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Antioxidants (Basel, Switzerland) Nov 2023The article presents a review of the relationships between melatonin and neurodevelopmental disorders. First, the antioxidant properties of melatonin and its... (Review)
Review
The article presents a review of the relationships between melatonin and neurodevelopmental disorders. First, the antioxidant properties of melatonin and its physiological effects are considered to understand better the role of melatonin in typical and atypical neurodevelopment. Then, several neurodevelopmental disorders occurring during infancy, such as autism spectrum disorder or neurogenetic disorders associated with autism (including Smith-Magenis syndrome, Angelman syndrome, Rett's syndrome, Tuberous sclerosis, or Williams-Beuren syndrome) and neurodevelopmental disorders occurring later in adulthood like bipolar disorder and schizophrenia, are discussed with regard to impaired melatonin production and circadian rhythms, in particular, sleep-wake rhythms. This article addresses the issue of overlapping symptoms that are commonly observed within these different mental conditions and debates the role of abnormal melatonin production and altered circadian rhythms in the pathophysiology and behavioral expression of these neurodevelopmental disorders.
PubMed: 38001870
DOI: 10.3390/antiox12112017 -
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 -
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 -
Children (Basel, Switzerland) Aug 2023: Smith-Magenis syndrome (SMS) is caused by either interstitial deletions in the 17p11.2 region or pathogenic variants in the gene and is marked by a distinct set of...
: Smith-Magenis syndrome (SMS) is caused by either interstitial deletions in the 17p11.2 region or pathogenic variants in the gene and is marked by a distinct set of physical, developmental, neurological, and behavioral features. Hypercholesterolemia has been described in SMS, and obesity is also commonly found. : To describe and characterize the metabolic phenotype of a cohort of SMS patients with an age range of 2.9-32.4 years and to evaluate any correlations between their body mass index and serum lipids, glycated hemoglobin (HbA1c), and basal insulin levels. : Seven/thirty-five patients had high values of both total cholesterol and low-density lipoprotein cholesterol; 3/35 had high values of triglycerides; none of the patients with variants presented dyslipidemia. No patients had abnormal fasting glucose levels. Three/thirty-five patients had HbA1c in the prediabetes range. Ten/twenty-two patients with 17p11.2 deletion and 2/3 with variants had increased insulin basal levels. Three/twenty-three patients with the 17p11.2 deletion had prediabetes. : Our investigation suggests that SMS 'deleted' patients may show a dyslipidemic pattern, while SMS 'mutated' patients are more likely to develop early-onset obesity along with hyperinsulinism.
PubMed: 37761412
DOI: 10.3390/children10091451 -
Frontiers in Computational Neuroscience 2024This research work introduces a novel, nonintrusive method for the automatic identification of Smith-Magenis syndrome, traditionally studied through genetic markers. The...
This research work introduces a novel, nonintrusive method for the automatic identification of Smith-Magenis syndrome, traditionally studied through genetic markers. The method utilizes cepstral peak prominence and various machine learning techniques, relying on a single metric computed by the research group. The performance of these techniques is evaluated across two case studies, each employing a unique data preprocessing approach. A proprietary data "windowing" technique is also developed to derive a more representative dataset. To address class imbalance in the dataset, the synthetic minority oversampling technique (SMOTE) is applied for data augmentation. The application of these preprocessing techniques has yielded promising results from a limited initial dataset. The study concludes that the k-nearest neighbors and linear discriminant analysis perform best, and that cepstral peak prominence is a promising measure for identifying Smith-Magenis syndrome.
PubMed: 38585279
DOI: 10.3389/fncom.2024.1357607 -
Sleep Advances : a Journal of the Sleep... 2023To determine the trajectory of: (i) objective sleep parameters and (ii) caregiver-reported sleep questionnaire scores over 3 years in children with Smith-Magenis...
STUDY OBJECTIVES
To determine the trajectory of: (i) objective sleep parameters and (ii) caregiver-reported sleep questionnaire scores over 3 years in children with Smith-Magenis syndrome (SMS) compared to age-matched typically developing (TD) controls. We also aimed to (iii) describe individual profiles of change in sleep parameters over time.
METHODS
Week-long, overnight actigraphy and questionnaire data from 13 children with SMS and 13 age-matched TD children were collected at Time 1 and Time 2 (3 years later). Independent samples -tests, paired samples -tests, and Bayesian analyses were used to compare sleep parameters and sleep questionnaire scores between groups at each time point and compare data within groups to assess change over time.
RESULTS
Sleep parameters were consistently more disrupted in the SMS group than the TD group, with significantly reduced sleep efficiency, increased wake after sleep onset and earlier get up times at both time points. This was mirrored in the questionnaire data, with children with SMS evidencing higher scores for overall sleep disturbance, night waking, and daytime sleepiness. While TD sleep parameters demonstrated expected developmental changes over 3 years, in the SMS group sleep parameters and variability between and within children remained largely stable. However, some children with SMS showed substantial variation in sleep parameters over time. Questionnaire scores remained stable over 3 years in both groups.
CONCLUSIONS
Overall, sleep disturbance appears to be a stable feature of SMS, indicative of a divergent sleep trajectory compared to TD peers. Proactive intervention approaches should be considered for poor sleep in SMS.
PubMed: 37810798
DOI: 10.1093/sleepadvances/zpad034 -
Clinical Case Reports Apr 2024This case report aims to raise a physiotherapy intervention for subjects with SMS. The basis is an active work, based on postural control and balance training....
KEY CLINICAL MESSAGE
This case report aims to raise a physiotherapy intervention for subjects with SMS. The basis is an active work, based on postural control and balance training. Physiotherapists can play an important role in the management of these subjects.
ABSTRACT
Smith-Magenis syndrome (SMS) is a genetic alteration that encompasses a series of psychophysical repercussions that interferes with postural control and the autonomous functionality of the subjects who suffer from it. In this study, a clinical case of an 18-year-old adolescent with a genetic diagnosis of an SMS mutation is presented. This work proposes a physiotherapy intervention, adapted to the individual conditions and agreed upon with his family. The goal would be to analyze the effectiveness of postural control and balance training in a subject with SMS. A physiotherapy intervention based on postural control and balance was proposed. This approach is combined with the strengthening and readaptation of the antigravity muscles, through strength training, mobilization exercises, gait and transfers reeducation. An initial assessment was carried out. The interventions were developed at the home of the clinical case. The main variables were balance and postural control. For this, the following measurement scales and tests were used: Face Scale, Gross Motor Function Scale, Berg Balance Scale, Romberg Test, Barthel Index, and Functional Assessment of Sitting (SATco scale). After the intervention, the case presented under observation greater postural control in the transfers, less imbalances, and introduced new positions during their development, which allow more functional and autonomous movement. This was also extrapolated to gait, which was optimized in its development. This observation was not reflexed in test scores, which remained the same than the initial assessment. The intervention had a positive effect on the development of trunk control, transfers, and gait.
PubMed: 38550733
DOI: 10.1002/ccr3.8719 -
The Journal of International Medical... Sep 2023We report the clinical features and genetic testing of a child with Smith-Magenis syndrome (SMS) to improve the understanding of this disease. The clinical data and...
We report the clinical features and genetic testing of a child with Smith-Magenis syndrome (SMS) to improve the understanding of this disease. The clinical data and molecular genetic test results of a child with SMS caused by a novel mutation in the retinoic acid-induced-1 (RAI1) gene were reviewed. A female patient aged 12 years and 9 months presented to the clinic because her mental and motor development was lagging behind that of her peers. The child had learning difficulties, poor motor coordination, temper tantrums, and self-injurious behaviors, such as skin scratching. She had a peculiar facial appearance, dry skin with scattered eczema, low hairline, wide forehead, flat face, collapsed nasal bridge, turned out upper lip, and deep palmar lines on the right hand through the palm. Wechsler's IQ test score was 48. Her electroencephalogram was normal. The diagnosis of SMS was confirmed by a heterozygous mutation in exon 3 of the RAI1 gene on chromosome chr-1717696650 at locus c.388C>T (P.Q130X). In addition, this patient had severe eczema on the skin. The RAI1 mutation c.388C>T (P.Q130X) is a newly reported variant that will help in the clinical identification of SMS and the precise localization of more phenotypically related genes.
Topics: Humans; Child; Female; Smith-Magenis Syndrome; Transcription Factors; Trans-Activators; Phenotype; Mutation; Eczema
PubMed: 37756600
DOI: 10.1177/03000605231190553 -
Journal of Neurodevelopmental Disorders Apr 2024Overactivity is prevalent in several rare genetic neurodevelopmental syndromes, including Smith-Magenis syndrome, Angelman syndrome, and tuberous sclerosis complex,...
BACKGROUND
Overactivity is prevalent in several rare genetic neurodevelopmental syndromes, including Smith-Magenis syndrome, Angelman syndrome, and tuberous sclerosis complex, although has been predominantly assessed using questionnaire techniques. Threats to the precision and validity of questionnaire data may undermine existing insights into this behaviour. Previous research indicates objective measures, namely actigraphy, can effectively differentiate non-overactive children from those with attention-deficit hyperactivity disorder. This study is the first to examine the sensitivity of actigraphy to overactivity across rare genetic syndromes associated with intellectual disability, through comparisons with typically-developing peers and questionnaire overactivity estimates.
METHODS
A secondary analysis of actigraphy data and overactivity estimates from The Activity Questionnaire (TAQ) was conducted for children aged 4-15 years with Smith-Magenis syndrome (N=20), Angelman syndrome (N=26), tuberous sclerosis complex (N=16), and typically-developing children (N=61). Actigraphy data were summarized using the M10 non-parametric circadian rhythm variable, and 24-hour activity profiles were modelled via functional linear modelling. Associations between actigraphy data and TAQ overactivity estimates were explored. Differences in actigraphy-defined activity were also examined between syndrome and typically-developing groups, and between children with high and low TAQ overactivity scores within syndromes.
RESULTS
M10 and TAQ overactivity scores were strongly positively correlated for children with Angelman syndrome and Smith-Magenis syndrome. M10 did not substantially differ between the syndrome and typically-developing groups. Higher early morning activity and lower evening activity was observed across all syndrome groups relative to typically-developing peers. High and low TAQ group comparisons revealed syndrome-specific profiles of overactivity, persisting throughout the day in Angelman syndrome, occurring during the early morning and early afternoon in Smith-Magenis syndrome, and manifesting briefly in the evening in tuberous sclerosis complex.
DISCUSSION
These findings provide some support for the sensitivity of actigraphy to overactivity in children with rare genetic syndromes, and offer syndrome-specific temporal descriptions of overactivity. The findings advance existing descriptions of overactivity, provided by questionnaire techniques, in children with rare genetic syndromes and have implications for the measurement of overactivity. Future studies should examine the impact of syndrome-related characteristics on actigraphy-defined activity and overactivity estimates from actigraphy and questionnaire techniques.
Topics: Child; Humans; Smith-Magenis Syndrome; Angelman Syndrome; Tuberous Sclerosis; Intellectual Disability
PubMed: 38637764
DOI: 10.1186/s11689-024-09535-y -
Bioengineering (Basel, Switzerland) Nov 2023Perceptual and statistical evidence has highlighted voice characteristics of individuals affected by genetic syndromes that differ from those of normophonic subjects. In...
Perceptual and statistical evidence has highlighted voice characteristics of individuals affected by genetic syndromes that differ from those of normophonic subjects. In this paper, we propose a procedure for systematically collecting such pathological voices and developing AI-based automated tools to support differential diagnosis. Guidelines on the most appropriate recording devices, vocal tasks, and acoustical parameters are provided to simplify, speed up, and make the whole procedure homogeneous and reproducible. The proposed procedure was applied to a group of 56 subjects affected by Costello syndrome (CS), Down syndrome (DS), Noonan syndrome (NS), and Smith-Magenis syndrome (SMS). The entire database was divided into three groups: pediatric subjects (PS; individuals < 12 years of age), female adults (FA), and male adults (MA). In line with the literature results, the Kruskal-Wallis test and post hoc analysis with Dunn-Bonferroni test revealed several significant differences in the acoustical features not only between healthy subjects and patients but also between syndromes within the PS, FA, and MA groups. Machine learning provided a k-nearest-neighbor classifier with 86% accuracy for the PS group, a support vector machine (SVM) model with 77% accuracy for the FA group, and an SVM model with 84% accuracy for the MA group. These preliminary results suggest that the proposed method based on acoustical analysis and AI could be useful for an effective, non-invasive automatic characterization of genetic syndromes. In addition, clinicians could benefit in the case of genetic syndromes that are extremely rare or present multiple variants and facial phenotypes.
PubMed: 38135966
DOI: 10.3390/bioengineering10121375