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CNS Neuroscience & Therapeutics Nov 2016Individuals with Smith-Magenis syndrome (SMS) are reported to have a disrupted circadian rhythm. Our aim was to examine problematic sleeping in those attending our sleep...
AIMS
Individuals with Smith-Magenis syndrome (SMS) are reported to have a disrupted circadian rhythm. Our aim was to examine problematic sleeping in those attending our sleep clinic for the first time.
METHODS
At intake, caregivers of 50 children and nine adults with SMS were surveyed about the sleep pattern and potential melatonin administration. Sampling of salivary melatonin levels was performed.
RESULTS
At intake, exogenous melatonin was used by 16 children (27.1% of sample; 56.3% male) with mean age 6.8 ± 2.8 years, whereas 34 children (57.6%; 7.5 ± 4.8 years old; 64.7% male) and nine adults (15.3%; 36.8 ± 15.3 years old; 44.4% male) were not taking melatonin at intake. Participants were reported to have problems with night waking and early awakenings regardless of melatonin administration. Overall, moderate to high levels of salivary melatonin at noon were found in individuals with SMS. In particular, children with SMS showed a disrupted melatonin pattern. Furthermore, the endogenous melatonin level, age, and gender may potentially interact, yielding the severity range of sleep disturbances reported in SMS.
CONCLUSION
Treatment of sleep problems in SMS is complex, and our findings may support person-centered sleep and medication management. Future clinical trials including larger groups may shed light on such approaches.
Topics: Adult; Age Factors; Child; Child, Preschool; Circadian Rhythm; Eating; Female; Humans; Male; Melatonin; Middle Aged; Radioimmunoassay; Saliva; Sleep Wake Disorders; Smith-Magenis Syndrome; Young Adult
PubMed: 27743421
DOI: 10.1111/cns.12653 -
Molecular Autism Jan 2023Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic...
BACKGROUND
Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic uncertainty and compromised access to autism-related support. Previous research has tended to include small samples and diverse measures, which limits the generalisability of findings. In this study, we generated detailed profiles of autistic characteristics in a large sample of > 1500 individuals with rare genetic syndromes.
METHODS
Profiles of autistic characteristics based on the Social Communication Questionnaire (SCQ) scores were generated for thirteen genetic syndrome groups (Angelman n = 154, Cri du Chat n = 75, Cornelia de Lange n = 199, fragile X n = 297, Prader-Willi n = 278, Lowe n = 89, Smith-Magenis n = 54, Down n = 135, Sotos n = 40, Rubinstein-Taybi n = 102, 1p36 deletion n = 41, tuberous sclerosis complex n = 83 and Phelan-McDermid n = 35 syndromes). It was hypothesised that each syndrome group would evidence a degree of specificity in autistic characteristics. To test this hypothesis, a classification algorithm via support vector machine (SVM) learning was applied to scores from over 1500 individuals diagnosed with one of the thirteen genetic syndromes and autistic individuals who did not have a known genetic syndrome (ASD; n = 254). Self-help skills were included as an additional predictor.
RESULTS
Genetic syndromes were associated with different but overlapping autism-related profiles, indicated by the substantial accuracy of the entire, multiclass SVM model (55% correctly classified individuals). Syndrome groups such as Angelman, fragile X, Prader-Willi, Rubinstein-Taybi and Cornelia de Lange showed greater phenotypic specificity than groups such as Cri du Chat, Lowe, Smith-Magenis, tuberous sclerosis complex, Sotos and Phelan-McDermid. The inclusion of the ASD reference group and self-help skills did not change the model accuracy.
LIMITATIONS
The key limitations of our study include a cross-sectional design, reliance on a screening tool which focuses primarily on social communication skills and imbalanced sample size across syndrome groups.
CONCLUSIONS
These findings replicate and extend previous work, demonstrating syndrome-specific profiles of autistic characteristics in people with genetic syndromes compared to autistic individuals without a genetic syndrome. This work calls for greater precision of assessment of autistic characteristics in individuals with genetic syndromes associated with ID.
Topics: Humans; Autistic Disorder; Tuberous Sclerosis; Cross-Sectional Studies; Intellectual Disability; Syndrome
PubMed: 36639821
DOI: 10.1186/s13229-022-00530-5 -
American Journal of Human Genetics Jun 2012Haploinsufficiency of RAI1 results in Smith-Magenis syndrome (SMS), a disorder characterized by intellectual disability, multiple congenital anomalies, obesity,...
Haploinsufficiency of RAI1 results in Smith-Magenis syndrome (SMS), a disorder characterized by intellectual disability, multiple congenital anomalies, obesity, neurobehavioral abnormalities, and a disrupted circadian sleep-wake pattern. An inverted melatonin rhythm (i.e., melatonin peaks during the day instead of at night) and associated sleep-phase disturbances in individuals with SMS, as well as a short-period circadian rhythm in mice with a chromosomal deletion of Rai1, support SMS as a circadian-rhythm-dysfunction disorder. However, the molecular cause of the circadian defect in SMS has not been described. The circadian oscillator temporally orchestrates metabolism, physiology, and behavior largely through transcriptional modulation. Data support RAI1 as a transcriptional regulator, but the genes it might regulate are largely unknown. Investigation into the role that RAI1 plays in the regulation of gene transcription and circadian maintenance revealed that RAI1 regulates the transcription of circadian locomotor output cycles kaput (CLOCK), a key component of the mammalian circadian oscillator that transcriptionally regulates many critical circadian genes. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. These data suggest that heterozygous mutation of RAI1 and Rai1 leads to a disrupted circadian rhythm and thus results in an abnormal sleep-wake cycle, which can contribute to an abnormal feeding pattern and dependent cognitive performance. Finally, we conclude that RAI1 is a positive transcriptional regulator of CLOCK, pinpointing a novel and important role for this gene in the circadian oscillator.
Topics: Animals; CLOCK Proteins; Circadian Rhythm; Female; Fibroblasts; Gene Expression Regulation; Heterozygote; Humans; Hypothalamus; Male; Mice; Mice, Transgenic; Mutation; Oligonucleotide Array Sequence Analysis; Oscillometry; Phenotype; RNA, Small Interfering; Smith-Magenis Syndrome; Trans-Activators; Transcription Factors; Transcription, Genetic
PubMed: 22578325
DOI: 10.1016/j.ajhg.2012.04.013 -
The Journal of Allergy and Clinical... 2017Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome...
BACKGROUND
Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy.
OBJECTIVES
The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods.
METHODS
We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays.
RESULTS
Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens.
CONCLUSIONS
Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.
Topics: Adolescent; Adult; B-Lymphocytes; Child; Child, Preschool; Cohort Studies; DEAD Box Protein 58; Female; Humans; Immunoglobulin Class Switching; Immunologic Deficiency Syndromes; Immunologic Memory; Infant; Intellectual Disability; Male; Mutation; Otitis; Pneumonia; Prevalence; Receptors, Immunologic; Sinusitis; Smith-Magenis Syndrome; Young Adult
PubMed: 28286158
DOI: 10.1016/j.jaip.2017.01.028 -
Cureus Jan 2022Smith-Magenis syndrome (SMS) is a severe neurodevelopmental disorder characterized by intellectual disability, sleep abnormalities, behavioral dyscontrol, and a distinct...
Smith-Magenis syndrome (SMS) is a severe neurodevelopmental disorder characterized by intellectual disability, sleep abnormalities, behavioral dyscontrol, and a distinct somatic phenotype. This report describes the case of a 10-year-old female with SMS who presented with aggression, self-injurious behavior, impulsivity, and attention deficits. She had failed trials of several stimulants and clonidine prior to presentation. An evening-dosed, delayed-release/extended-release methylphenidate formulation was added to her regimen, and she demonstrated significant improvement in her presenting symptoms. To our knowledge, this is the first published case of the use of an evening-dosed, delayed-release/extended-release methylphenidate formulation in a patient with SMS. This case highlights the need for further research on the role of these medications in managing behavioral and attentional symptoms associated with SMS.
PubMed: 35178313
DOI: 10.7759/cureus.21255 -
Molecular Autism 2018A substantial amount of research shows a higher rate of autistic type of problems in males compared to females. The 4:1 male to female ratio is one of the most...
BACKGROUND
A substantial amount of research shows a higher rate of autistic type of problems in males compared to females. The 4:1 male to female ratio is one of the most consistent findings in autism spectrum disorder (ASD).Lately, the interest in studying ASD in genetic disorders has increased, and research has shown a higher prevalence of ASD in some genetic disorders than in the general population.Smith-Magenis syndrome (SMS) is a rare and complex genetic syndrome caused by an interstitial deletion of chromosome 17p11.2 or a mutation on the retinoic acid induced 1 gene. The disorder is characterised by intellectual disability, multiple congenital anomalies, obesity, neurobehavioural abnormalities and a disrupted circadian sleep-wake pattern.
METHODS
Parents of 28 persons with SMS between 5 and 50 years old participated in this study. A total of 12 of the persons with SMS were above the age of 18 at the time of the study. A total of 11 came from Sweden and 17 were from Norway.We collected information regarding the number of autism spectrum symptoms using the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS). Adaptive behaviour was also measured using the Vineland Adaptive Behavior Scale II. The level of intellectual disability was derived from a review of the medical chart.
RESULTS
We found significant gender differences in ASD symptomatology using the SCQ and SRS questionnaires. We found approximately three females per male above the SCQ cutoff. The same differences were not found in the intellectual level and adaptive behaviour or for behavioural and emotional problems.Gender had an independent contribution in a regression model predicting the total SCQ score, and neither the Vineland Adaptive Behavior Scale II nor the Developmental Behaviour Checklist had an independent contribution to the SCQ scores.
CONCLUSION
We found a clear reversed gender difference in ASD symptomatology in persons with SMS. This may be relevant in the search for female protective factors assumed to explain the male bias in ASD.
Topics: Adolescent; Adult; Autism Spectrum Disorder; Child; Female; Humans; Male; Middle Aged; Sex Ratio; Smith-Magenis Syndrome
PubMed: 29321841
DOI: 10.1186/s13229-017-0184-2 -
Journal of Pediatric Genetics Sep 2015Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6... (Review)
Review
Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid-inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome.
PubMed: 27617127
DOI: 10.1055/s-0035-1564443 -
Journal of Intellectual Disability... Feb 2011The prevalence, phenomenology aetiology and correlates of four forms of challenging behaviour in 32 children and adults with Smith-Magenis syndrome (SMS) were...
BACKGROUND
The prevalence, phenomenology aetiology and correlates of four forms of challenging behaviour in 32 children and adults with Smith-Magenis syndrome (SMS) were investigated.
METHODS
Cognitive assessments, questionnaires and semi-structured interviews were used to gather data on intellectual disability, verbal and physical aggression, destructive behaviour and self-injury and on characteristics known to be associated with aggression.
RESULTS
Aggression in SMS was more prevalent (87%), but not more severe than aggression in contrast groups. Aggressive behaviour was more frequently associated with environmental contingencies (e.g. attention, escape and access to tangibles) than self-injury and destructive behaviours. Severity of challenging behaviours was associated with high impulsivity.
CONCLUSION
Aggression is seen in the majority of people with SMS. Results suggest that behavioural disinhibition and operant social reinforcement are associated with the manifestation of aggression.
Topics: Adolescent; Adult; Aggression; Behavioral Symptoms; Child; Female; Humans; Inhibition, Psychological; Intellectual Disability; Male; Self-Injurious Behavior; Severity of Illness Index; Smith-Magenis Syndrome; Social Adjustment; Verbal Behavior; Young Adult
PubMed: 21199049
DOI: 10.1111/j.1365-2788.2010.01371.x -
American Journal of Medical Genetics.... Jun 2021
Topics: Adolescent; Adult; Age of Onset; Birt-Hogg-Dube Syndrome; Child; Female; Humans; Male; Pediatrics; Pneumothorax; Smith-Magenis Syndrome; Young Adult
PubMed: 33666332
DOI: 10.1002/ajmg.a.62159 -
Hematology. American Society of... Dec 2016It is an unprecedented time for the treatment of patients with chronic lymphocytic leukemia (CLL) with the recent approval of several targeted agents for use in... (Review)
Review
It is an unprecedented time for the treatment of patients with chronic lymphocytic leukemia (CLL) with the recent approval of several targeted agents for use in frontline, relapsed, refractory, and high-risk disease. Traditionally, frontline management of CLL has been a combination of chemotherapy (fludarabine, cyclophosphamide, bendamustine, or chlorambucil) with an anti-CD20 monoclonal antibody (rituximab, ofatumumab, obinutuzumab). The current landscape is rapidly evolving with the advent of therapies that demonstrate selective inhibition of important pathways necessary for CLL proliferation and survival. Despite considerable progress, much is still unknown and optimal treatment selection and sequence is still debatable. None of the new agents have been compared against each other and the impact of adding an additional agent to monotherapy is not yet fully elucidated. In routine clinical practice, the choice of therapy is based on nonrandomized comparisons, presence of comorbidities, and toxicity considerations. These recently approved drugs (ibrutinib, idelalisib, and venetoclax) are reporting excellent outcomes, including patients with high-risk disease such as 17p deletion (17p-) or TP53 mutations (TP53mut). Ibrutinib and venetoclax have been approved for use in 17p- patients (frontline and relapsed, respectively). Ibrutinib is currently moving into the frontline space given recent regulatory approvals. This review will summarize and interpret the limited therapeutic sequencing data available, highlighting the need for additional studies to optimize combination strategies and treatments after failure or discontinuation of these novel agents.
Topics: Alanine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cell Proliferation; Chlorambucil; Chromosome Deletion; Chromosomes, Human, Pair 17; Cyclophosphamide; DNA Mutational Analysis; Disease-Free Survival; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Rituximab; Smith-Magenis Syndrome; Tumor Suppressor Protein p53
PubMed: 27913471
DOI: 10.1182/asheducation-2016.1.128