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Editorial

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Open AccessEditorial

Special Issue: Genetics of Prader–Willi Syndrome

by David E. Godler and Merlin G. Butler

Genes 2021, 12(9), 1429; https://doi.org/10.3390/genes12091429 - 16 Sep 2021

Cited by 6 | Viewed by 3210

Abstract

This Special Issue includes 15 peer-reviewed articles for publication by experts in Prader–Willi syndrome (PWS) and their reflective area of interest impacting this rare disorder [...] Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

Research

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11 pages, 1759 KiB

Open AccessArticle

Genetic Subtype-Phenotype Analysis of Growth Hormone Treatment on Psychiatric Behavior in Prader-Willi Syndrome

by Andrea S. Montes, Kathryn E. Osann, June Anne Gold, Roy N. Tamura, Daniel J. Driscoll, Merlin G. Butler and Virginia E. Kimonis

Genes 2020, 11(11), 1250; https://doi.org/10.3390/genes11111250 - 23 Oct 2020

Cited by 7 | Viewed by 3034

Abstract

Prader-Willi syndrome (PWS) is a complex multisystemic condition caused by a lack of paternal expression of imprinted genes from the 15q11.2–q13 region. Limited literature exists on the association between molecular classes, growth hormone use, and the prevalence of psychiatric phenotypes in PWS. In [...] Read more.

Prader-Willi syndrome (PWS) is a complex multisystemic condition caused by a lack of paternal expression of imprinted genes from the 15q11.2–q13 region. Limited literature exists on the association between molecular classes, growth hormone use, and the prevalence of psychiatric phenotypes in PWS. In this study, we analyzed nine psychiatric phenotypes (depressed mood, anxiety, skin picking, nail picking, compulsive counting, compulsive ordering, plays with strings, visual hallucinations, and delusions) recognized in PWS and investigated associations with growth hormone treatment (GHT), deletions (DEL) and uniparental disomy (UPD) in a cohort of 172 individuals with PWS who met the criteria for analysis. Associations were explored using Pearson chi-square tests and univariable and multivariable logistic regression analyses to control for confounding exposures. This observational study of the largest dataset of patients with PWS to date suggested the following genetic subtype and phenotype correlations in psychiatric behaviors: (1) skin picking was more frequent in those with DEL vs. UPD; (2) anxiety was more common in those with UPD vs. DEL; and (3) an increased frequency of anxiety was noted in the UPD group treated with GHT compared to the DEL group. No other significant associations were found between the genetic subtype or GHT including for depressed mood, nail picking, compulsive counting, compulsive ordering, playing with strings, and visual hallucinations. Further studies will be required before any conclusions can be reached. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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12 pages, 229 KiB

Open AccessArticle

A 24-Week Physical Activity Intervention Increases Bone Mineral Content without Changes in Bone Markers in Youth with PWS

by Daniela A. Rubin, Kathleen S. Wilson, Camila E. Orsso, Erik R. Gertz, Andrea M. Haqq, Diobel M. Castner and Marilyn Dumont-Driscoll

Genes 2020, 11(9), 984; https://doi.org/10.3390/genes11090984 - 24 Aug 2020

Cited by 6 | Viewed by 3562

Abstract

Bone mineral density (BMD) is of concern in Prader-Willi syndrome (PWS). This study compared responses to a physical activity intervention in bone parameters and remodeling markers in youth with PWS (n = 45) and youth with non-syndromic obesity (NSO; n = 66). [...] Read more.

Bone mineral density (BMD) is of concern in Prader-Willi syndrome (PWS). This study compared responses to a physical activity intervention in bone parameters and remodeling markers in youth with PWS (n = 45) and youth with non-syndromic obesity (NSO; n = 66). Measurements occurred at baseline (PRE) and after 24 weeks (POST) of a home-based active games intervention with strengthening and jumping exercises (intervention group = I) or after a no-intervention period (control group = C). Dual x-ray absorptiometry scans of the hip and lumbar spine (L1-L4) determined BMD and bone mineral content (BMC). Bone markers included fasting bone-specific alkaline phosphatase (BAP) and C-terminal telopeptide of type I collagen (CTx). Both I and C groups increased their hip BMD and BMC (p < 0.001). Youth with PWS-I increased their spine BMC from PRE to POST (p < 0.001) but not youth with PWS-C (p = 1.000). Youth with NSO (I and C) increased their spine BMC between PRE and POST (all p < 0.001). Youth with PWS showed lower BAP (108.28 ± 9.19 vs. 139.07 ± 6.41 U/L; p = 0.006) and similar CTx (2.07 ± 0.11 vs.1.84 ± 0.14 ng/dL; p = 0.193) than those with NSO regardless of time. Likely, the novelty of the intervention exercises for those with PWS contributed to gains in spine BMC beyond growth. Bone remodeling markers were unaltered by the intervention. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

18 pages, 3550 KiB

Open AccessArticle

The Gut Microbiota Profile in Children with Prader–Willi Syndrome

by Ye Peng, Qiming Tan, Shima Afhami, Edward C. Deehan, Suisha Liang, Marie Gantz, Lucila Triador, Karen L. Madsen, Jens Walter, Hein M. Tun and Andrea M. Haqq

Genes 2020, 11(8), 904; https://doi.org/10.3390/genes11080904 - 7 Aug 2020

Cited by 19 | Viewed by 5865

Abstract

Although gut microbiota has been suggested to play a role in disease phenotypes of Prader–Willi syndrome (PWS), little is known about its composition in affected children and how it relates to hyperphagia. This cross-sectional study aimed to characterize the gut bacterial and fungal [...] Read more.

Although gut microbiota has been suggested to play a role in disease phenotypes of Prader–Willi syndrome (PWS), little is known about its composition in affected children and how it relates to hyperphagia. This cross-sectional study aimed to characterize the gut bacterial and fungal communities of children with PWS, and to determine associations with hyperphagia. Fecal samples were collected from 25 children with PWS and 25 age-, sex-, and body mass index-matched controls. Dietary intake data, hyperphagia scores, and relevant clinical information were also obtained. Fecal bacterial and fungal communities were characterized by 16S rRNA and ITS2 sequencing, respectively. Overall bacterial α-diversity and compositions of PWS were not different from those of the controls, but 13 bacterial genera were identified to be differentially abundant. Interestingly, the fungal community, as well as specific genera, were different between PWS and controls. The majority of the variation in the gut microbiota was not attributed to differences in dietary intake or the impact of genotype. Hyperphagia scores were associated with fungal α-diversity and relative abundance of several taxa, such as Staphylococcus, Clostridium, SMB53, and Candida. Further longitudinal studies correlating changes in the microbiome with the degree of hyperphagia and studies integrating multi-omics data are warranted. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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15 pages, 1081 KiB

Open AccessArticle

Growth Trajectories in Genetic Subtypes of Prader–Willi Syndrome

by Daisy A. Shepherd, Niels Vos, Susan M. Reid, David E. Godler, Angela Guzys, Margarita Moreno-Betancur and David J. Amor

Genes 2020, 11(7), 736; https://doi.org/10.3390/genes11070736 - 2 Jul 2020

Cited by 5 | Viewed by 3431

Abstract

Prader–Willi syndrome (PWS) is a rare disorder caused by the loss of expression of genes on the paternal copy of chromosome 15q11-13. The main molecular subtypes of PWS are the deletion of 15q11-13 and non-deletion, and differences in neurobehavioral phenotype are recognized between [...] Read more.

Prader–Willi syndrome (PWS) is a rare disorder caused by the loss of expression of genes on the paternal copy of chromosome 15q11-13. The main molecular subtypes of PWS are the deletion of 15q11-13 and non-deletion, and differences in neurobehavioral phenotype are recognized between the subtypes. This study aimed to investigate growth trajectories in PWS and associations between PWS subtype (deletion vs. non-deletion) and height, weight and body mass index (BMI). Growth data were available for 125 individuals with PWS (63 males, 62 females), of which 72 (57.6%) had the deletion subtype. There was a median of 28 observations per individual (range 2–85), producing 3565 data points distributed from birth to 18 years of age. Linear mixed models with cubic splines, subject-specific random effects and an autoregressive correlation structure were used to model the longitudinal growth data whilst accounting for the nature of repeated measures. Height was similar for males in both PWS subtypes, with non-deletion females being shorter than deletion females for older ages. Weight and BMI were estimated to be higher in the deletion subtype compared to the non-deletion subtype, with the size of difference increasing with advancing age for weight. These results suggest that individuals with deletion PWS are more prone to obesity. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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13 pages, 267 KiB

Open AccessArticle

Food and Non-Food-Related Behavior across Settings in Children with Prader–Willi Syndrome

by Marie G. Gantz, Sara M. Andrews and Anne C. Wheeler

Genes 2020, 11(2), 204; https://doi.org/10.3390/genes11020204 - 17 Feb 2020

Cited by 8 | Viewed by 3354

Abstract

This study sought to describe food- and non-food-related behaviors of children aged 3 to 18 years with Prader–Willi syndrome (PWS) in home and school settings, as assessed by 86 parents and 63 teachers using 7 subscales of the Global Assessment of Individual’s Behavior [...] Read more.

This study sought to describe food- and non-food-related behaviors of children aged 3 to 18 years with Prader–Willi syndrome (PWS) in home and school settings, as assessed by 86 parents and 63 teachers using 7 subscales of the Global Assessment of Individual’s Behavior (GAIB). General Behavior Problem, Non-Food-Related Behavior Problem, and Non-Food-Related Obsessive Speech and Compulsive Behavior (OS/CB) scores did not differ significantly between parent and teacher reports. Food-Related Behavior Problem scores were higher in parent versus teacher reports when the mother had less than a college education (difference of 13.6 points, 95% Confidence Interval (CI) 5.1 to 22). Parents assigned higher Food-Related OS/CB scores than teachers (difference of 5.7 points, 95% CI 2.4 to 9.0). Although teachers reported fewer Food-Related OS/CB, they scored overall OS/CB higher for interfering with daily activities compared with parents (difference of 0.9 points, 95% CI 0.4 to 1.4). Understanding how behaviors manifest in home and school settings, and how they vary with socio-demographic and patient characteristics can help inform strategies to reduce behavior problems and improve outcomes. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

11 pages, 1063 KiB

Open AccessArticle

Age Distribution, Comorbidities and Risk Factors for Thrombosis in Prader–Willi Syndrome

by Merlin G. Butler, Aderonke Oyetunji and Ann M. Manzardo

Genes 2020, 11(1), 67; https://doi.org/10.3390/genes11010067 - 7 Jan 2020

Cited by 10 | Viewed by 3549

Abstract

Prader–Willi syndrome (PWS) is an imprinting disorder caused by lack of expression of the paternally inherited 15q11.2–q13 chromosome region. The risk of death from obesity-related complications can worsen with age, but survival trends are improving. Comorbidities and their complications such as thrombosis or [...] Read more.

Prader–Willi syndrome (PWS) is an imprinting disorder caused by lack of expression of the paternally inherited 15q11.2–q13 chromosome region. The risk of death from obesity-related complications can worsen with age, but survival trends are improving. Comorbidities and their complications such as thrombosis or blood clots and venous thromboembolism (VTE) are uncommon but reported in PWS. Two phases of analyses were conducted in our study: unadjusted and adjusted frequency with odds ratios and a regression analysis of risk factors. Individuals with PWS or non-PWS controls with exogenous obesity were identified by specific International Classification of Diseases (ICD)-9 diagnostic codes reported on more than one occasion to confirm the diagnosis of PWS or exogenous obesity in available national health claims insurance datasets. The overall average age or average age per age interval (0–17 year, 18–64 year, and 65 year+) and gender distribution in each population were similar in 3136 patients with PWS and 3945 non-PWS controls for comparison purposes, with exogenous obesity identified from two insurance health claims dataset sources (i.e., commercial and Medicare advantage or Medicaid). For example, 65.1% of the 3136 patients with PWS were less than 18 years old (subadults), 33.2% were 18–64 years old (adults), and 1.7% were 65 years or older. After adjusting for comorbidities that were identified with diagnostic codes, we found that commercially insured PWS individuals across all age cohorts were 2.55 times more likely to experience pulmonary embolism (PE) or deep vein thrombosis (DVT) than for obese controls (p-value: 0.013; confidence interval (CI): 1.22–5.32). Medicaid-insured individuals across all age cohorts with PWS were 0.85 times more likely to experience PE or DVT than obese controls (p-value: 0.60; CI: 0.46–1.56), with no indicated age difference. Age and gender were statistically significant predictors of VTEs, and they were independent of insurance coverage. There was an increase in occurrence of thrombotic events across all age cohorts within the PWS patient population when compared with their obese counterparts, regardless of insurance type. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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11 pages, 654 KiB

Open AccessArticle

Early Diagnosis in Prader–Willi Syndrome Reduces Obesity and Associated Co-Morbidities

by Virginia E. Kimonis, Roy Tamura, June-Anne Gold, Nidhi Patel, Abhilasha Surampalli, Javeria Manazir, Jennifer L. Miller, Elizabeth Roof, Elisabeth Dykens, Merlin G. Butler and Daniel J. Driscoll

Genes 2019, 10(11), 898; https://doi.org/10.3390/genes10110898 - 6 Nov 2019

Cited by 28 | Viewed by 5580

Abstract

Prader–Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11–q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity [...] Read more.

Prader–Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11–q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS. We studied 352 subjects with PWS, recruited from the NIH Rare Disease Clinical Research Network, to determine if age at diagnosis, ethnicity, gender, and PWS molecular class influenced the age they first become heavy, as determined by their primary care providers, and the age they first developed an increased appetite and began seeking food. The median ages that children with PWS became heavy were 10 years, 6 years and 4 years for age at diagnosis < 1 year, between 1 and 3 years, and greater than 3 years of age, respectively. The age of diagnosis and ethnicity were significant factors influencing when PWS children first became heavy (p < 0.01), however gender and the PWS molecular class had no influence. Early diagnosis delayed the onset of becoming heavy in individuals with PWS, permitting early GH and other treatment, thus reducing the risk of obesity-associated co-morbidities. Non-white individuals had an earlier onset of becoming heavy. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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14 pages, 1453 KiB

Open AccessArticle

The Global Prader–Willi Syndrome Registry: Development, Launch, and Early Demographics

by Jessica Bohonowych, Jennifer Miller, Shawn E. McCandless and Theresa V. Strong

Genes 2019, 10(9), 713; https://doi.org/10.3390/genes10090713 - 14 Sep 2019

Cited by 47 | Viewed by 14583

Abstract

Advances in technologies offer new opportunities to collect and integrate data from a broad range of sources to advance the understanding of rare diseases and support the development of new treatments. Prader–Willi syndrome (PWS) is a rare, complex neurodevelopmental disorder, which has a [...] Read more.

Advances in technologies offer new opportunities to collect and integrate data from a broad range of sources to advance the understanding of rare diseases and support the development of new treatments. Prader–Willi syndrome (PWS) is a rare, complex neurodevelopmental disorder, which has a variable and incompletely understood natural history. PWS is characterized by early failure to thrive, followed by the onset of excessive appetite (hyperphagia). Additional characteristics include multiple endocrine abnormalities, hypotonia, hypogonadism, sleep disturbances, a challenging neurobehavioral phenotype, and cognitive disability. The Foundation for Prader–Willi Research’s Global PWS Registry is one of more than twenty-five registries developed to date through the National Organization of Rare Disorders (NORD) IAMRARE Registry Program. The Registry consists of surveys covering general medical history, system-specific clinical complications, diet, medication and supplement use, as well as behavior, mental health, and social information. Information is primarily parent/caregiver entered. The platform is flexible and allows addition of new surveys, including updatable and longitudinal surveys. Launched in 2015, the PWS Registry has enrolled 1696 participants from 37 countries, with 23,550 surveys completed. This resource can improve the understanding of PWS natural history and support medical product development for PWS. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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7 pages, 1395 KiB

Open AccessArticle

Venous Thromboembolism in Prader–Willi Syndrome: A Questionnaire Survey

by Ann M. Manzardo, Janalee Heinemann, Barbara McManus, Carolyn Loker, James Loker and Merlin G. Butler

Genes 2019, 10(7), 550; https://doi.org/10.3390/genes10070550 - 19 Jul 2019

Cited by 12 | Viewed by 3662

Abstract

Prader–Willi Syndrome Association (USA) monitors the ongoing health and welfare of individuals with Prader–Willi syndrome (PWS) through active communication with members by membership surveys and data registries. Thromboembolism and blood clots have emerged in clinical studies as significant risk factors for injury and [...] Read more.

Prader–Willi Syndrome Association (USA) monitors the ongoing health and welfare of individuals with Prader–Willi syndrome (PWS) through active communication with members by membership surveys and data registries. Thromboembolism and blood clots have emerged in clinical studies as significant risk factors for injury and death in PWS. A 66-item questionnaire was developed by a panel of PWS medical and scientific experts, with input from Prader–Willi Syndrome Association (USA) leadership, so as to probe their membership on the frequency, risk, and protective factors for venous thromboembolism, pulmonary embolism, and related findings. The characteristics of those with and without a reported history of blood clots and related health factors were tabulated and analyzed. Responses were obtained for 1067 individuals with PWS (554 females and 513 males), and 38 (23 females and 15 males) had a history of blood clots. The individuals with clots did not differ by gender, but were significantly older 32.8 ± 15 years vs 20.4 ± 13 years, and were more likely to have a reported history of obesity (76%), edema (59%), hypertension (24%), vasculitis (33%), and family history of blood clots (33%) than those without clots. Growth hormone treatment was more common in individuals without clots. The risk factors for thromboembolism in PWS overlap those commonly observed for the general population. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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Review

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16 pages, 709 KiB

Open AccessReview

The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity

by Neil Cowen and Anish Bhatnagar

Genes 2020, 11(4), 450; https://doi.org/10.3390/genes11040450 - 21 Apr 2020

Cited by 14 | Viewed by 5593

Abstract

To evaluate the potential role of ATP-sensitive potassium (K_ATP) channel activation in the treatment of hyperphagic obesity, a PubMed search was conducted focused on the expression of genes encoding the K_ATP channel, the response to activating the K_ATP channel [...] Read more.

To evaluate the potential role of ATP-sensitive potassium (K_ATP) channel activation in the treatment of hyperphagic obesity, a PubMed search was conducted focused on the expression of genes encoding the K_ATP channel, the response to activating the K_ATP channel in tissues regulating appetite and the establishment and maintenance of obesity, the evaluation of K_ATP activators in obese hyperphagic animal models, and clinical studies on syndromic obesity. K_ATP channel activation is mechanistically involved in the regulation of appetite in the arcuate nucleus; the regulation of hyperinsulinemia, glycemic control, appetite and satiety in the dorsal motor nucleus of vagus; insulin secretion by β-cells; and the synthesis and β-oxidation of fatty acids in adipocytes. K_ATP channel activators have been evaluated in hyperphagic obese animal models and were shown to reduce hyperphagia, induce fat loss and weight loss in older animals, reduce the accumulation of excess body fat in growing animals, reduce circulating and hepatic lipids, and improve glycemic control. Recent experience with a K_ATP channel activator in Prader–Willi syndrome is consistent with the therapeutic responses observed in animal models. K_ATP channel activation, given the breadth of impact and animal model and clinical results, is a viable target in hyperphagic obesity. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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16 pages, 4259 KiB

Open AccessReview

Clinical Observations and Treatment Approaches for Scoliosis in Prader–Willi Syndrome

by Harold J.P. van Bosse and Merlin G. Butler

Genes 2020, 11(3), 260; https://doi.org/10.3390/genes11030260 - 28 Feb 2020

Cited by 27 | Viewed by 8043

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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29 pages, 4125 KiB

Open AccessCase Report

Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome

by Janice Forster, Jessica Duis and Merlin G. Butler

Genes 2021, 12(2), 152; https://doi.org/10.3390/genes12020152 - 24 Jan 2021

Cited by 14 | Viewed by 4461

Abstract

Prader-Willi syndrome (PWS) is associated with co-morbid psychiatric symptoms (disruptive behavior, anxiety, mood disorders, and psychosis) often requiring psychotropic medications. In this clinical case series of 35 patients with PWS, pharmacogenetic testing was obtained to determine allele frequencies predicting variations in activity of [...] Read more.

Prader-Willi syndrome (PWS) is associated with co-morbid psychiatric symptoms (disruptive behavior, anxiety, mood disorders, and psychosis) often requiring psychotropic medications. In this clinical case series of 35 patients with PWS, pharmacogenetic testing was obtained to determine allele frequencies predicting variations in activity of cytochrome (CYP) P450 drug metabolizing enzymes 2D6, 2B6, 2C19, 2C9, 3A4, and 1A2. Results were deidentified, collated, and analyzed by PWS genetic subtype: 14 deletion (DEL), 16 maternal uniparental disomy (UPD) and 5 DNA-methylation positive unspecified molecular subtype (PWS Unspec). Literature review informed comparative population frequencies of CYP polymorphisms, phenotypes, and substrate specificity. Among the total PWS cohort, extensive metabolizer (EM) activity prevailed across all cytochromes except CYP1A2, which showed greater ultra-rapid metabolizer (UM) status (p < 0.05), especially among UPD. Among PWS genetic subtypes, there were statistically significant differences in metabolizing status for cytochromes 2D6, 2C19, 2C9, 3A4 and 1A2 acting on substrates such as fluoxetine, risperidone, sertraline, modafinil, aripiprazole, citalopram, and escitalopram. Gonadal steroid therapy may further impact metabolism of 2C19, 2C9, 3A4 and 1A2 substrates. The status of growth hormone treatment may affect CYP3A4 activity with gender specificity. Pharmacogenetic testing together with PWS genetic subtyping may inform psychotropic medication dosing parameters and risk for adverse events. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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7 pages, 477 KiB

Open AccessCase Report

Prader–Willi-Like Phenotype Caused by an Atypical 15q11.2 Microdeletion

by Qiming Tan, Kathryn J. Potter, Lisa Cole Burnett, Camila E. Orsso, Mark Inman, Davis C. Ryman and Andrea M. Haqq

Genes 2020, 11(2), 128; https://doi.org/10.3390/genes11020128 - 25 Jan 2020

Cited by 29 | Viewed by 4277

Abstract

We report a 17-year-old boy who met most of the major Prader–Willi syndrome (PWS) diagnostic criteria, including infantile hypotonia and poor feeding followed by hyperphagia, early-onset morbid obesity, delayed development, and characteristic facial features. However, unlike many children with PWS, he had spontaneous [...] Read more.

We report a 17-year-old boy who met most of the major Prader–Willi syndrome (PWS) diagnostic criteria, including infantile hypotonia and poor feeding followed by hyperphagia, early-onset morbid obesity, delayed development, and characteristic facial features. However, unlike many children with PWS, he had spontaneous onset of puberty and reached a tall adult stature without growth hormone replacement therapy. A phenotype-driven genetic analysis using exome sequencing identified a heterozygous microdeletion of 71 kb in size at chr15:25,296,613-25,367,633, genome build hg 19. This deletion does not affect the SNURF-SNRPN locus, but results in the loss of several of the PWS-associated non-coding RNA species, including the SNORD116 cluster. We compared with six previous reports of patients with PWS who carried small atypical deletions encompassing the snoRNA SNORD116 cluster. These patients share similar core symptoms of PWS while displaying some atypical features, suggesting that other genes in the region may make lesser phenotypic contributions. Altogether, these rare cases provide convincing evidence that loss of the paternal copy of the SNORD116 snoRNA is sufficient to cause most of the major clinical features of PWS. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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14 pages, 1381 KiB

Open AccessConcept Paper

Defining Mental and Behavioural Disorders in Genetically Determined Neurodevelopmental Syndromes with Particular Reference to Prader-Willi Syndrome

by Anthony J. Holland, Lucie C.S. Aman and Joyce E. Whittington

Genes 2019, 10(12), 1025; https://doi.org/10.3390/genes10121025 - 9 Dec 2019

Cited by 21 | Viewed by 4093

Abstract

Genetically determined neurodevelopmental syndromes are frequently associated with a particular developmental trajectory, and with a cognitive profile and increased propensity to specific mental and behavioural disorders that are particular to, but not necessarily unique to the syndrome. How should these mental and behavioural [...] Read more.

Genetically determined neurodevelopmental syndromes are frequently associated with a particular developmental trajectory, and with a cognitive profile and increased propensity to specific mental and behavioural disorders that are particular to, but not necessarily unique to the syndrome. How should these mental and behavioural disorders best be conceptualised given that similar symptoms are included in the definition of different mental disorders as listed in DSM-5 and ICD-10? In addition, a different conceptual framework, that of applied behavioural analysis, has been used to inform interventions for what are termed ‘challenging behaviours’ in contrast to types of interventions for those conditions meeting diagnostic criteria for a ‘mental disorder’. These syndrome-specific developmental profiles and associated co-morbidities must be a direct or indirect consequence of the genetic abnormality associated with that syndrome, but the genetic loci associated with the syndrome may not be involved in the aetiology of similar symptoms in the general population. This being so, should we expect underlying brain mechanisms and treatments for specific psychopathology in one group to be effective in the other? Using Prader-Willi syndrome as an example, we propose that the conceptual thinking that informed the development of the Research Domain Criteria provides a model for taxonomy of psychiatric and behavioural disorders in genetically determined neurodevelopmental syndromes. This model brings together diagnostic, psychological and developmental approaches with the aim of matching specific behaviours to identifiable neural mechanisms. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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7 pages, 219 KiB

Open AccessCase Report

Single-Case Study of Appetite Control in Prader-Willi Syndrome, Over 12-Years by the Indian Extract Caralluma fimbriata

by Joanne Griggs

Genes 2019, 10(6), 447; https://doi.org/10.3390/genes10060447 - 12 Jun 2019

Cited by 7 | Viewed by 4253

Abstract

This paper reports on the successful management of hyperphagia (exaggerated hunger) in a 14yr-old female with Prader–Willi syndrome (PWS). This child was diagnosed with PWS, (maternal uniparental disomy) at 18 months due to developmental delay, hypertonia, weight gain and extreme eating behaviour. Treatment [...] Read more.

This paper reports on the successful management of hyperphagia (exaggerated hunger) in a 14yr-old female with Prader–Willi syndrome (PWS). This child was diagnosed with PWS, (maternal uniparental disomy) at 18 months due to developmental delay, hypertonia, weight gain and extreme eating behaviour. Treatment of a supplement for appetite suppression commenced at 2 years of age. This single-case records ingestion of an Indian cactus succulent Caralluma fimbriata extract (CFE) over 12 years, resulting in anecdotal satiety, free access to food and management of weight within normal range. CFE was administered in a drink daily and dose was slowly escalated by observation for appetite suppression. Rigorous testing determined blood count, vitamins, key minerals, HbA1c, IGF-1 and function of the liver and thyroid all within normal range. The report suggests a strategy for early intervention against hyperphagia and obesity in PWS. This case was the instigator of the successful Australian PWS/CFE pilot and though anecdotal, the adolescent continues to ingest CFE followed by paediatricians at the Royal Children’s Hospital Melbourne, Victoria, Australia. Future clinical trials are worth considering, to determine an appropriate dose for individuals with PWS. Full article

(This article belongs to the Special Issue Genetics of Prader-Willi syndrome)

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