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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 -
Orphanet Journal of Rare Diseases Sep 2015Smith-Magenis syndrome is a complex neurodevelopmental disorder that includes intellectual deficiency, speech delay, behavioral disturbance and typical sleep disorders....
BACKGROUND
Smith-Magenis syndrome is a complex neurodevelopmental disorder that includes intellectual deficiency, speech delay, behavioral disturbance and typical sleep disorders. Ninety percent of the cases are due to a 17p11.2 deletion encompassing the RAI1 gene; other cases are linked to mutations of the same gene. Behavioral disorders often include outbursts, attention deficit/hyperactivity disorders, self-injury with onychotillomania and polyembolokoilamania (insertion of objects into body orifices), etc. Interestingly, the stronger the speech delay and sleep disorders, the more severe the behavioral issues. Sleep disturbances associate excessive daytime sleepiness with nighttime agitation. They are underpinned by an inversion of the melatonin secretion cycle. However, the combined intake of beta-blockers in the morning and melatonin in the evening may radically alleviate the circadian rhythm problems.
DISCUSSION
Once sleep disorders are treated, the next challenge is finding an effective treatment for the remaining behavioral problems. Unfortunately, there is a lack of objective guidelines. A comprehensive evaluation of such disorders should include sleep disorders, potential causes of pain, neurocognitive level and environment (i.e. family and school). In any case, efforts should focus on improving communication skills, identifying and treating attention deficit/hyperactivity, aggressiveness and anxiety. Treatment of Smith-Magenis syndrome is complex and requires a multidisciplinary team including, among others, geneticists, psychiatrists, neuropediatricians/neurologists, somnologists, developmental and behavioral pediatricians, and speech and language therapists.
Topics: Adult; Humans; Mental Disorders; Pain; Sleep Wake Disorders; Smith-Magenis Syndrome
PubMed: 26336863
DOI: 10.1186/s13023-015-0330-x -
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 -
CMAJ : Canadian Medical Association... Sep 2003
Topics: Abnormalities, Multiple; Chromosome Deletion; Chromosome Disorders; Diagnostic Errors; Foreign Bodies; Humans; Intellectual Disability; Stomach; Syndrome
PubMed: 12975219
DOI: No ID Found -
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 -
Journal of Intellectual Disabilities :... Dec 2021Smith-Magenis syndrome (SMS) is a genetic syndrome most often caused by a deletion on chromosome 17 or more rarely by a mutation in the retinoic acid-induced 1 gene. The...
Smith-Magenis syndrome (SMS) is a genetic syndrome most often caused by a deletion on chromosome 17 or more rarely by a mutation in the retinoic acid-induced 1 gene. The aim of this study was to investigate the Developmental Behavior Checklist (DBC) profile of persons with SMS and the associations between behavioural and emotional problems, age, gender, adaptive behaviour and autism symptomatology. Twenty-eight persons with SMS were represented by their parents in this study. DBC Total scores are reduced with age, but they still show a mean that is clearly above the cut-off of 46. The differences between the age groups <9 years and 9-17 years ( = 0.024) and between the age groups <9 years and >18 years ( = 0.007) are significant. We found a significant decrease in behavioural and emotional problems with age in SMS. We did not find a relationship between adapted behaviour and communication and behavioural and emotional problems.
Topics: Checklist; Child; Humans; Intellectual Disability; Parents; Problem Behavior; Smith-Magenis Syndrome
PubMed: 31984836
DOI: 10.1177/1744629519901056 -
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 -
Medicine May 2015The Smith-Magenis syndrome (SMS) is a complex and rare congenital condition that is characterized by minor craniofacial anomalies, short stature, sleep disturbances,... (Review)
Review
The Smith-Magenis syndrome (SMS) is a complex and rare congenital condition that is characterized by minor craniofacial anomalies, short stature, sleep disturbances, behavioral, and neurocognitive abnormalities, as well as variable multisystemic manifestations. Little is reported about spinal deformity associated with this syndrome.This study is to present a case of scoliosis occurring in the setting of SMS and explore the possible mechanisms between the 2 diseases.The patient is a 13-year-old Chinese female with congenital scoliosis and Tetralogy of Fallot, mental retardation, obstructive sleep apnea, hypertrophy of tonsil, conductive hearing loss, and agenesis of the epiglottis. An interphase fluorescent in situ hybridization at chromosome 17p11.2 revealed a heterozygous deletion, confirming a molecular diagnosis of SMS. She underwent a posterior correction at thoracic 1-lumbar 1 (T1-L1) levels, using the Moss-SI spinal system. At 6-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of correction.Congenital cardiac disease, immunodeficiency, and severe behavioral problems can affect the surgical outcome following spine fusion and need to be taken into consideration for the surgeon and anesthesiologist. Scoliosis is not uncommon among patients with SMS, and there is a potential association between congenital scoliosis and SMS. The potential mechanisms in the pathogenesis of congenital scoliosis of SMS included retinoic acid-induced 1 (RAI1) microdeletion and RAI1 gene point mutation.
Topics: Adolescent; Female; Humans; Radiography; Scoliosis; Smith-Magenis Syndrome; Spinal Fusion
PubMed: 25929900
DOI: 10.1097/MD.0000000000000705 -
Journal of Pediatric Genetics Dec 2020As a multisystemic congenital mental retardation disorder/anomaly, Smith-Magenis syndrome (SMS) is commonly aroused from de novo interstitial deletion of the 17p11.2...
As a multisystemic congenital mental retardation disorder/anomaly, Smith-Magenis syndrome (SMS) is commonly aroused from de novo interstitial deletion of the 17p11.2 chromosome. The deletion of this chromosome results with haploinsufficiency for the retinoic acid-induced 1 ( ) gene. In this article, we present three cases, who were diagnosed with SMS with mental retardation and behavioral problems such as self-hugging and sleeping disturbances. During the evaluation of the patients, it has been found that there was a 3.4-Mb deletion in the 17p11.2 chromosome region of these patients. This deletion includes that is a critically involved gene in SMS.
PubMed: 32765933
DOI: 10.1055/s-0039-1700965 -
Orphanet Journal of Rare Diseases Feb 2022Smith-Magenis syndrome (SMS) is a rare genetic syndrome associated with a unique profile of early morning waking and daytime sleepiness. Children with SMS evidence high...
BACKGROUND
Smith-Magenis syndrome (SMS) is a rare genetic syndrome associated with a unique profile of early morning waking and daytime sleepiness. Children with SMS evidence high rates of self-injury and aggression and have a preference for adult over peer attention, with strong motivation to interact with a particular caregiver. In addition, people with SMS have lower adaptive functioning skills relative to cognitive abilities and demonstrate high levels of impulsivity. Taken together, these factors may result in individuals being awake overnight requiring vigilant caregiver supervision. Despite these complexities, no study has described the strategies caregivers take to keep their children with SMS safe overnight or considered the impact of these experiences on caregivers or the wider family.
METHODS
The current study used a mixed-methods approach to consider sleep management strategies and challenges for caregivers of people with SMS at different ages. Caregivers completed an international online survey about sleep management and related difficulties, use of interventions and access to services and support. Semi-structured interviews were conducted with 14 caregivers in the UK to increase understanding of caregiver experiences and priorities for change in the UK context. Interviews were transcribed verbatim and coded using thematic analysis.
RESULTS
Evidence from the online survey (n = 40) revealed wide-ranging impacts of poor sleep on the person with SMS and the wider family. Only 5% of caregivers reported that the sleep problems had no impact on their child, and 76% reported a moderately or extremely significant impact on themselves. For some individual caregivers, sleep management difficulties improved over time whereas for others no change was reported. Weekly respite emerged as the ideal provision for 49% of caregivers, although only 14% had access to this. The majority of caregivers (54%) received no respite. Thematic analysis of qualitative interviews revealed interactions between aspects of the behavioural phenotype of SMS which may contribute to complex and unusual presentations in relation to sleep management and safety.
CONCLUSIONS
Caregivers' priorities for sleep management and support were delineated, with key implications for services in terms of the use of SMS-sensitive strategies and respite provision.
Topics: Caregivers; Family; Humans; Sleep; Smith-Magenis Syndrome; Surveys and Questionnaires
PubMed: 35120534
DOI: 10.1186/s13023-021-02159-8