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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 -
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 -
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 -
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 -
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 -
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 -
ELife Nov 2023() haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism...
() haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS () mice. Selective loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that ablation decreased the intrinsic excitability of PVH neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.
Topics: Animals; Mice; Brain-Derived Neurotrophic Factor; Homeostasis; Hypothalamus; Neurons; Obesity; Smith-Magenis Syndrome; Trans-Activators; Transcription Factors; Nerve Growth Factors; Body Weight
PubMed: 37956053
DOI: 10.7554/eLife.90333 -
Cell Death & Disease Nov 2022Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been...
Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.
Topics: Humans; Smith-Magenis Syndrome; Haploinsufficiency; Lipid Metabolism; Transcription Factors; Trans-Activators; Phenotype; Autophagy; Tretinoin; Lipids
PubMed: 36411275
DOI: 10.1038/s41419-022-05410-7 -
Genes Jul 2023Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the gene. SMS is associated with... (Review)
Review
AIM
Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the gene. SMS is associated with developmental delay, intellectual disability (ID), and major sleep and behavioral disturbances. To explore how genetic variants may affect intellectual functioning and behavior, we compared intellectual and behavioral phenotypes between individuals with a 17p11.2 deletion and pathogenic variant.
METHOD
We reviewed available clinical records from individuals (aged 0-45 years) with SMS, ascertained through a Dutch multidisciplinary SMS specialty clinic.
RESULTS
We included a total of 66 individuals ( = 47, 71.2% with a 17p11.2 deletion and = 19, 28.8% with a pathogenic variant) for whom data were available on intellectual functioning, severity of ID ( = 53), and behavioral problems assessed with the Child Behavior Checklist (CBCL, = 39). Median full-scale IQ scores were lower (56.0 vs. 73.5, = 0.001) and the proportion of individuals with more severe ID was higher ( = 0.01) in the 17p11.2 deletion group. Median total CBCL 6-18 scores (73.5 vs. 66.0, = 0.02) and scores on the sub-scales somatic complaints (68.0 vs. 57.0, = 0.001), withdrawn/depressed behavior (69.5 vs. 55.0, = 0.02), and internalizing behavior (66.0 vs. 55.0, = 0.002) were higher in the group.
CONCLUSION
The results of this study suggest that 17p11.2 deletions are associated with a lower level of intellectual functioning and less internalizing of problems compared to pathogenic variants. The findings of this study may contribute to personalized-management strategies in individuals with SMS.
Topics: Humans; Smith-Magenis Syndrome; Problem Behavior; Chromosome Structures; Cognition; Intellectual Disability; Phenotype
PubMed: 37628566
DOI: 10.3390/genes14081514