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Frontiers in Endocrinology 2023Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and...
BACKGROUND
Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria.
METHODS
We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS.
RESULTS
We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (=0.027, =0.019, <0.001, <0.001, =0.011 and respectively).
CONCLUSION
Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS.
Topics: Humans; Adult; Male; Young Adult; Female; Cohort Studies; Prader-Willi Syndrome; Diabetes Mellitus, Type 2; Retrospective Studies; Creatinine; Albuminuria; Hypertension; Cardiovascular Diseases; Renal Insufficiency, Chronic; Albumins
PubMed: 37547314
DOI: 10.3389/fendo.2023.1168648 -
Frontiers in Genetics 2021Establishing or ruling out a molecular diagnosis of Prader-Willi or Angelman syndrome (PWS/AS) presents unique challenges due to the variety of different genetic...
Establishing or ruling out a molecular diagnosis of Prader-Willi or Angelman syndrome (PWS/AS) presents unique challenges due to the variety of different genetic alterations that can lead to these conditions. Point mutations, copy number changes, uniparental isodisomy (i-UPD) 15 of two subclasses (segmental or total isodisomy), uniparental heterodisomy (h-UPD), and defects in the chromosome 15 imprinting center can all cause PWS/AS. Here, we outline a combined approach using whole-exome sequencing (WES) and DNA methylation data with methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) to establish both the disease diagnosis and the mechanism of disease with high sensitivity using current standard of care technology and improved efficiency compared to serial methods. The authors encourage the use of this approach in the clinical setting to confirm and establish the diagnosis and genetic defect which may account for the secondary genetic conditions that may be seen in those with isodisomy 15, impacting surveillance and counseling with more accurate recurrence risks. Other similarly affected individuals due to other gene disorders or cytogenetic anomalies such as Rett syndrome or microdeletions would also be identified with this streamlined approach.
PubMed: 34046054
DOI: 10.3389/fgene.2021.608889 -
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 -
BMC Pediatrics Feb 2024Prader-Willi syndrome (PWS) is a rare genetic disease often associated with bone problems, mainly scoliosis and hip dysplasia (HD). This study aimed to analyze the...
BACKGROUND
Prader-Willi syndrome (PWS) is a rare genetic disease often associated with bone problems, mainly scoliosis and hip dysplasia (HD). This study aimed to analyze the clinical characteristics of orthopedic deformities in patients with PWS.
METHODS
A retrospective study was conducted on 175 patients up to March 2023. The Cobb angle(CA) of the spine, the alpha angle of the hip joint, and the acetabular index (AI) were measured. This study aimed to evaluate the relationship between demographic parameters and bone deformities.
RESULTS
Scoliosis was found in 66 patients (43.7%), including 52 (78.8%) with mild scoliosis, 10 (15.2%) with moderate scoliosis, and 4 (6.1%) with severe scoliosis. Only seven patients received orthopedic treatment (10.6%). The median age of scoliosis was 4.5 years old, and the prevalence of scoliosis increased rapidly at the age of 5 years and adolescence. The mean CA in this study increased gradually with age. HD was found in 47 patients (38.2%), and 6 patients received orthopedic treatment (12.7%). The median age at HD was 1.8 years old. The mean AI of the study population decreased with age. The prevalence of HD treated with recombinant human growth hormone (rhGH) was low. No significant differences were observed in sex, genotype, body mass index (BMI), obesity rate, or onset of scoliosis and HD.
CONCLUSION
The prevalence of scoliosis and HD was higher in patients with PWS. The onset age and developmental trends of the different skeletal malformations were different. Early diagnosis and treatment are important for the prognosis and treatment of orthopedic diseases in patients with PWS.
Topics: Child; Adolescent; Humans; Child, Preschool; Infant; Prader-Willi Syndrome; Scoliosis; Retrospective Studies; Human Growth Hormone; Obesity
PubMed: 38355440
DOI: 10.1186/s12887-024-04603-7 -
Orphanet Journal of Rare Diseases Feb 2022Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder with distinct genetic and clinical features. Among other clinical symptoms, PWS is characterized by...
BACKGROUND
Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder with distinct genetic and clinical features. Among other clinical symptoms, PWS is characterized by severe infantile hypotonia with feeding problems, childhood onset hyperphagia, obesity, scoliosis, short stature combined with growth hormone deficiency and developmental delay. PWS is associated with facial dysmorphology, orofacial dysfunction, oral abnormalities, low salivary flow and subsequent severe tooth wear. Little is known about the craniofacial growth direction or dental and skeletal relationships in individuals with PWS in different ages. The purpose of this study was to assess the craniofacial and dentoalveolar characteristics and to investigate the craniofacial growth direction separately in children, young adults and adults with PWS, using a cephalometric analysis of lateral cephalograms.
RESULTS
Lateral cephalograms of 42 individuals with a confirmed genetic diagnosis of PWS were analysed and divided into three groups according to their age: Children (< 12 years), young adults (12-20 years) and adults (> 20 years). Cephalometric variables were compared between PWS patients and controls by age and sex. Significant deviations and distinct craniofacial patterns were found in children, young adults and adults with PWS compared with the control group. Children showed retrognatic mandible with a skeletal class II relationship, posterior growth direction and longer anterior face height. The young adults had smaller cranial base angle, a skeletal class II pattern and a higher anterior lower face than the control group. Adults with PWS had a prognathic mandible, skeletal class III relationship with anterior growth direction, more retroclined lower incisors and proclined upper incisors than the controls. Similar results were found when comparing the three groups with PWS; the adults had a prognathic mandible, skeletal class III pattern and anterior growth direction. Children had a retropositioned mandibula, skeletal class II relationship and posterior growth direction.
CONCLUSION
This study may contribute to a better understanding of the craniofacial growth pattern in children, young adults and adults with PWS and may have a clinical importance when planning dental treatment, such as prosthodontics and/or orthodontics.
Topics: Case-Control Studies; Cephalometry; Child; Humans; Muscle Hypotonia; Prader-Willi Syndrome; Scoliosis; Young Adult
PubMed: 35193626
DOI: 10.1186/s13023-022-02222-y -
Endocrine Connections Jun 2024Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000.... (Review)
Review
Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability, and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.
PubMed: 38838713
DOI: 10.1530/EC-24-0091 -
Genes Feb 2020Prader-Willi syndrome (PWS) is recognized as the first example of genomic imprinting, generally due to a de novo paternal 15q11-q13 deletion. PWS is considered the most... (Review)
Review
Prader-Willi syndrome (PWS) is recognized as the first example of genomic imprinting, generally due to a de novo paternal 15q11-q13 deletion. PWS is considered the most common genetic cause of marked obesity in humans. Scoliosis, kyphosis, and kyphoscoliosis are commonly seen in children and adolescents with PWS with a prevalence of spinal deformities cited between 15% to 86%. Childhood risk is 70% or higher, until skeletal maturity, with a bimodal age distribution with one peak before 4 years of age and the other nearing adolescence. As few reports are available on treating scoliosis in PWS, we described clinical observations, risk factors, therapeutic approaches and opinions regarding orthopedic care based on 20 years of clinical experience. Treatments include diligent radiographic screening, starting once a child can sit independently, ongoing physical therapy, and options for spine casting, bracing and surgery, depending on the size of the curve, and the child's age. Similarly, there are different surgical choices including a spinal fusion at or near skeletal maturity, versus a construct that allows continued growth while controlling the curve for younger patients. A clear understanding of the risks involved in surgically treating children with PWS is important and will be discussed.
Topics: Adolescent; Child; Chromosome Deletion; Chromosomes, Human, Pair 15; Genomic Imprinting; Humans; Kyphosis; Prader-Willi Syndrome; Risk Factors; Scoliosis; Spinal Fusion
PubMed: 32121146
DOI: 10.3390/genes11030260 -
International Journal of Molecular... Oct 2022This article reviews what we know of the phenotype and genotype of Prader-Willi syndrome and hypothesizes two possible paths from phenotype to genotype. It then suggests... (Review)
Review
This article reviews what we know of the phenotype and genotype of Prader-Willi syndrome and hypothesizes two possible paths from phenotype to genotype. It then suggests research that may strengthen the case for one or other of these hypotheses.
Topics: Humans; Prader-Willi Syndrome; Phenotype; Genotype
PubMed: 36292940
DOI: 10.3390/ijms232012089 -
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 -
Current Issues in Molecular Biology Jun 2023Prader-Willi Syndrome (PWS) is a genetic neurodevelopmental disorder that is caused by either the deletion of the paternal allele of 15q11-q13, maternal uniparental... (Review)
Review
Prader-Willi Syndrome (PWS) is a genetic neurodevelopmental disorder that is caused by either the deletion of the paternal allele of 15q11-q13, maternal uniparental disomy of chromosome 15 or defects in the chromosome 15 imprinting centre and is characterized by cognitive impairment, hyperphagia and low metabolic rate with significant risk of obesity, as well as a variety of other maladaptive behaviours and autistic spectrum disorder (ASD). Many of the features seen in PWS are thought to be due to hypothalamic dysfunction resulting in hormonal abnormalities and impaired social functioning. The preponderance of evidence indicates that the Oxytocin system is dysregulated in PWS individuals and that this neuropeptide pathways may provide promising targets for therapeutic intervention although the process by which this dysregulation occurs in PWS awaits mechanistic investigation. PWS individuals present abnormalities in thermoregulation an impaired detection for temperature change and altered perception of pain indicating an altered autonomic nervous system. Recent studies indicate that Oxytocin is involved in thermoregulation and pain perception. This review will describe the update on PWS and the recent discoveries on Oxytocin regulation of thermogenesis together with the potential link between Oxytocin regulation of thermogenesis and PWS to create a new groundwork for the treatment of this condition.
PubMed: 37367062
DOI: 10.3390/cimb45060313