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Journal of Clinical Medicine Jun 2024: Strict regimens of restricted caloric intake and daily physical exercise are life-saving in Prader-Willi syndrome (PWS) but are extremely challenging in home...
: Strict regimens of restricted caloric intake and daily physical exercise are life-saving in Prader-Willi syndrome (PWS) but are extremely challenging in home environments. PWS-specialized hostels (SH) succeed in preventing morbid obesity and in coping with behavioral disorders; however, effects of restricted living environments on quality of life (QOL) have not been described. Evidence on QOL is critical for clinicians involved in placement decisions. : We examined the impact of living in SH versus at home or in non-specialized hostels (H and NSH) on QOL, behavior, and health parameters. All 58 adults (26 males) followed-up in the National Multidisciplinary Clinic for PWS were included: 33 resided in SH, 18 lived at home, and 7 lived in NSH. Questionnaires were administered to primary caregivers to measure QOL, and data were obtained from the medical records. : The H and NSH group were compared with those for adults in SH. Despite strict diet and exercise regimens, QOL was similar for both groups. Eight-year follow-up showed that food-seeking behavior decreased in SH but increased in H and NSH. BMI, cholesterol, and triglyceride levels were lower in SH. : Our results suggest that living in SH is associated with benefits for physical health and behavior without negatively affecting QOL.
PubMed: 38893034
DOI: 10.3390/jcm13113323 -
Orphanet Journal of Rare Diseases Jun 2024Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in...
BACKGROUND
Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in PWS is crucial for improved genetic counseling and prognosis. In this study, we aimed to investigate the correlation between genotype and phenotype in 45 PWS patients who previously underwent methylation-sensitive high-resolution melting (MS-HRM) for diagnosis.
RESULTS
We employed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and Sanger sequencing, along with collecting phenotypic data from the patients for comparison. Among the 45 patients, 29 (64%) exhibited a deletion of 15q11-q13, while the remaining 16 (36%) had uniparental disomy. No statistically significant differences were found in the main signs and symptoms of PWS. However, three clinical features showed significant differences between the groups. Deletion patients had a higher prevalence of myopia than those with uniparental disomy, as well as obstructive sleep apnea and an unusual skill with puzzles.
CONCLUSIONS
The diagnostic tests (MS-HRM, MS-MLPA, and Sanger sequencing) yielded positive results, supporting their applicability in PWS diagnosis. The study's findings indicate a general similarity in the genotype-phenotype correlation across genetic subtypes of PWS.
Topics: Humans; Prader-Willi Syndrome; Female; Male; Genotype; Phenotype; Brazil; Child, Preschool; Child; Adolescent; Adult; Uniparental Disomy; Chromosomes, Human, Pair 15; Infant; Young Adult
PubMed: 38902749
DOI: 10.1186/s13023-024-03157-2 -
Journal of Neurodevelopmental Disorders Nov 2023The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman...
OBJECTIVE
The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]).
METHODS
Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences.
RESULTS
The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications.
CONCLUSION
Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.
Topics: Humans; Child; Infant; Prader-Willi Syndrome; Chromosome Disorders; Chromosomes; Angelman Syndrome; Trisomy
PubMed: 37936142
DOI: 10.1186/s11689-023-09504-x -
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 -
Journal of Clinical Medicine Aug 2023This literature review of growth hormone (GH) therapy and sleep-related health outcomes in children diagnosed with Prader-Willi syndrome (PWS) assembles evidence for the... (Review)
Review
This literature review of growth hormone (GH) therapy and sleep-related health outcomes in children diagnosed with Prader-Willi syndrome (PWS) assembles evidence for the consequences of sleep deprivation and poor sleep quality: difficulty concentrating and learning at school, behavioral problems, diminished quality of life, and growth impairment. Sleep-disordered breathing (SDB) is another factor that impacts a child's well-being. We searched the electronic databases Medline PubMed Advanced Search Builder, Scopus, and Web of Science using MeSH terms and text words to retrieve articles on GH deficiency, recombinant human growth hormone (rhGH) therapy, sleep quality, SDB, and PWS in children. The censor date was April 2023. The initial search yielded 351 articles, 23 of which were analyzed for this review. The study findings suggest that while GH may have a role in regulating sleep, the relationship between GH treatment and sleep in patients with PWS is complex and influenced by GH dosage, patient age, and type and severity of respiratory disorders, among other factors. GH therapy can improve lung function, linear growth, and body composition in children with PWS; however, it can also trigger or worsen obstructive sleep apnea or hypoventilation in some. Long-term GH therapy may contribute to adenotonsillar hypertrophy and exacerbate sleep apnea in children with PWS. Finally, GH therapy can improve sleep quality in some patients but it can also cause or worsen SDB in others, leading to diminished sleep quality and overall quality of life. The current evidence suggests that the initial risk of worsening SDB may improve with long-term therapy. In conclusion, rhGH is the standard for managing patients with PWS. Nonetheless, its impact on respiratory function during sleep needs to be thoroughly evaluated. Polysomnography is advisable to assess the need for adenotonsillectomy before initiating rhGH therapy. Close monitoring of sleep disorders in patients with PWS receiving GH therapy is essential to ensure effective and safe treatment.
PubMed: 37685570
DOI: 10.3390/jcm12175504 -
World Journal of Pediatrics : WJP Jan 2024Obesity is a multifactorial chronic disease with a high, increasing worldwide prevalence. Genetic causes account for 7% of the cases in children with extreme obesity. (Review)
Review
BACKGROUND
Obesity is a multifactorial chronic disease with a high, increasing worldwide prevalence. Genetic causes account for 7% of the cases in children with extreme obesity.
DATA SOURCES
This narrative review was conducted by searching for papers published in the PubMed/MEDLINE, Embase and SciELO databases and included 161 articles. The search used the following search terms: "obesity", "obesity and genetics", "leptin", "Prader-Willi syndrome", and "melanocortins". The types of studies included were systematic reviews, clinical trials, prospective cohort studies, cross-sectional and prospective studies, narrative reviews, and case reports.
RESULTS
The leptin-melanocortin pathway is primarily responsible for the regulation of appetite and body weight. However, several important aspects of the pathophysiology of obesity remain unknown. Genetic causes of obesity can be grouped into syndromic, monogenic, and polygenic causes and should be assessed in children with extreme obesity before the age of 5 years, hyperphagia, or a family history of extreme obesity. A microarray study, an analysis of the melanocortin type 4 receptor gene mutations and leptin levels should be performed for this purpose. There are three therapeutic levels: lifestyle modifications, pharmacological treatment, and bariatric surgery.
CONCLUSIONS
Genetic study technologies are in constant development; however, we are still far from having a personalized approach to genetic causes of obesity. A significant proportion of the affected individuals are associated with genetic causes; however, there are still barriers to its approach, as it continues to be underdiagnosed. Video Abstract (MP4 1041807 KB).
Topics: Child; Humans; Child, Preschool; Leptin; Prospective Studies; Cross-Sectional Studies; Obesity; Obesity, Morbid; Melanocortins
PubMed: 37725322
DOI: 10.1007/s12519-023-00757-z -
European Journal of Pediatrics Mar 2024Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of imprinted gene expression on the paternal chromosome 15q11-q13. PWS is characterized by... (Review)
Review
Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of imprinted gene expression on the paternal chromosome 15q11-q13. PWS is characterized by varying degrees of early psychomotor developmental deficits, primarily in cognition, language, and motor development. This review summarizes the early mental cognitive development, language development, and motor development in patients with PWS, compares the correlation of genotype with phenotype, and provides an update regarding the effects and concerns related to potential main side effects of treatment with recombinant human growth hormone on early psycho-cognitive and motor function development along with the linear growth and body composition of children with PWS.Conclusion: Early psychomotor development is strongly correlated with the prognosis of patients with PWS; moreover, current studies support that the initiation of interventions at an early age can exert significant beneficial effects on enhancing the cognitive and linguistic development of patients with PWS and allow them to "catch up" with motor development. What is Known: • Prader-Willi syndrome is a rare genetic disorder characterized by multisystem damage, and children with Prader-Willi syndrome are typically characterized by early developmental delays, specifically in the areas of cognitive and motor development. • Recombinant human growth hormone therapy is the only medical treatment approved for Prader-Willi syndrome. What is New: • Extensive presentation of psycho-cognitive and motor development features and genotype-phenotype correlation in children with Prader-Willi syndrome. • The effects of growth hormone on early psychomotor development in children with Prader-Willi syndrome were thoroughly reviewed, including their short- and long-term outcomes and any associated adverse effects.
Topics: Child; Humans; Human Growth Hormone; Growth Hormone; Prader-Willi Syndrome; Cognition; Growth and Development
PubMed: 37987848
DOI: 10.1007/s00431-023-05327-z -
Wiley Interdisciplinary Reviews. RNA Sep 2023The 14q32.2 (DLK1-DIO3) and 15q11-q13 (SNURF-SNRPN) imprinted gene loci harbor the largest known small nucleolar RNA clusters expressed from the respective maternal and... (Review)
Review
The 14q32.2 (DLK1-DIO3) and 15q11-q13 (SNURF-SNRPN) imprinted gene loci harbor the largest known small nucleolar RNA clusters expressed from the respective maternal and paternal alleles. Recent studies have demonstrated significant roles for the 15q11-q13 located SNORD115-SNORD116 C/D box snoRNAs in Prader-Willi syndrome (PWS), a neurodevelopmental disorder. Even though the effect of SNORD116 deletion is apparent in the PWS phenotype, similar effects of a SNORD113-SNORD114 cluster deletion from the 14q32.2 locus in Kagami-Ogata syndrome (KOS14) and upregulation in Temple syndrome (TS14) remain to be explored. Moreover, apart from their probable involvement in neurodevelopmental disorders, snoRNAs from the SNORD113-SNORD114 cluster have been implicated in multiple biological processes, including pluripotency, development, cancers, and RNA modifications. Here we summarize the current understanding of the system to explore the possibility of a link between developmental disorders and C/D box snoRNA expression from the imprinted 14q32.2 locus. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development RNA Processing > Processing of Small RNAs.
PubMed: 37722601
DOI: 10.1002/wrna.1818 -
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 -
Orphanet Journal of Rare Diseases Feb 2024Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal... (Review)
Review
BACKGROUND
Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal locus 15q11-13. This absence of expression occurs as a consequence of a deletion on the chromosome 15 of paternal origin (ca. 70%), a chromosome 15 maternal uniparental disomy (mUPD; ca. 25%), or an imprinting centre defect (IC; ca. 1-3%). At birth, individuals with PWS are severely hypotonic and fail to thrive. Hyperphagia and characteristic physical and neuropsychiatric phenotypes become apparent during childhood. The risk for the development of a co-morbid psychotic illness increases during the teenage years, specifically in those with PWS due to the presence of an mUPD. The primary aim of this literature review is to inform clinical practice. To achieve this, we have undertaken a systematic analysis of the clinical research literature on prevalence, presentation, course, characteristics, diagnosis and treatment of psychotic illness in people with PWS. The secondary aim is to identify clinical aspects of psychotic illness in PWS in need of further investigation.
METHODS AND FINDINGS
A systematic literature review on psychosis in PWS was conducted on the databases Web of Knowledge, PubMed and Scopus, using the terms "((Prader-Willi syndrome) OR (Prader Willi Syndrome)) AND ((psychosis) OR (psychotic illness))". All articles written in English and reporting original human research were reviewed. In all but three of the 16 cohort studies in which the genetic types were known, the authors reported higher rates of psychosis in people with PWS resulting from an mUPD, compared to those with the deletion subtype of PWS. When psychosis was present the presentation was psychosis similar regardless of genetic type and was usually characterised by an acute onset of hallucinations and delusions accompanied by confusion, anxiety and motor symptoms.
CONCLUSIONS
The onset of confusion, an affective cyclical pattern with the presence of abnormal mental beliefs and experiences, usually of rapid onset is suggestive of the development of psychotic illness. Phenomenologically, this psychosis in people with PWS is atypical in comparison to schizophrenia and bipolar disorder in the general population. The relationship to psychosis in the general population and the optimum treatments remain uncertain.
Topics: Adolescent; Infant, Newborn; Humans; Prader-Willi Syndrome; Psychotic Disorders; Comorbidity; Family; Anxiety; Chromosomes, Human, Pair 15
PubMed: 38360662
DOI: 10.1186/s13023-024-03026-y