scholarly journals Ghrelin-Reactive Autoantibodies are elevated in Children with Prader-Willi Syndrome

2016 ◽  
Author(s):  
Gabrielle Crisp ◽  
Ohn Nyunt ◽  
Lisa Chopin ◽  
Inge Seim ◽  
Mark Harris ◽  
...  
Keyword(s):  
Pediatric Population ◽  
Genetic Disorder ◽  
Peptide Hormone ◽  
Prader Willi Syndrome ◽  
Acylated Ghrelin ◽  
Carrier Proteins ◽  
Unacylated Ghrelin ◽  
Complex Genetic Disorder ◽  
Growth Abnormalities ◽  
Insatiable Appetite

AbstractPrader-Willi Syndrome (PWS) is a complex genetic disorder characterized by developmental and growth abnormalities, insatiable appetite, and excessive eating (hyperphagia). The underlying cause of hyperphagia in PWS is currently unknown, however, elevated levels of the peptide hormone ghrelin is believed to contribute. Recently, ghrelin-reactive autoantibodies (isotype IgG) were identified in non-genetic obesity. These autoantibodies act as ghrelin carrier proteins and potentiate its orexigenic effects. Here, we describe the identification of ghrelin-reactive autoantibodies in a cohort of 16 children with PWS. In comparison to unaffected siblings, autoantibody levels are significantly increased in PWS children. We further show that autoantibody levels are unaffected by food intake, unlike plasma ghrelin which declines postprandially in both groups. Critically, we also demonstrate that the autoantibodies bind the major circulating ghrelin isoforms, unacylated ghrelin, which does not stimulate appetite, and the orexigen acylated ghrelin. In excess, unacylated ghrelin may compete with acylated ghrelin for autoantibody binding. Taken together, this is the first report on ghrelin-reactive antibodies in a pediatric population, and the first to demonstrate that the antibodies do not discriminate between orexigenic and non-orexigenic ghrelin isoforms. Our work suggests that ghrelin autoantibodies can be targeted using non-orexigenic forms of ghrelin, thereby providing a novel therapeutic target for PWS and for obesity in general.

scholarly journals SUN-609 Livoletide (AZP-531), an Unacylated Ghrelin Analogue, Improves Hyperphagia and Food-Related Behaviors Both in Obese and Non-Obese People with Prader-Willi Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Rania Harisseh ◽  
Thomas Delale ◽  
Michael Yeh ◽  
Soraya Allas
Keyword(s):  
Genetic Disorder ◽  
The Body ◽  
Controlled Study ◽  
Prader Willi Syndrome ◽  
Obese People ◽  
Double Blind ◽  
Unacylated Ghrelin ◽  
Pivotal Study ◽  
Significant Difference ◽  
Significant Burden

Abstract Prader-Willi syndrome (PWS) is a rare, complex neuro-developmental genetic disorder characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity and early mortality and to significant burden on patients and caregivers. While a majority of people with PWS is obese, hyperphagia is observed in both obese and non-obese people with PWS. There is currently no approved treatment for hyperphagia in PWS. People with PWS have increased circulating levels of the orexigenic hormone acylated ghrelin (AG) with a relative deficit of unacylated ghrelin (UAG), a hormone which counteracts many of AG’s effects. Livoletide (AZP-531) is a first-in-class UAG analogue previously shown to improve hyperphagia, food-related behaviors, and metabolic parameters, and to be well-tolerated in a Phase 2a trial in PWS. [Allas S et al. (2018) PLoS ONE 13(1): e0190849] Here we present additional analyses that examine the effects of livoletide in obese vs non-obese people with hyperphagia in PWS. Methods: The Phase 2a trial was a randomized, double-blind, placebo-controlled study which included 47 people with PWS. Participants received a daily subcutaneous injection of livoletide (n=23) or placebo (n=24) during a 2-week treatment period. The study population was divided based on the body mass index (BMI) into obese (BMI ≥ 30 kg/m2) and non-obese (BMI < 30 kg/m2) groups. The effect of livoletide on hyperphagia and food-related behaviors was assessed by the change from baseline in the 9-item Hyperphagia Questionnaire (HQ). Results: There was a total of 34 obese and 13 non-obese subjects in the study. As expected, baseline BMI, body weight (BW) and waist circumference (WC) were significantly higher in obese vs. non-obese PWS subjects (BMI: 42.6 ± 6.0 vs 26.1 ± 2.8, BW: 103.5 ± 23.0 vs 68.5 ± 9.1 and WC: 118.3 ± 15.5 vs 91.8 ± 7.7, respectively, p<0.0001). There was no significant difference with respect to the ratios of males to females or of deletion to non-deletion between the 2 populations. Hyperphagia scores were similar at baseline for obese and non-obese participants (HQ score adjusted for 0 to 36 scale to reflect 9-item HQ-CT: 12.8 ± 7.0 vs 14.0 ± 7.8, p=0.6083, respectively). Fasting AG and UAG levels were lower in the obese vs. non-obese groups (AG: 93.6 ± 72.6 vs 122.1 ± 54.4, p=0.0275, UAG: 123.9 ± 87.2 vs 154.1 ± 62.6, p=0.0219, respectively). Livoletide-treated participants experienced similar improvements in hyperphagia and food-related behaviors as measured by the HQ whether they were obese or non-obese. Conclusions: These results highlight the potential of livoletide for treating hyperphagia in both obese and non-obese people with PWS and hyperphagia. Livoletide is being investigated further in the ZEPHYR Phase 2b/3 trial, an ongoing pivotal study on the long-term safety and efficacy of livoletide in the treatment of hyperphagia and food-related behaviors in people with PWS.

scholarly journals Prader-Willi syndrome: an update on obesity and endocrine problems

2021 ◽  
Vol 26 (4) ◽  
pp. 227-236
Author(s):  
Su Jin Kim ◽  
Sung Yoon Cho ◽  
Dong-Kyu Jin
Keyword(s):  
Behavioral Problems ◽  
Genetic Disorder ◽  
Nutritional Therapy ◽  
Hormone Deficiency ◽  
Endocrine Disorders ◽  
Prader Willi Syndrome ◽  
Metabolic Complications ◽  
Obstructive Sleep ◽  
History Of ◽  
Complex Genetic Disorder

Prader-Willi syndrome (PWS) is a rare complex genetic disorder that results from a lack of expression of the paternally inherited chromosome 15q11-q13. PWS is characterized by hypotonia and feeding difficulty in early infancy and development of morbid obesity aggravated by uncontrolled hyperphagia after childhood and adolescent. Dysmorphic facial features, delayed motor and language development, various degrees of cognitive impairment, and behavioral problems are common in PWS. Without early, intensive nutritional therapy along with behavioral modification, PWS patients develop severe obesity associated with type 2 diabetes, obstructive sleep apnea, right-side heart failure, and other obesity-related metabolic complications. Hypothalamic dysfunction in PWS can lead to several endocrine disorders, including short stature with growth hormone deficiency, hypothyroidism, central adrenal insufficiency, and hypogonadism. In this review, we discuss the natural history of PWS and the mechanisms of hyperphagia and obesity. We also provide an update on obesity treatments and recommendations for screening and monitoring of various endocrine problems that can occur in PWS.

scholarly journals Hypogonadism in Patients with Prader Willi Syndrome: A Narrative Review

2021 ◽  
Vol 22 (4) ◽  
pp. 1993
Author(s):  
Luigi Napolitano ◽  
Biagio Barone ◽  
Simone Morra ◽  
Giuseppe Celentano ◽  
Roberto La Rocca ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Hormone Deficiency ◽  
Evidence Based ◽  
Prader Willi Syndrome ◽  
Complex Genetic Disorder ◽  
Evidence Based Therapy ◽  
Behavioral Disability

Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder related to the lack of a functional paternal copy of chromosome 15q11-q13. Several clinical manifestations are reported, such as short stature, cognitive and behavioral disability, temperature instability, hypotonia, hypersomnia, hyperphagia, and multiple endocrine abnormalities, including growth hormone deficiency and hypogonadism. The hypogonadism in PWS is due to central and peripheral mechanisms involving the hypothalamus-pituitary-gonadal axis. The early diagnosis and management of hypogonadism in PWS are both important for physicians in order to reach a better quality of life for these patients. The aim of this study is to summarize and investigate causes and possible therapies for hypogonadism in PWS. Additional studies are further needed to clarify the role of different genes related to hypogonadism and to establish a common and evidence-based therapy.

scholarly journals Endocrine Dysfunction in Prader-Willi Syndrome: A Review with Special Reference to GH

2001 ◽  
Vol 22 (6) ◽  
pp. 787-799 ◽  
Author(s):  
Pia Burman ◽  
E. Martin Ritzén ◽  
Ann Christin Lindgren
Keyword(s):  
Replacement Therapy ◽  
Lean Body Mass ◽  
Body Mass ◽  
Genetic Disorder ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Endocrine Disorders ◽  
Prader Willi Syndrome ◽  
Gh Treatment ◽  
Pituitary Dysfunction

Abstract Prader-Willi syndrome is a genetic disorder occurring in 1 in 10,000–16,000 live-born infants. In the general population, approximately 60 people in every 1,000,000 are affected. The condition is characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. Furthermore, morbidity and mortality are high, probably as a result of gross obesity. Most patients have reduced GH secretory capacity and hypogonadotropic hypogonadism, suggesting hypothalamic-pituitary dysfunction. Replacement of GH and/or sex hormones may therefore be beneficial in Prader-Willi syndrome, and several clinical trials have now evaluated GH replacement therapy in affected children. Results of GH treatment have been encouraging: improved growth, increased lean body mass, and reduced fat mass. There was also some evidence of improvements in respiratory function and physical activity. The long-term benefits of GH treatment are, however, still to be established. Similarly, the role of sex hormone replacement therapy needs to be clarified as few data exist on its efficacy and potential benefits. In summary, Prader-Willi syndrome is a disabling condition associated with GH deficiency and hypogonadism. More active treatment of these endocrine disorders is likely to benefit affected individuals.

Loss of FancC Function Results in Decreased Hematopoietic Stem Cell Repopulating Ability

Blood ◽  
1999 ◽  
Vol 94 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Laura S. Haneline ◽  
Troy A. Gobbett ◽  
Rema Ramani ◽  
Madeleine Carreau ◽  
Manuel Buchwald ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Genetic Disorder ◽  
Test Cell ◽  
Hematopoietic Stem ◽  
Murine Homologue ◽  
Complex Genetic Disorder

Fanconi anemia (FA) is a complex genetic disorder characterized by progressive bone marrow (BM) aplasia, chromosomal instability, and acquisition of malignancies, particularly myeloid leukemia. We used a murine model containing a disruption of the murine homologue ofFANCC (FancC) to evaluate short- and long-term multilineage repopulating ability of FancC −/− cells in vivo. Competitive repopulation assays were conducted where “test”FancC −/− or FancC +/+ BM cells (expressing CD45.2) were cotransplanted with congenic competitor cells (expressing CD45.1) into irradiated mice. In two independent experiments, we determined that FancC −/− BM cells have a profound decrease in short-term, as well as long-term, multilineage repopulating ability. To determine quantitatively the relative production of progeny cells by each test cell population, we calculated test cell contribution to chimerism as compared with 1 × 105 competitor cells. We determined that FancC −/− cells have a 7-fold to 12-fold decrease in repopulating ability compared with FancC +/+cells. These data indicate that loss of FancC function results in reduced in vivo repopulating ability of pluripotential hematopoietic stem cells, which may play a role in the development of the BM failure in FA patients. This model system provides a powerful tool for evaluation of experimental therapeutics on hematopoietic stem cell function.

scholarly journals Atypical presentation of Prader-Willi syndrome with Klinefelter (XXY karytype) and craniosynostosis

2006 ◽  
Vol 64 (2a) ◽  
pp. 303-305 ◽  
Author(s):  
Daniel R. Carvalho ◽  
Clovis S. Trad ◽  
João M. Pina-Neto
Keyword(s):  
Mental Retardation ◽  
Klinefelter Syndrome ◽  
Genetic Disorder ◽  
Prader Willi Syndrome ◽  
Atypical Presentation

Prader-Willi syndrome is a mental retardation genetic disorder also characterized by hypogonadism, hyperphagia and obesity. We report on a four-years-old boy, born to consanguineous parents, with uncommon co-occurrence of Prader-Willi syndrome, 47,XXY karyotype (Klinefelter syndrome) and coronal craniosynostosis. These are different unrelated conditions and it was not described before in the same patient to the best of our knowledge.

scholarly journals Two Monogenetic Disorders, Activated PI3-Kinase-δ Syndrome 2 and Smith–Magenis Syndrome, in One Patient: Case Report and a Literature Review of Neurodevelopmental Impact in Primary Immunodeficiencies Associated With Disturbed PI3K Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Nidia Moreno-Corona ◽  
Loïc Chentout ◽  
Lucie Poggi ◽  
Romane Thouenon ◽  
Cecile Masson ◽  
...  
Keyword(s):  
Viral Infections ◽  
Genetic Disorder ◽  
Pi3 Kinase ◽  
Pi3k Signaling ◽  
Gene Encoding ◽  
Regulatory Subunits ◽  
Neurodevelopmental Delay ◽  
Exon 11 ◽  
Complex Genetic Disorder ◽  
Splice Product

Activated PI3-kinase-δ syndrome 2 (APDS2) is caused by autosomal dominant mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits. Most diagnosed APDS2 patients carry mutations affecting either the splice donor or splice acceptor sites of exon 11 of the PIK3R1 gene responsible for an alternative splice product and a shortened protein. The clinical presentation of APDS2 patients is highly variable, ranging from mild to profound combined immunodeficiency features as massive lymphoproliferation, increased susceptibility to bacterial and viral infections, bronchiectasis, autoimmune manifestations, and occurrence of cancer. Non-immunological features such as growth retardation and neurodevelopmental delay have been reported for APDS2 patients. Here, we describe a patient suffering from an APDS2 associated with a Smith–Magenis syndrome (SMS), a complex genetic disorder affecting, among others, neurological manifestations and review the literature describing neurodevelopmental impacts in APDS2 and other PIDs/monogenetic disorders associated with dysregulated PI3K signaling.

857 Too sleepy: A pediatric case of Prader Willi Syndrome and Narcolepsy

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A333-A333
Author(s):  
Elizabeth Lam ◽  
Sonal Malhotra ◽  
Daniel Glaze
Keyword(s):  
Daytime Sleepiness ◽  
Sleep Latency ◽  
Chromosome Region ◽  
Genetic Disorder ◽  
Sleep Onset ◽  
Apnea Hypopnea Index ◽  
Prader Willi Syndrome ◽  
Obstructive Sleep ◽  
Patient Reported

Abstract Introduction Prader Willi syndrome (PWS) is a genetic disorder due to deletion of the paternal copies of genes within the chromosome region 15q11-q13. Individuals with PWS are commonly seen with obesity, sleep disordered breathing, and excessive daytime sleepiness (EDS). While the exact cause of EDS in individuals with PWS is not fully understood, there have been reports of PWS with narcolepsy-like syndrome. We report a case of a patient with PWS with findings suggesting the diagnosis of Narcolepsy Type 2. Report of case(s) Our patient is a 12-year-old male with PWS and 2nd degree heart block who was evaluated in our pediatric sleep center. He has a previous diagnosis of mild obstructive sleep apnea (OSA) with an apnea hypopnea index (oAHI) of 3.2. At 12 years of age, mother and patient reported that he had increased snoring, weight gain, EDS with a Pediatric Daytime Sleepiness Score (PDSS) of 10 and frequent refreshing naps during the daytime. Patient denied cataplexy during that visit. Subsequently, 2-week actigrapghy was performed which demonstrated an average total night sleep of 8 hours and 8 minutes. Overnight PSG with Multiple Sleep Latency Test (MSLT) demonstrated an oAHI of 4.8, total sleep time of 6.88 hours. During the MSLT, the mean sleep latency was 6.2 minutes and 5 sleep onset REM periods were observed over 5 nap opportunities. At his follow-up visit, methylphenidate was initiated after clearance by his cardiologist. Patient and mother opted for medical management of his mild OSA with Fluticisone and Montelukast. At his follow-up appointment, the patient had improvement in daytime sleepiness with a PDSS of 2 despite taking his Methylphenidate at night. Patient was instructed to switch to morning Methylphenidate dosing to optimize treatment of his EDS. Conclusion EDS is a common complaint seen in patients with PWS, however the etiology of it is not entirely understood. It is thought to be centrally mediated with components of hypersomnia and narcolepsy like-symptoms. More research is needed to better understand, diagnose and adequately treat patients with PWS and EDS. Support (if any):

Clinical Profile of Polycystic Ovarian Syndrome Patients In Tertiary Care Hospital

2021 ◽  
Vol 8 (3) ◽  
pp. 99-103
Author(s):  
Dr. Urmila Gavali ◽  
Dr. Mayuri Pawar ◽  
Dr. Gautam Aher ◽  
Dr. Suhas Shinde
Keyword(s):  
Polycystic Ovarian Syndrome ◽  
Genetic Disorder ◽  
Tertiary Care ◽  
Care Hospital ◽  
Tertiary Care Centre ◽  
Cross Sectional ◽  
Clinical Presentations ◽  
Complex Genetic Disorder ◽  
Uncertain Etiology ◽  
Ovarian Syndrome

ABSTRACT: Background: Polycystic ovarian syndrome (PCOS)is common gynecological endocrinopathy characterized by chronic anovulation and hyperandrogenism affecting 5-10% of women worldwide.  It is a heterogenous, multifactorial, complex genetic disorder with uncertain etiology and is one of the most common treatable cause of infertility. AIM: To study the various clinical presentations in polycystic ovarian syndrome. MATERIALS AND METHODS: Present study is cross sectional observational study carried out in tertiary care centre. This study was performed in the Out Patient Department of Obstetrics and Gynecology. RESULTS: The mean age of 41 patients in the study was 23.6 years. Most common presenting symptom in patients is menstrual irregularities (89%) followed by infertility and hirsutism. USG (abdo+pelvis) showing polycystic ovarian syndrome ovaries. Around 39% patients with PCOS developed insulin resistance. KEYWORDS: - Amenorrhea, Infertility, Oligomenorrhea, Polycystic Ovarian Syndrome.

Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio

2019 ◽  
Vol 57 (7) ◽  
pp. 1102-1110 ◽  
Author(s):  
Maria Donata Di Taranto ◽  
Renato de Falco ◽  
Ornella Guardamagna ◽  
Giulia Massini ◽  
Carola Giacobbe ◽  
...  
Keyword(s):  
Lipid Profile ◽  
Familial Hypercholesterolemia ◽  
Pediatric Population ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Density Lipoprotein ◽  
Compound Heterozygous ◽  
Premature Coronary Artery Disease ◽  
Degree Relative ◽  
Genetic Status

Abstract Background Familial hypercholesterolemia (FH) is a genetic disorder caused by mutations in genes involved in low-density lipoprotein (LDL) uptake (LDLR, APOB and PCSK9). Genetic diagnosis is particularly useful in asymptomatic children allowing for the detection of definite FH patients. Furthermore, defining their genetic status may be of considerable importance as the compound heterozygous status is much more severe than the heterozygous one. Our study aims at depicting the genetic background of an Italian pediatric population with FH focusing on the correlation between lipid profile and genetic status. Methods Out of 196 patients with clinically suspected FH (LDL-cholesterol [LDL-C] levels above 3.37 mmol/L, cholesterol level above 6.46 mmol/L in a first-degree relative or the presence of premature cardiovascular acute disease in a first/second-degree relative), we screened 164 index cases for mutations in the LDLR, APOB and PCSK9 genes. Results Patients with mutations (129/164) showed increased levels of LDL-C, 95th percentile-adjusted LDL-C and LDL/high-density lipoprotein (HDL) ratio and decreased levels of HDL-C, adjusted HDL-C. The association of the LDL/HDL ratio with the presence of mutations was assessed independently of age, (body mass index) BMI, parental hypercholesterolemia, premature coronary artery disease (CAD), triglycerides by multivariate logistic regression (odds ratio [OR]=1.701 [1.103–2.621], p=0.016). The LDL/HDL ratio gradually increased from patients without mutations to patients with missense mutations, null mutations and compound heterozygotes. Conclusions In conclusion, the LDL/HDL ratio proved to be a better parameter than LDL-C for discriminating patients with from patients without mutations across different genetic statuses.

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