Development and validation of the Pediatric-Youth Hyperphagia Assessment for Prader-Willi syndrome.

OBJECTIVES: Hyperphagia is a highly stressful, life-threatening feature of Prader-Willi syndrome (PWS). It is important to assess this complex behavior accurately over time. This study aimed to develop and validate the Pediatric-Youth Hyperphagia Assessment for Prader-Willi syndrome (PYHAP) as a tool targeting children and adolescents. METHODS: After an extensive literature review and qualitative interviews, the final version of the PYHAP with 14 questions in 3 domains (verbal [5], behavior [4], and social [5]) was developed and tested at Samsung Medical Center in Seoul, Korea from July 2018 to September 2019. Exploratory factor analysis and confirmatory factor analysis (CFA) were performed to confirm construct validity. The correlations between the PYHAP and the Korean Children's Eating Behavior Questionnaire (K-CEBQ) were calculated to evaluate convergent and discriminant validity. Criterion validity and the validity of the response categories were also tested. RESULTS: Cronbach's alpha coefficient of the PYHAP was 0.91. The fit indices for CFA were good (comparative fit index, 0.87; standardized root mean squared residual, 0.08). The domains of the PYHAP were closely correlated with the relevant domains of the K-CEBQ. The accuracy of the PYHAP score for predicting uncontrolled hyperphagia was good (area under the curve, 0.75; 95% confidence interval, 0.65 to 0.85). CONCLUSIONS: The PYHAP was confirmed to be a reliable and valid tool to evaluate hyperphagia in children and adolescents with PWS via caregivers' assessments. It is recommended to use the PYHAP to communicate with parents or caregivers about patients' hyperphagia or to monitor and manage extreme behaviors in children with PWS.

'In the night kitchen': A scoping review on the night eating syndrome.

BACKGROUND: First described in 1955, night eating syndrome refers to an abnormal eating behavior clinically defined by the presence of evening hyperphagia (>25% of daily caloric intake) and/or nocturnal awaking with food ingestion occurring ⩾ 2 times per week. AIMS: Although the syndrome is frequently comorbid with obesity, metabolic and psychiatric disorders, its etiopathogenesis, diagnosis, assessment and treatment still remain not fully understood. METHODS: This review was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines; PubMed database was searched until 31 October 2020, using the key terms: 'Night Eating Syndrome' AND 'complications' OR 'diagnosis' OR 'drug therapy' OR 'epidemiology' OR 'etiology' OR 'physiology' OR 'physiopathology' OR 'psychology' OR 'therapy'. RESULTS: From a total of 239 citations, 120 studies assessing night eating syndrome met the inclusion criteria to be included in the review. CONCLUSION: The inclusion of night eating syndrome into the Diagnostic and Statistical Manual of Mental Disorders-5 'Other Specified Feeding or Eating Disorders' category should drive the attention of clinician and researchers toward this syndrome that is still defined by evolving diagnostic criteria. The correct identification and assessment of NES could facilitate the detection and the diagnosis of this disorder, whose bio-psycho-social roots support its multifactorial nature. The significant rates of comorbid illnesses associated with NES and the overlapping symptoms with other eating disorders require a focused clinical attention. Treatment options for night eating syndrome include both pharmacological (selective serotonin reuptake inhibitors, topiramate and melatonergic drugs) and non-pharmachological approaches; the combination of such strategies within a multidisciplinary approach should be addressed in future, well-sized and long-term studies.

Nutritional phases of Prader-Willi syndrome. / Fases nutricionales en Síndrome de Prader-Willi.

INTRODUCTION: Prader-Willi Syndrome (PWS) is the most common cause of genetic obesity. Hyperphagia and obe sity are the most associated concepts with this condition. However, undernutrition secondary to severe hypotonia and feeding difficulties is the predominant initial feature. OBJECTIVE: to reprodu ce and communicate the nutritional phases on a series of Chilean cases with PWS. PATIENTS AND METHOD: Cross-sectional study in which clinical records of PWS individuals under nutritional con trol at the Clínica Santa María in Santiago, Chile between 2017 and 2018 were analyzed. The anthro pometric references of the World Health Organization were used to carry out the nutritional as sessment. The classification into nutritional phases was according to the Miller criteria. RESULTS: 24 patients from infants to adults were included. All children aged under 9 months were in phase I and had malnutrition or were eutrophic; those between 9 and 25 months were classified in phase 2a; pa tients between 2.1 and 4.5 years were distributed between phases 1 and 2 and 66% were eutrophic; those between 4.5 to 8 years, 80% were in phase 2a and 2b and obesity begins to appear, and patients over 8 years of age, 75% were in phase 3 and all are overweight or obese. There was an association bet ween nutritional phase and age but not between it and nutritional status. CONCLUSIONS: In our series, the nutritional phases described according to age were reproduced according to those internationally described. There was no association between nutritional status and age.

Excessive eating and weight gain:A rare post-acute COVID-19 syndrome.

The coronavirus disease - 2019 (COVID-19) is a multisystem illness associated with several metabolic derangements. Studies report that post-acute COVID-19 syndromes (PACs) continue to evolve, however, polyphagia is not uncommon. Herein, we report a rare occurrence of polyphagia in a patient following acute COVID-19 illness. A-41-year-old Ugandan female with a negative past medical history presented with complains of excessive appetite, eating large amounts of food, inability to feel satisfied, failure to control desire to eat, and weight gain 6 months following recovery from a mild episode of acute COVID-19 pneumonia. Her body mass index rose to 30 Kg/m2 from 22 Kg/m2 prior to suffering from COVID-19. There was no history of polyuria, polydipsia, pruritus, or prior eating disorder or related history. Investigation found that brain computed tomography scan was normal, fasting blood sugar to be 5.6 mmol/L (normal range, 3.9-7.0 mmol/L), adrenocorticotropin hormone level to be 8.763 pg/mL (normal range, 6-40 pg/mL), erythrocyte sedimentation rate to be 12 mm/hour (0-30 mm/hour), but there was an elevation in glycosylated hemoglobin level (HbA1c, 7.7%). She was commenced on psychotherapy and behavioral changes with good outcomes. Polyphagia may be one of the rare PACs, requiring further research.

A case of isolated hypothalamitis with a literature review and a comparison with autoimmune hypophysitis.

Idiopathic hypothalamitis is a rare condition that can cause anterior pituitary dysfunction and central diabetes insipidus (CDI), occasionally accompanied by a disturbance of autonomic regulation known as hypothalamic syndrome. This condition has been described as a subtype of autoimmune (lymphocytic) hypophysitis; however, some cases of isolated hypothalamic involvement with no inflammatory lesions in either the pituitary gland or infundibulum have been reported. The detailed epidemiology and pathophysiology of isolated hypothalamitis have not been clarified. We herein report a case of a solitary hypothalamic lesion in a young woman who showed spontaneous development of CDI and panhypopituitarism accompanied by hyperphagia. The hypothalamic lesion increased from 11 × 7 to 17 × 7 mm over 16 months based on the sagittal slices of magnetic resonance imaging examinations. The negative results for anti-pituitary antibodies and anti-Rabphilin-3A antibodies suggested that upward extension of lymphocytic adenohypophysitis or infundibulo-neurohypophysitis was unlikely. Infectious disease, granulomatosis, Langerhans cell histiocytosis, vasculitis, and systemic neoplastic diseases were excluded by the findings of a laboratory investigation, cerebrospinal fluid examination, and imaging studies. To make a definitive diagnosis, we performed a ventriculoscopic biopsy of the hypothalamic lesion. Histology revealed an infiltration of nonspecific lymphoplasmacytes with no evidence of neoplasm, which was consistent with a diagnosis of idiopathic hypothalamitis. Subsequently, the patient was treated with methylprednisolone pulse therapy followed by oral prednisolone. The hypothalamic lesion improved and remained undetectable after withdrawal of the prednisolone, suggesting that the glucocorticoid treatment was effective for isolated hypothalamitis while the patient remains dependent on the replacement of multiple hormones.

Identifying stress-related eating in behavioural research: A review.

Stress is a commonly reported precipitant of overeating. Understanding the relationship between stress and food intake is important, particularly in view of the increasing prevalence of obesity. The purpose of this review is to examine how stress-related eating has been defined and measured in the literature to date. There are no established diagnostic criteria or gold standards for quantification of stress-related eating. Questionnaires relying on the accuracy of self-report are the mainstay of identifying people who tend to eat in response to stress and emotions. There is a paucity of clinical research linking objective measurements of stress and appetite with self-reported eating behaviour. Limitations of the methodological approaches used and the heterogeneity between studies leave significant knowledge gaps in our understanding of the mechanism of stress related eating, and how best to identify it. These issues are discussed, and areas for further research are explored.

Searching food during the night: the role of video-polysomnography in the characterization of the night eating syndrome.

OBJECTIVES: To describe the video-polysomnographic (VPSG) features of the night eating syndrome (NES), exploring the existence of potential subtypes. METHODS: In this study, 20 consecutive patients with NES according to the most recent diagnostic criteria underwent an overnight VPSG. None of them presented with a sleep-related eating disorder (SRED). VPSG recordings were reviewed identifying all eating episodes. For each episode, eating latency (time delay from awakening to food intake), eating duration (time between eating onset to eating offset) and sleep latency after eating offset (time delay from eating offset to sleep) were calculated. Total episode duration was considered as the time between awakening and sleep latency after eating offset. RESULTS: Ten patients fulfilled the A1 core criterion for NES (evening hyperphagia with consumption of at least 25% of the daily caloric intake after the evening meal); within this group, eight patients also fulfilled the A2 criterion (at least two episodes of nocturnal eating per week) and were thus included in the evening hyperphagia (EH) subgroup. The remaining 10 patients satisfied only the A2 core criterion for NES, constituting the nocturnal ingestion (NI) subgroup. We recorded 20 eating episodes, seven in the EH group and 13 in the NI group. In the EH subgroup, three eating episodes occurred before sleep onset, one after an awakening from non-rapid eye movement (NREM) stage 1 sleep, two from NREM stage 2 and one from REM sleep. All 13 NI episodes occurred after an awakening from sleep (1 from NREM stage 1 sleep, 8 from NREM stage 2 and four from NREM stage 3). In EH patients, eating latency, total episode duration and sleep latency after eating offset were significantly longer than in NI patients. CONCLUSION: Our VPSG data from a case series of 20 patients referred to our center for nocturnal eating indicate potential different NES subtypes. This distinction may have an impact on patients' treatment and follow-up.

Food Addiction: Implications for the Diagnosis and Treatment of Overeating.

With the obesity epidemic being largely attributed to overeating, much research has been aimed at understanding the psychological causes of overeating and using this knowledge to develop targeted interventions. Here, we review this literature under a model of food addiction and present evidence according to the fifth edition of the Diagnostic and Statistical Manual (DSM-5) criteria for substance use disorders. We review several innovative treatments related to a food addiction model ranging from cognitive intervention tasks to neuromodulation techniques. We conclude that there is evidence to suggest that, for some individuals, food can induce addictive-type behaviours similar to those seen with other addictive substances. However, with several DSM-5 criteria having limited application to overeating, the term 'food addiction' is likely to apply only in a minority of cases. Nevertheless, research investigating the underlying psychological causes of overeating within the context of food addiction has led to some novel and potentially effective interventions. Understanding the similarities and differences between the addictive characteristics of food and illicit substances should prove fruitful in further developing these interventions.

A toddler with a novel LEPR mutation.

There are numerous causes, such as environmental factors, medications, endocrine disorders, and genetic factors, that can lead to obesity. However, severe early-onset obesity with abnormal feeding behavior, mental retardation, dysmorphic features, organ-specific developmental abnormalities, and endocrine disorders suggest a genetic etiology. Mutations in genes related to the leptin-melanocortin pathway play a key role in genetic obesity. This pathway controls hypothalamic regulation of food intake. A few cases have been reported to have mutations in leptin (LEP) or leptin receptor (LEPR) genes. The cases had severe early-onset obesity, hyperphagia, and additional features, such as altered immune function, hypogonadism, and hypothyroidism. We present a 3-year-old male patient with severe early-onset obesity whose genetic analysis revealed a homozygous, novel, and pathogenic variant (c.1603+2T>C) in LEPR.

High-fat diet accelerates extreme obesity with hyperphagia in female heterozygous Mecp2-null mice.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutation of the methyl-CpG-binding protein 2 (MECP2) gene. Although RTT has been associated with obesity, the underlying mechanism has not yet been elucidated. In this study, female heterozygous Mecp2-null mice (Mecp2+/- mice), a model of RTT, were fed a normal chow diet or high-fat diet (HFD), and the changes in molecular signaling pathways were investigated. Specifically, we examined the expression of genes related to the hypothalamus and dopamine reward circuitry, which represent a central network of feeding behavior control. In particular, dopamine reward circuitry has been shown to regulate hedonic feeding behavior, and its disruption is associated with HFD-related changes in palatability. The Mecp2+/- mice that were fed the normal chow showed normal body weight and food consumption, whereas those fed the HFD showed extreme obesity with hyperphagia, an increase of body fat mass, glucose intolerance, and insulin resistance compared with wild-type mice fed the HFD (WT-HFD mice). The main cause of obesity in Mecp2+/--HFD mice was a remarkable increase in calorie intake, with no difference in oxygen consumption or locomotor activity. Agouti-related peptide mRNA and protein levels were increased, whereas proopiomelanocortin mRNA and protein levels were reduced in Mecp2+/--HFD mice with hyperleptinemia, which play an essential role in appetite and satiety in the hypothalamus. The conditioned place preference test revealed that Mecp2+/- mice preferred the HFD. Tyrosine hydroxylase and dopamine transporter mRNA levels in the ventral tegmental area, and dopamine receptor and dopamine- and cAMP-regulated phosphoprotein mRNA levels in the nucleus accumbens were significantly lower in Mecp2+/--HFD mice than those of WT-HFD mice. Thus, HFD feeding induced dysregulation of food intake in the hypothalamus and dopamine reward circuitry, and accelerated the development of extreme obesity associated with addiction-like eating behavior in Mecp2+/- mice.

An Exceptional Case of Acute Respiratory Failure Caused by Intra-Thoracic Gastric Perforation Secondary to Overeating.

An 18-year-old female patient arrived at the emergency department complaining of abdominal pain and fullness after a heavy meal. Physical examination revealed she was filthy and cover in feces, and she experienced severe abdominal distension. She died in ED and a diagnostic autopsy examination was requested. At external examination, the pathologist observed a significant dilation of the anal sphincter and suspected sexual assault, thus alerting the Judicial Authority who assigned the case to our department for a forensic autopsy. During the autopsy, we observed anal orifice expansion without signs of violence; food was found in the pleural cavity. The stomach was hyper-distended and perforated at three different points as well as the diaphragm. The patient was suffering from anorexia nervosa with episodes of overeating followed by manual voiding of her feces from the anal cavity (thus explaining the anal dilatation). The forensic pathologists closed the case as an accidental death.

Identification of novel LEPR mutations in Pakistani families with morbid childhood obesity.

BACKGROUND: Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early-onset childhood obesity. The aim of the current study was to examine the prevalence of damaging LEP, LEPR, and MC4R mutations in Pakistani families having a recessive heritance of early-onset obesity. METHODS: Using targeted resequencing, the presence of rare mutations in LEP, LEPR, and MC4R, was investigated in individuals from 25 families suspected of having autosomal recessive early-onset obesity. Segregation patterns of variants were assessed based on chip-based genotyping. RESULTS: Homozygous LEPR variants were identified in two probands. One carried a deletion (c.3260AG) resulting in the frameshift mutation p.Ser1090Trpfs*6, and the second carried a substitution (c.2675C > G) resulting in the missense mutation p.Pro892Arg. Both mutations were located within regions of homozygosity shared only among affected individuals. Both probands displayed early-onset obesity, hyperphagia and diabetes. No mutations were found in LEP and MC4R. CONCLUSIONS: The current study highlights the implication of LEPR mutations in cases of severe early-onset obesity in consanguineous Pakistani families. Through targeted resequencing, we identified novel damaging mutations, and our approach may therefore be utilized in clinical testing or diagnosis of known forms of monogenic obesity with the aim of optimizing obesity treatment.

Glucose Homeostasis and Energy Balance in Children With Pseudohypoparathyroidism.

Context: Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterized by early-onset obesity and multihormone resistance. To treat abnormal weight gain and prevent complications such as diabetes, we must understand energy balance and glucose homeostasis in PHP types 1A and 1B. Objective: The aim of this study was to evaluate food intake, energy expenditure, and glucose homeostasis in children with PHP. Design: Assessments included resting energy expenditure (REE), physical activity, food intake, sucrose preference, questionnaires, endocrine status, and auxological status. All patients underwent an oral glucose tolerance test (OGTT). Setting: Vanderbilt University Medical Center. Patients: We assessed 16 children with PHP1A, three with PHP1B, and 15 healthy controls. Main Outcome Measures: Food intake during an ad lib buffet meal and glucose at five time points during OGTT. Results: PHP1A and control groups were well matched. Participants with PHP1A had significantly lower REE without concomitant change in food intake or physical activity. At baseline, participants with PHP1A had significantly lower fasting glucose and insulin resistance. During OGTT, participants with PHP1A had significantly delayed peak glucose and a slower rate of glucose decline despite similar oral glucose insulin sensitivity. Participants with PHP1A had 0.46% lower HbA1c levels than controls from a clinic database after adjustment for OGTT 2-hour glucose. The PHP1B group was similar to the PHP1A group. Conclusions: In contrast to other monogenic obesity syndromes, our results support reduced energy expenditure, not severe hyperphagia, as the primary cause of abnormal weight gain in PHP. Patients with PHP are at high risk for dysglycemia without reduced insulin sensitivity.

Eye Tracking as a Marker of Hyperphagia in Prader-Willi Syndrome.

This study examined the feasibility of eye tracking measures as markers of hyperphagia in 42 children and adults with Prader-Willi syndrome (PWS). Gaze data collected during free visual exploration of complex displays revealed that food images may not have an overall superior salience in PWS. However, increased attention to food in the context of other high-interest items was associated with higher scores on caregiver reports of hyperphagia. The study also provided preliminary evidence of test-retest reliability of eye tracking measures, suggesting that gaze characteristics may be a promising objective marker of food-related interests in PWS.

Anthony Sclafani: Consummate scientist.

In this article we review the scientific contributions of Anthony Sclafani, with specific emphasis on his early work on the neural substrate of the ventromedial hypothalamic (VMH) hyperphagia-obesity syndrome, and on the development of diet-induced obesity (DIO). Over a period of 20 years Sclafani systematically investigated the neuroanatomical basis of the VMH hyperphagia-obesity syndrome, and ultimately identified a longitudinal oxytocin-containing neural tract contributing to its expression. This tract has since been implicated in mediating the effects of at least two gastrointestinal satiety factors. Sclafani was one of the first investigators to demonstrate DIO in rats as a result of exposure to multiple palatable food items (the "supermarket diet"), and concluded that diet palatability was the primary factor responsible for DIO. Sclafani went on to investigate the potency of specific carbohydrate and fat stimuli for inducing hyperphagia, and in so doing discovered that post-ingestive nutrient effects contribute to the elevated intake of palatable food items. To further investigate this effect, he devised an intragastric infusion system which allowed the introduction of nutrients into the gut paired with the oral intake of flavored solutions, an apparatus her termed the "electronic esophagus". Sclafani coined the term "appetition" to describe the effect of intestinal nutrient sensing on post-ingestive appetite stimulation. Sclafani's productivity in the research areas he chose to investigate has been nothing short of extraordinary, and his studies are characterized by inventive hypothesizing and meticulous experimental design. His results and conclusions, to our knowledge, have never been contradicted.

Young girl with severe early-onset obesity and hyperphagia.

This case report of an infant with severe early-onset obesity illustrates the societal condemnation of persons with obesity. In addition, it underlines the importance of diagnosing rare forms of monogenic obesity, even if no drug treatment is available. Here, we describe a 2-year-old girl with severe progressive obesity from birth onwards due to insatiable hunger. Genetic studies eventually reveal that the girl has a monogenic form of obesity caused by two mutations in the LEPR gene. No drug treatment is available (as yet) for this disease. Parents describe the stigmatic remarks they have to deal with every day. Diagnosing this rare genetic disorder was very important for understanding that satiety regulation is a complex system, of which willpower is only a small portion. In these patients, reduction of obesity can be achieved, but a different approach to lifestyle intervention is needed.

Food addiction and obesity: unnecessary medicalization of hedonic overeating.

The concept of addiction is loaded with connotations and is often used for its political as much as its medical utility. The scientific case for 'food addiction' as a clinical phenotype currently rests on its association with generic diagnostic criteria for substance-related disorders being applied to everyday foods and eating-related problems. This has fused the concept of obesity with addiction regardless of whether it fits the definition. The hedonic, or reward, system can account for the ingestion of foods and drugs, confirming that they share neural substrates that differentiate liking and wanting. These are normal processes that are recruited for natural homeostatic behaviours and can explain the phenomenon of hedonic overeating as a consequence of human motivation pushed to extremes by an obesogenic environment. Food addiction constitutes a medicalization of common eating behaviours, taking on the properties of a disease. The use of this medical language has implications for the way in which society views overeating and obesity.

Attentional and motor impulsivity interactively predict 'food addiction' in obese individuals.

BACKGROUND: Impulsivity is a multifaceted construct and constitutes a common risk factor for a range of behaviors associated with poor self-control (e.g., substance use or binge eating). The short form of the Barratt Impulsiveness Scale (BIS-15) measures impulsive behaviors related to attentional (inability to focus attention or concentrate), motor (acting without thinking), and non-planning (lack of future orientation or forethought) impulsivity. Eating-related measures appear to be particularly related to attentional and motor impulsivity and recent findings suggest that interactive effects between these two facets may play a role in eating- and weight-regulation. METHODS: One-hundred thirty-three obese individuals presenting for bariatric surgery (77.4% female) completed the BIS-15 and the Yale Food Addiction Scale (YFAS) 2.0, which measures addiction-like eating based on the eleven symptoms of substance use disorder outlined in the fifth version of the Diagnostic and Statistical Manual of Mental Disorders. RESULTS: Sixty-three participants (47.4%) were classified as being 'food addicted'. Scores on attentional and motor impulsivity interactively predicted 'food addiction' status: higher attentional impulsivity was associated with a higher likelihood of receiving a YFAS 2.0 diagnosis only at high (+1 SD), but not at low (-1 SD) levels of motor impulsivity. CONCLUSIONS: Results support previous findings showing that non-planning impulsivity does not appear to play a role in eating-related self-regulation. Furthermore, this is the first study that shows interactive effects between different impulsivity facets when predicting 'food addiction' in obese individuals. Self-regulatory failure in eating-regulation (e.g., addiction-like overeating) may particularly emerge when both attentional and motor impulsivity levels are elevated.

Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity.

Neuroligins are post-synaptic, cellular adhesion molecules implicated in synaptic formation and function. NLGN2 is strongly linked to inhibitory, GABAergic signaling and is crucial for maintaining the excitation-inhibition balance in the brain. Disruption of the excitation-inhibition balance is associated with neuropsychiatric disease. In animal models, altered NLGN2 expression causes anxiety, developmental delay, motor discoordination, social impairment, aggression, and sensory processing defects. In humans, mutations in NLGN3 and NLGN4 are linked to autism and schizophrenia; NLGN2 missense variants are implicated in schizophrenia. Copy number variants encompassing NLGN2 on 17p13.1 are associated with autism, intellectual disability, metabolic syndrome, diabetes, and dysmorphic features, but an isolated NLGN2 nonsense variant has not yet been described in humans. Here, we describe a 15-year-old male with severe anxiety, obsessive-compulsive behaviors, developmental delay, autism, obesity, macrocephaly, and some dysmorphic features. Exome sequencing identified a heterozygous, de novo, c.441C>A p.(Tyr147Ter) variant in NLGN2 that is predicted to cause loss of normal protein function. This is the first report of an NLGN2 nonsense variant in humans, adding to the accumulating evidence that links synaptic proteins with a spectrum of neurodevelopmental phenotypes. © 2016 Wiley Periodicals, Inc.