment of the circadian system. Third, the inversion is not linked to a global circadian clock shift but rather to a specific impairment in the melatonin secretion pathway between the suprachiasmatic nuclei (SCN) and pinealocytes. The development of diurnal SMS animal models that produce melatonin appears to be an indispensable step to further understand the molecular basis of the circadian melatonin secretion rhythm.
Topics: Animals; Chromosome Mapping; Circadian Rhythm; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Melatonin; Quantitative Trait Loci; Quantitative Trait, Heritable; Smith-Magenis Syndrome
PubMed: 31330985
DOI: 10.3390/ijms20143533 -
Current Opinion in Psychiatry Mar 2019To provide an update of the most recent studies on Smith-Magenis syndrome (SMS) with a focus on the unique pattern of behavioral and sleep disturbances associated with... (Review)
Review
PURPOSE OF REVIEW
To provide an update of the most recent studies on Smith-Magenis syndrome (SMS) with a focus on the unique pattern of behavioral and sleep disturbances associated with the condition.
RECENT FINDINGS
The recent literature on SMS has focused on the characteristic severe behavioral and sleep disturbances. A better understanding of the underlying pathophysiological mechanisms and common clinical course has helped further characterize SMS, while much is left to be discovered in regard to effective treatment/management.
SUMMARY
SMS is a difficult to manage genetic condition defined by pervasive and progressive behavioral and sleep disturbances with a unique pattern that can often be easily discerned from other neurodevelopmental disorders. Common behavioral features include maladaptive/self-injurious, aggressive, stereotypic, and the newly appreciated food seeking behaviors associated with SMS. In addition, there is a sleep disturbance defined by an altered circadian rhythm with frequent nighttime waking and daytime sleepiness, causing patients and families significant distress. Small studies have suggested some treatment/management approaches to the behavioral and sleep disturbances, however, much remains to be discovered.
Topics: Aggression; Disease Progression; Female; Humans; Male; Psychopathology; Sleep Disorders, Circadian Rhythm; Smith-Magenis Syndrome; Somnambulism; Stereotyped Behavior
PubMed: 30557269
DOI: 10.1097/YCO.0000000000000474 -
Genome Medicine Feb 2019Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum...
De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.
BACKGROUND
Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).
METHODS
Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.
RESULTS
We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.
CONCLUSIONS
TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.
Topics: Adolescent; Child; Child, Preschool; Craniofacial Abnormalities; Developmental Disabilities; Female; Humans; INDEL Mutation; Infant; Intellectual Disability; Male; Muscle Hypotonia; Smith-Magenis Syndrome; Transcription Factors; Young Adult
PubMed: 30819258
DOI: 10.1186/s13073-019-0623-0 -
Journal of Family Medicine and Primary... Mar 2022Smith-Magenis syndrome is a rare genetic disorder involving multiple body systems, along with mental retardation and sleep disturbances. It is attributed to micro...
Smith-Magenis syndrome is a rare genetic disorder involving multiple body systems, along with mental retardation and sleep disturbances. It is attributed to micro deletion at 17p11.2 chromosome region encoding for RAI1 gene. This article presents a case report of a 7-year-old patient having this rare syndrome along with his genetic analysis.
PubMed: 35495804
DOI: 10.4103/jfmpc.jfmpc_1279_21 -
The Application of Clinical Genetics 2017Smith-Magenis syndrome (SMS; OMIM #182290) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a... (Review)
Review
Smith-Magenis syndrome (SMS; OMIM #182290) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions, encompassing multiple genes and including the retinoic acid-induced 1 gene (), or by mutations in itself. About 10% of all the SMS patients, in fact, carry an mutation responsible for the phenotype. (OMIM *607642) is a dosage-sensitive gene expressed in many tissues and highly conserved among species. Over the years, several studies have demonstrated that (or its homologs in animal models) acts as a transcriptional factor implicated in embryonic neurodevelopment, neuronal differentiation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucose metabolisms, behavioral functions, and circadian activity. Patients with pathogenic variants show some phenotypic differences when compared to those carrying the typical deletion. They usually have lower incidence of hypotonia and less cognitive impairment than those with 17p11.2 deletions but more frequently show the behavioral characteristics of the syndrome and overeating issues. These differences reflect the primary pathogenetic role of without the pathogenetic contribution of the other genes included in the typical 17p11.2 deletion. The better comprehension of physiological roles of , its molecular co-workers and interactors, and its contribution in determining the typical SMS phenotype will certainly open a new path for therapeutic interventions.
PubMed: 29138588
DOI: 10.2147/TACG.S128455