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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 -
Pharmacotherapy Jun 2019Neurodevelopmental disorders (NDDs), a group of disorders affecting ~1-2% of the general population, are caused by changes in brain development that result in behavioral... (Review)
Review
Neurodevelopmental disorders (NDDs), a group of disorders affecting ~1-2% of the general population, are caused by changes in brain development that result in behavioral and cognitive alterations, sensory and motor changes, and speech and language deficits. Neurodevelopmental disorders encompass a heterogeneous group of disorders including, but not limited to, Smith-Magenis syndrome, Lesch-Nyhan disease, cri du chat syndrome, Prader-Willi syndrome, pervasive developmental disorders, fragile X syndrome, Rett syndrome, Cornelia de Lange syndrome, and Down syndrome. Self-injurious behaviors (SIBs) are common in children with NDDs; depending on the specific NDD, the incidence of SIBs is nearly 100%. The management of SIBs in this population is complex, and little high-quality data exist to guide a consistent approach to therapy. However, managing SIBs is of the utmost importance for the child as well as the family and caregivers. Behavior therapies must be implemented as first-line therapy. If behavioral interventions alone fail, pharmacotherapy becomes an essential part of management plans. The limited available evidence for the use of common pharmacologic agents, such as second-generation antipsychotics, and less common agents, such as clonidine, n-acetylcysteine, riluzole, naltrexone, and topical anesthetics, is reviewed. Additional data from well-designed studies in children with NDDs are needed to gain a better understanding of this common and troublesome problem including efficacy and safety implications associated with pharmacotherapy. Until then, clinicians must rely on the limited available data, clinical expertise, and ongoing systematic monitoring when managing SIBs in children with NDDs.
Topics: Humans; Neurodevelopmental Disorders; Psychotropic Drugs; Self-Injurious Behavior
PubMed: 30793794
DOI: 10.1002/phar.2238 -
Neuroscience and Biobehavioral Reviews Jan 2018Self-injurious behavior (SIB) is a relatively common behavior in individuals with intellectual disabilities (ID). Severe SIB can be devastating and potentially... (Review)
Review
Self-injurious behavior (SIB) is a relatively common behavior in individuals with intellectual disabilities (ID). Severe SIB can be devastating and potentially life-threatening. There is increasing attention for somatic substrates of behavior in genetic syndromes, and growing evidence of an association between pain and discomfort with SIB in people with ID and genetic syndromes. In this review on SIB phenomenology in people with ID in general and in twelve genetic syndromes, we summarize different SIB characteristics across these etiologically distinct entities and identify influencing factors. We demonstrate that the prevalence of SIB in several well-known genetic intellectual disability syndromes is noticeably higher than in individuals with ID in general, and that characteristics such as age of onset and topographies differ widely across syndromes. Each syndrome is caused by a mutation in a different gene, and this allows detection of several pathways that lead to SIB. Studying these with the behavioral consequences as specific aim will be an important step toward targeted early interventions and prevention.
Topics: Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Intellectual Disability; Self-Injurious Behavior
PubMed: 28694012
DOI: 10.1016/j.neubiorev.2017.02.027 -
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 -
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 -
Journal of the American Academy of... Nov 2017To assess the efficacy and safety of novel pediatric-appropriate, prolonged-release melatonin minitablets (PedPRM) versus placebo for insomnia in children and... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess the efficacy and safety of novel pediatric-appropriate, prolonged-release melatonin minitablets (PedPRM) versus placebo for insomnia in children and adolescents with autism spectrum disorder (ASD), with or without attention-deficit/hyperactivity disorder (ADHD) comorbidity, and neurogenetic disorders (NGD).
METHOD
A total of 125 children and adolescents (2-17.5 years of age; 96.8% ASD, 3.2% Smith-Magenis syndrome [SMS]) whose sleep failed to improve on behavioral intervention alone were randomized (1:1 ratio), double-blind, to receive PedPRM (2 mg escalated to 5 mg) or placebo for 13 weeks. Sleep measures included the validated caregivers' Sleep and Nap Diary (SND) and Composite Sleep Disturbance Index (CSDI). The a priori primary endpoint was SND-reported total sleep time (TST) after 13 weeks of treatment.
RESULTS
The study met the primary endpoint: after 13 weeks of double-blind treatment, participants slept on average 57.5 minutes longer at night with PedPRM compared to 9.14 minutes with placebo (adjusted mean treatment difference PedPRM-placebo -32.43 minutes; p = .034). Sleep latency (SL) decreased by 39.6 minutes on average with PedPRM and 12.5 minutes with placebo (adjusted mean treatment difference -25.30 minutes; p = .011) without causing earlier wakeup time. The rate of participants attaining clinically meaningful responses in TST and/or SL was significantly higher with PedPRM than with placebo (68.9% versus 39.3% respectively; p = .001) corresponding to a number needed to treat (NNT) of 3.38. Overall sleep disturbance (CSDI) tended to decrease. PedPRM was generally safe; somnolence was more commonly reported with PedPRM than placebo.
CONCLUSION
PedPRM was efficacious and safe for treatment of insomnia in children and adolescents with ASD with/without ADHD and NGD. The acceptability of this pediatric formulation in a population who usually experience significant difficulties in swallowing was remarkably high. Clinical trial registration information-Efficacy and Safety of Circadin in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities; http://clinicaltrials.gov/; NCT01906866.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Central Nervous System Depressants; Child; Child, Preschool; Delayed-Action Preparations; Female; Humans; Male; Melatonin; Outcome Assessment, Health Care; Sleep Initiation and Maintenance Disorders
PubMed: 29096777
DOI: 10.1016/j.jaac.2017.09.414 -
Children (Basel, Switzerland) Sep 2017enetic advances in the past three decades have transformed our understanding and treatment of many human diseases including neurogenetic disorders. Most neurogenetic... (Review)
Review
enetic advances in the past three decades have transformed our understanding and treatment of many human diseases including neurogenetic disorders. Most neurogenetic disorders can be classified as "rare disease," but collectively neurogenetic disorders are not rare and are commonly encountered in general pediatric practice. The authors decided to select eight relatively well-known neurogenetic disorders including Down syndrome, Angelman syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, congenital central hypoventilation syndrome, achondroplasia, mucopolysaccharidoses, and Duchenne muscular dystrophy. Each disorder is presented in the following format: overview, clinical characteristics, developmental aspects, associated sleep disorders, management and research/future directions.
PubMed: 28895939
DOI: 10.3390/children4090082 -
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 -
Proceedings of the National Academy of... Oct 2022Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, (), causes Smith-Magenis...
Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, (), causes Smith-Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns. The molecular and neural mechanisms underlying abnormal brain activity in SMS remain unclear. Here we show that panneural deletions in mice result in increased seizure susceptibility and prolonged hippocampal seizure duration in vivo and increased dentate gyrus population spikes ex vivo. Brain-wide mapping of neuronal activity pinpointed selective cell types within the limbic system, including the hippocampal dentate gyrus granule cells (dGCs) that are hyperactivated by chemoconvulsant administration or sensory experience in -deficient brains. Deletion of from glutamatergic neurons, but not from gamma-aminobutyric acidergic (GABAergic) neurons, was responsible for increased seizure susceptibility. Deleting from the -lineage glutamatergic neurons resulted in abnormal dGC properties, including increased excitatory synaptic transmission and increased intrinsic excitability. Our work uncovers the mechanism of neuronal hyperexcitability in SMS by identifying Rai1 as a negative regulator of dGC intrinsic and synaptic excitability.
Topics: Mice; Animals; Smith-Magenis Syndrome; Trans-Activators; Phenotype; Disease Models, Animal; Chromatin; Hippocampus; Seizures; Tretinoin
PubMed: 36256819
DOI: 10.1073/pnas.2210122119