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Frontiers in Genetics 2023Obesity is known as a heterogeneous and multifactorial disease. The distribution of body fat is crucial for the development of metabolic complications. Comprehensive...
Obesity is known as a heterogeneous and multifactorial disease. The distribution of body fat is crucial for the development of metabolic complications. Comprehensive genetic analyses on different fat tissues are rare but necessary to provide more detailed information. Therefore, we performed genetic analyses of three patients with obesity using high resolution genome wide SNP array (blood, visceral fat tissue) and fluorescence hybridization (FISH) analyses (visceral and subcutaneous fat tissue). Altogether, we identified 31 small Copy Number Variations (losses: 1p31.1, 1p22.2, 1q21.3, 2q34, 2q37.1, 3q28, 6p25.3, 7q31.33, 7q33, 8p23.3, 10q22.3, 11p15.4, 11p15.1, 11p14.2, 11p12, 13q12.3, 15q11.2-q13.1, 15q13.3, 20q13.2, 22q11.21; gains: 2q22.1-q22.2, 3p14.3, 4p16.3, 4q32.2, 6q27, 7p14.3, 7q34, 11p12, 12p11.21, 16p11.2-p11.1, 17q21.31) and 289 small copy-neutral Loss of Heterozygosity (cn-LOH). For the chromosomal region 15q11.2-q13.1, we detected a microdeletion (Prader-Willi-Syndrome) in one patient. Interestingly, we identified chromosomal SNP differences between EDTA-blood and visceral fat tissue (deletion and gain). Small losses of 7q31.33, 7q33, 11p14.2, 11p12, 13q12.3 as well as small gain of 7q34 were detected only in fat tissue and not in blood. Furthermore, FISH analyses on 7q31.33, 7q33 and 11p12 revealed differences between subcutaneous and visceral fat tissue. Generally, the deletions were detected more frequent in visceral fat tissue. Predominantly detected cn-LOH vs. CNV suggests a meaning of these cn-LOH for the pathogenesis of obesity. We conclude that the SNP array and FISH analyses used is applicable to generate more information for basic research on difficult cell subpopulations (e.g., visceral adipose tissue) and could opens up new diagnostic aspects in the field of obesity. Altogether, the significance of these mostly not yet described genetic aberrations in different fat tissues needs to confirmed in a larger series.
PubMed: 38516060
DOI: 10.3389/fgene.2023.1323052 -
Pharmacogenomics Mar 2024The study aim was to determine caregiver interest and planned utilization of pharmacogenomic (PGx) results for their child with Prader-Willi syndrome. Caregivers...
The study aim was to determine caregiver interest and planned utilization of pharmacogenomic (PGx) results for their child with Prader-Willi syndrome. Caregivers consented to PGx testing for their child and completed a survey before receiving results. Of all caregivers (n = 48), 93.8% were highly interested in their child's upcoming PGx results. Most (97.9%) planned to share results with their child's medical providers. However, only 47.9% of caregivers were confident providers would utilize the PGx results. Caregivers are interested in utilizing PGx but are uncertain providers will use these results in their child's care. More information about provider comfort with PGx utilization is needed to understand how PGx education would benefit providers and ultimately patients with PGx results.
Topics: Child; Humans; Pharmacogenetics; Caregivers; Prader-Willi Syndrome; Surveys and Questionnaires; Pharmacogenomic Testing
PubMed: 38506331
DOI: 10.2217/pgs-2023-0189 -
Frontiers in Endocrinology 2024Anti-Müllerian hormone (AMH) is a Sertoli cell-secreted glycoprotein involved in male fetal sex differentiation: it provokes the regression of Müllerian ducts, which... (Review)
Review
Anti-Müllerian hormone (AMH) is a Sertoli cell-secreted glycoprotein involved in male fetal sex differentiation: it provokes the regression of Müllerian ducts, which otherwise give rise to the Fallopian tubes, the uterus and the upper part of the vagina. In the first trimester of fetal life, AMH is expressed independently of gonadotropins, whereas from the second trimester onwards AMH testicular production is stimulated by FSH and oestrogens; at puberty, AMH expression is inhibited by androgens. AMH has also been suggested to participate in testicular descent during fetal life, but its role remains unclear. Serum AMH is a well-recognized biomarker of testicular function from birth to the first stages of puberty. Especially in boys with nonpalpable gonads, serum AMH is the most useful marker of the existence of testicular tissue. In boys with cryptorchidism, serum AMH levels reflect the mass of functional Sertoli cells: they are lower in patients with bilateral than in those with unilateral cryptorchidism. Interestingly, serum AMH increases after testis relocation to the scrotum, suggesting that the ectopic position result in testicular dysfunction, which may be at least partially reversible. In boys with cryptorchidism associated with micropenis, low AMH and FSH are indicative of central hypogonadism, and serum AMH is a good marker of effective FSH treatment. In patients with cryptorchidism in the context of disorders of sex development, low serum AMH is suggestive of gonadal dysgenesis, whereas normal or high AMH is found in patients with isolated androgen synthesis defects or with androgen insensitivity. In syndromic disorders, assessment of serum AMH has shown that Sertoli cell function is preserved in boys with Klinefelter syndrome until mid-puberty, while it is affected in patients with Noonan, Prader-Willi or Down syndromes.
Topics: Female; Humans; Male; Anti-Mullerian Hormone; Cryptorchidism; Androgens; Follicle Stimulating Hormone; Peptide Hormones
PubMed: 38501100
DOI: 10.3389/fendo.2024.1361032 -
BioRxiv : the Preprint Server For... Mar 2024Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For...
Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi Syndrome (PWS) is caused by loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control expression of the PWS gene from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.
PubMed: 38496583
DOI: 10.1101/2024.03.03.583177 -
Frontiers in Neuroscience 2024
PubMed: 38476870
DOI: 10.3389/fnins.2024.1370030 -
Frontiers in Cellular Neuroscience 2024This perspective review aims to explore the potential neurobiological mechanisms involved in the application of transcranial Direct Current Stimulation (tDCS) for Down...
This perspective review aims to explore the potential neurobiological mechanisms involved in the application of transcranial Direct Current Stimulation (tDCS) for Down syndrome (DS), the leading cause of genetically-based intellectual disability. The neural mechanisms underlying tDCS interventions in genetic disorders, typically characterized by cognitive deficits, are grounded in the concept of brain plasticity. We initially present the neurobiological and functional effects elicited by tDCS applications in enhancing neuroplasticity and in regulating the excitatory/inhibitory balance, both associated with cognitive improvement in the general population. The review begins with evidence on tDCS applications in five neurogenetic disorders, including Rett, Prader-Willi, Phelan-McDermid, and Neurofibromatosis 1 syndromes, as well as DS. Available evidence supports tDCS as a potential intervention tool and underscores the importance of advancing neurobiological research into the mechanisms of tDCS action in these conditions. We then discuss the potential of tDCS as a promising non-invasive strategy to mitigate deficits in plasticity and promote fine-tuning of the excitatory/inhibitory balance in DS, exploring implications for cognitive treatment perspectives in this population.
PubMed: 38456063
DOI: 10.3389/fncel.2024.1328963 -
European Journal of Endocrinology Mar 2024A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches.
OBJECTIVE
To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO.
DESIGN
A double-blind multicenter superiority randomized clinical in trial in two parallel arms.
SETTING
Eleven French University Hospital Centers.
PARTICIPANTS
Adults with CRO (body mass index > 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year.
INTERVENTIONS
Exenatide or placebo injected subcutaneously twice a day during 26 weeks.
MAIN OUTCOMES AND MEASURES
The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile.
RESULTS
At week 26, weight decreased from baseline by a mean of -3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. The adjusted mean treatment difference was -3.1 kg (95% confidence interval [CI] -7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: -2.3, 95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events).
CONCLUSIONS AND RELEVANCE
Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity.
Topics: Adult; Humans; Exenatide; Hypoglycemic Agents; Quality of Life; Craniopharyngioma; Obesity; Weight Loss; Feeding Behavior; Pituitary Neoplasms; Double-Blind Method
PubMed: 38450721
DOI: 10.1093/ejendo/lvae024 -
Clinical Dysmorphology Apr 2024
Review
Topics: Humans; Syndrome; Facies; Chromosome Disorders; Developmental Disabilities; Hypopituitarism; Imprinting Disorders
PubMed: 38441201
DOI: 10.1097/MCD.0000000000000491 -
Neurotherapeutics : the Journal of the... Apr 2024Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological... (Review)
Review
Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological derangements. Recent developments in advanced neuroimaging have led to a growing understanding of PWS as a neural circuit disorder, as well as subsequent interests in the application of neuromodulatory therapies. Various non-invasive and invasive device-based neuromodulation methods, including vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) have all been reported to be potentially promising treatments for addressing the major symptoms of PWS. In this systematic literature review, we summarize the recent literature that investigated these therapies, discuss the underlying circuits which may underpin symptom manifestations, and cover future directions of the field. Through our comprehensive search, there were a total of 47 patients who had undergone device-based neuromodulation therapy for PWS. Two articles described VNS, 4 tDCS, 1 rTMS and 2 DBS, targeting different symptoms of PWS, including aberrant behavior, hyperphagia and weight. Multi-center and multi-country efforts will be required to advance the field given the low prevalence of PWS. Finally, given the potentially vulnerable population, neuroethical considerations and dialogue should guide the field.
Topics: Humans; Prader-Willi Syndrome; Vagus Nerve Stimulation; Transcranial Magnetic Stimulation; Deep Brain Stimulation; Transcranial Direct Current Stimulation
PubMed: 38430811
DOI: 10.1016/j.neurot.2024.e00339 -
Journal of Clinical Sleep Medicine :... Mar 2024Our aim was to characterize the 14 and 6 like spike wave activity seen on electroencephalogram (EEG) in children with Prader-Willi syndrome (PWS) undergoing...
STUDY OBJECTIVES
Our aim was to characterize the 14 and 6 like spike wave activity seen on electroencephalogram (EEG) in children with Prader-Willi syndrome (PWS) undergoing polysomnogram (PSG).
METHODS
We performed a retrospective review of children with PWS and healthy controls who underwent diagnostic PSGs between January 1, 2007 to December 31, 2020 at SickKids, Toronto, Canada. EEGs from the PSGs were reviewed for the presence of the 14 and 6 like spike wave activity and its characteristics. Clinical correlation of the EEG variant with sleep disordered breathing indices from the PSG was also evaluated.
RESULTS
94 children with PWS and 50 healthy controls were included. The age, median (IQR) for the cohort was 1.42 (0.6, 4.2) years. There were 50 (53.2%) males in the PWS cohort. The EEG variant prevalence in this cohort was 51.0% (n=48) in children with PWS and 0% for the healthy controls. 14 and 6 Hz like spike wave activity was bilateral in 52% (25/48) children with PWS. The waves had a negative deflection in almost all patients 44/48 (92%) with PWS. It was predominantly located in the frontal leads for children with PWS, 23/48 (47.9%). It most frequently occurred during NREM stage 2 sleep for children with PWS, 25/48 (52.0%). The mean (SD) frequency was 6.8 (0.97) Hz. The median (IQR) length of the waves was 1.1 (0.8, 1.4) seconds in children with PWS. There was no correlation between the presence of the EEG variant and sleep disordered breathing indices in children with PWS.
CONCLUSIONS
14 and 6 Hz like spike wave activity EEG variant was present in more than 50% of a pediatric cohort of PWS as compared to 0% in healthy children. This EEG variant did not appear to be associated with sleep disordered breathing indices in children with PWS and is of unknown clinical significance.
PubMed: 38427317
DOI: 10.5664/jcsm.11078