KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Development of Momentary Appetite Capture (MAC): A versatile tool for monitoring appetite over long periods.

Understanding how an intervention impacts appetite in real-life settings and over several days remains a challenging and under-explored research question. To this end, we developed Momentary Appetite Capture (MAC), a form of ecological momentary assessment that combines automated text messaging with an online platform. Participants report their appetite using visual analogue scales (hunger, desire to eat, and fullness) and a virtual portion-size selection task. In two separate studies, we assessed the feasibility and test-retest reliability of MAC. Participants were prompted every 2 hours over a 14-hour window, and they repeated this assessment over two consecutive weekdays. For each participant, we calculated a daily time-averaged area under the curve (AUC) for each appetite measure. In Study One (N = 25) time-averaged AUC was significantly positively correlated across test days for hunger (r = 0.563, p = .003), desire to eat (r = 0.515, p = .008) and prospective portion size (r = 0.914, p < .001), but not for fullness (r = 0.342, p = .094). Participants completed 95% of MACs (380 of 400), and we used participant feedback to improve the MAC tool and study protocol for Study Two. In Study Two (N = 31), 94% of MACs were completed (468 of 496). Across days, time-averaged AUC was significantly positively correlated for hunger (r = 0.595, p = < .001), fullness (r = 0.501, p = .004), desire to eat (r = 0.585, p < .001), and prospective portion size (r = 0.757, p < .001). Together, these studies suggest that MAC could be an acceptable and reliable tool to track appetite throughout the day. In the future, MAC could be used to explore the impact of weight-loss interventions on natural fluctuations in appetite.

Exploring the acute effects of running on cerebral blood flow and food cue reactivity in healthy young men using functional magnetic resonance imaging.

Acute exercise suppresses appetite and alters food-cue reactivity, but the extent exercise-induced changes in cerebral blood flow (CBF) influences the blood-oxygen-level-dependent (BOLD) signal during appetite-related paradigms is not known. This study examined the impact of acute running on visual food-cue reactivity and explored whether such responses are influenced by CBF variability. In a randomised crossover design, 23 men (mean ± SD: 24 ± 4 years, 22.9 ± 2.1 kg/m2 ) completed fMRI scans before and after 60 min of running (68% ± 3% peak oxygen uptake) or rest (control). Five-minute pseudo-continuous arterial spin labelling fMRI scans were conducted for CBF assessment before and at four consecutive repeat acquisitions after exercise/rest. BOLD-fMRI was acquired during a food-cue reactivity task before and 28 min after exercise/rest. Food-cue reactivity analysis was performed with and without CBF adjustment. Subjective appetite ratings were assessed before, during and after exercise/rest. Exercise CBF was higher in grey matter, the posterior insula and in the region of the amygdala/hippocampus, and lower in the medial orbitofrontal cortex and dorsal striatum than control (main effect trial p ≤ .018). No time-by-trial interactions for CBF were identified (p ≥ .087). Exercise induced moderate-to-large reductions in subjective appetite ratings (Cohen's d = 0.53-0.84; p ≤ .024) and increased food-cue reactivity in the paracingulate gyrus, hippocampus, precuneous cortex, frontal pole and posterior cingulate gyrus. Accounting for CBF variability did not markedly alter detection of exercise-induced BOLD signal changes. Acute running evoked overall changes in CBF that were not time dependent and increased food-cue reactivity in regions implicated in attention, anticipation of reward, and episodic memory independent of CBF.

Developments in the design and delivery of self-management support for children and young people with diabetes: A narrative synthesis of systematic reviews.

AIMS: Facilitated self-management support programmes have become central to the treatment of chronic diseases including diabetes. For many children and young people with diabetes (CYPD), the impact on glycated haemoglobin (HbA1c ) and a range of self-management behaviours promised by these programmes remain unrealised. This warrants an appraisal of current thinking and the existing evidence to guide the development of programmes better targeted at this age group. METHODS: Create a narrative review of systematic reviews produced in the last 3 years that have explored the impact on CYPD of the four key elements of self-management support programmes: education, instruction and advice including peer support; psychological counselling via a range of therapies; self-monitoring, including diaries and telemetric devices; and telecare, the technology-enabled follow-up and support by healthcare providers. RESULTS: Games and gamification appear to offer a promising means of engaging and educating CYPD. Psychological interventions when delivered by trained practitioners, appear to improve HbA1c and quality of life although effect sizes were small. Technology-enabled interactive diaries can increase the frequency of self-monitoring and reduce levels of HbA1c . Telecare provided synchronously via telephone produced significant improvements in HbA1c . CONCLUSIONS: The cost-effective flexibility of increasing the reliance on technology is an attractive proposition; however, there are resource implications for digital connectivity in underserved populations. The need remains to improve the understanding of which elements of each component are most effective in a particular context, and how to optimise the influence and input of families, caregivers and peers.

Evaluating the benefit of early patient and public involvement for product development and testing with small companies.

INTRODUCTION: There is a growing understanding of the benefits of patient and public involvement (PPI), and its evaluation, in research. An online version of the CUBE PPI evaluation framework has been developed. We sought to use the CUBE to evaluate the value of early PPI with two small healthcare companies during product development. METHODS: Contributors were recruited online and had lived experience of either type 1 diabetes or obesity. Two 1-h sessions were run with a company developing a smartphone application to manage diabetes (DEE-EM): one with young people (YP; n = 5) and one with parents (n = 7). Two 1-h sessions were run with a company developing a weight-loss product, both with adults (n = 7 in each session). Sessions were facilitated by an independent University researcher and attended by company representatives, who presented their product. One facilitator led the evaluation of the session by giving a demonstration of the CUBE and asking simple questions in the YP session. RESULTS: A high proportion of contributors completed the CUBE (80.5% DEE-EM; 93% Oxford Medical Products). Responses were positive to all four CUBE dimensions (in italics). Contributors felt there were diverse ways to contribute to the sessions, and that they had a strong voice to add to the discussion. Balance was achieved regarding whose concerns (public or company) led the agenda, and contributors felt that both companies would make changes based on the discussion. The supportive attitude of both companies resulted in most contributors feeling comfortable participating in PPI sessions with the industry, while recognising the profit-making aspect of their work. CONCLUSIONS: PPI with small healthcare companies is both feasible and worthwhile. The CUBE framework facilitated the evaluation of the interaction between experts in different knowledge spaces. We provide recommendations for future projects, including considerations of who should participate and the level of implicit endorsement of the product that participation implies. PATIENT OR PUBLIC CONTRIBUTION: People with lived experience of type 1 diabetes or obesity were invited to contribute to one of four PPI sessions, which they then evaluated. One contributor agreed to contribute to the analysis of the evaluation data and interpretation and preparation of the manuscript.

Integrating COM-B and the person-based approach to develop an ACT based therapy programme to raise self-determination in adolescents with obesity.

BACKGROUND: This paper details the development of the Adolescent Intrinsic Motivation 'AIM2Change' intervention to support weight-management in young people previously unable to make changes whilst attending a tier 3 weight management service for children and young people. AIM2Change is an acceptance and commitment therapy based intervention that will be delivered one-to-one online over a seven-week period. METHODS: To develop this intervention, we have triangulated results from a qualitative research study, patient and public involvement groups (PPI) and a COM-B (capability, opportunity, motivation, behaviour) analysis, in a method informed by the person-based approach. RESULTS: The integrated development approach yielded a broad range of perspectives and facilitated the creation of a tailored intervention to meet the needs of the patient group whist remaining pragmatic and deliverable. CONCLUSIONS: The next steps for this intervention will be in-depth co-development of the therapy sessions with service users, before implementing a proof of concept trial.

The feasibility, acceptability, and benefit of interventions that target eating speed in the clinical treatment of children and adolescents with overweight or obesity: A systematic review and meta-analysis.

Eating at a faster speed is positively correlated with having a higher BMI. Modifying eating speed may offer a treatment opportunity for those with overweight and obesity. This review sought to understand the feasibility, acceptability, and benefit to using eating speed interventions in paediatric clinical weight-management settings. The PICO Framework was used. Clinical studies of eating speed interventions as a treatment for paediatric patients with overweight or obesity were included. No limits to search date were implemented. A systematic search of MEDLINE, PsychINFO and EMBASE via OVID, Web of Science and JBI, Database of systematic reviews and Implementation reports, along with trial registers NICE, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials was conducted. Two authors were responsible for screening, extraction, and evaluation of the risk of bias. Fifteen papers reporting twelve interventions addressing eating-speed were identified, involving a total of 486 active participants (range 7-297). Study design was weak with only one full RCT and there were some concerns over quality and risk of bias (Cochrane RoB 2.0). Limited sample sizes and different measured outcomes did not allow powered evaluations of effect for all outcomes. There is some indication, overall, that addressing eating speed has the potential to be a beneficial adjunct to clinical obesity treatment, although the pooled effect estimate did not demonstrate a difference in BMISDS status following eating speed interventions compared to control [pooled mean difference (0.04, 95% CI -0.39 to 0.46, N = 3)]. Developments to improve the engagement to, and acceptability of, interventions are required, alongside rigorous high-quality trials to evaluate effectiveness.

How full am I? The effect of rating fullness during eating on food intake, eating speed and relationship with satiety responsiveness.

Modifying eating behaviours may be an effective strategy to limit excess food intake, such as eating slower and mindfully. We hypothesized that regularly rating fullness whilst eating a standard meal in one course would increase post-meal satiety and reduce intake in a subsequent course during the same sitting. A between-subjects design was employed (n = 65; 75% female; mean age = 26.7 (s.d. = 9.5); mean body mass index = 22.4 (s.d. = 3.3)), with three conditions of within-meal visual-analogue-scale ratings: 'Fullness' (rated fullness); 'Taste' (rated pleasantness of taste of food); 'Control' (rated comfort of room). Fasted participants ate a pasta meal (327 kcal) followed by cookies ad libitum. Appetite ratings were measured at baseline, following each course and for 3-h post-meal. Satiety responsiveness was measured using the Adult Eating Behaviour Questionnaire, Intuitive Eating Scale and by calculating the satiety quotient of the pasta course alone and the whole meal. The primary outcomes were fullness ratings post-pasta course [mean (s.d.): Fullness = 67.1 (21.9); Taste = 64.4 (13.7); Control = 60.2 (21.5)] and cookie intake [mean kcal (s.d.): Fullness = 249 (236); Taste = 279 (231); Control = 255 (208)]. Eating speed was included as a secondary, control outcome [mean (s.d.): Fullness = 59.3 (9.0); Taste = 59.2 (17.7); Control = 60.7 (19.6)]. No evidence for a difference in outcomes was identified between conditions (p > 0.05). Future work could involve testing the impact of rating fullness during multiple meals over a longer period. Secondly, this study explored whether levels of satiety responsiveness influenced the impact of the manipulation on outcomes; however only weak evidence for a relationship with eating speed was found. Finally, only a weak relationship was found between the satiety responsiveness measures, suggesting that different aspects of the underlying construct are being captured.

When do children learn how to select a portion size?

The reduction of portion sizes supports weight-loss. This study looks at whether children have a conceptual understanding of portion size, by studying their ability to manually serve a portion size that corresponds to what they eat. In a clinical setting, discussion around portion size is subjective thus a computerised portion size tool is also trialled, with the portion sizes chosen on the screen being compared to amounts served manually. Children (n = 76) age 5-6, 7-8 and 10-11 were asked to rate their hunger (VAS scale), liking (VAS scale) and 'ideal portion size for lunch' of eight interactive meal images using a computerised portion size tool. Children then manually self-served and consumed a portion of pasta. Plates were weighed to allow for the calculation of calories served and eaten. A positive correlation was found between manually served food portions and the amount eaten (r = 0.53, 95%CI [0.34, 0.82, P < .001), indicating that many children were able to anticipate their likely food intake prior to meal onset. A regression model demonstrates that age contributes to 9.4% of the variance in portion size accuracy (t(68) = -2.3, p = .02). There was no relationship between portion size and either hunger or liking. The portion sizes chosen on the computer at lunchtime correlated to the amount manually served overall (r = .34, 95%CI [0.07, 0.55], p < .01), but not in 5-6-year-old children. Manual portion-size selection can be observed in five-year olds and from age seven, children's 'virtual' responses correlate with their manual portion selections. The application of the computerised portion-size tool requires further development but offers considerable potential.

Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring.

BACKGROUND: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance. METHODS: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found. RESULTS: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. CONCLUSION: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.

Insulin-like growth factor-II in adipocyte regulation: depot-specific actions suggest a potential role limiting excess visceral adiposity.

The IGF system has an important role in growth and development. IGF-II is a recognized fetal growth promoter. However, its physiological postnatal role remains uncertain, although it is maintained in the circulation at a substantially high level throughout life. IGF-II has been strongly linked to obesity in genetic studies, and more recent evidence suggests a metabolic role. We examined fat depot differences in IGF-II's action on differentiation and metabolism. We speculate a specific effect on visceral adipocytes in relation to the differential distribution of insulin receptors between visceral and subcutaneous fat depots. We used a previously established adipocyte, cell culture system of matched pairs of visceral and subcutaneous fat biopsies from 20 normal weight children undergoing routine surgery for nonmalignant, nonseptic conditions. Preadipocytes were differentiated for 14 days in the presence or absence of IGF-II. Oil Red O staining, Western blotting, and reverse transcription polymerase chain reaction techniques were employed to assess levels of adipogenesis markers and levels of the insulin receptor and insulin receptor isoforms. Our data indicate that IGF-II promotes preadipocyte differentiation in subcutaneous preadipocytes but showed a protective, opposing effect restricting visceral preadipocyte differentiation, confirmed by reductions in the differentiation markers peroxisome proliferator-activated receptor gamma and adiponectin and in triglyceride staining. Additionally, IGF-II reduced mRNA expression of the insulin receptor in adipocytes and downregulated insulin receptor isoform A and glucose transporter 4 abundance and corresponding glucose uptake in visceral adipocytes. In conclusion, IGF-II is a regulator of preadipocyte differentiation and metabolism by acting as a differential modulator of fat accumulation favoring less visceral fat deposition in children.

Treatment adherence and BMI reduction are key predictors of HbA1c 1 year after diagnosis of childhood type 2 diabetes in the United Kingdom.

BACKGROUND/OBJECTIVE: Type 2 Diabetes (T2DM) is increasing in childhood especially among females and South-Asians. Our objective was to report outcomes from a national cohort of children and adolescents with T2DM 1 year following diagnosis. METHODS: Clinician reported, 1-year follow-up of a cohort of children (<17 years) diagnosed with T2DM reported through the British Paediatric Surveillance Unit (BPSU) (April 2015-April 2016). RESULTS: One hundred (94%) of 106 baseline cases were available for review. Of these, five were lost to follow up and one had a revised diagnosis. Mean age at follow up was 15.3 years. Median BMI standard deviation scores (SDS) was 2.81 with a decrease of 0.13 SDS over a year. HbA1c <48 mmol/mol (UK target) was achieved in 38.8%. logHbA1c was predicted by clinician reported compliance and attendance concerns (ß = 0.12, P = <0.0001) and change in body mass index (BMI) SDS at 1-year (ß = 0.13, P=0.007). In over 50%, clinicians reported issues with compliance and attendance. Mean clinic attendance was 75%. Metformin was the most frequently used treatment at baseline (77%) and follow-up (87%). Microalbuminuria prevalence at 1-year was 16.4% compared to 4.2% at baseline and was associated with a higher HbA1c compared to those without microalbuminuria (60 vs 49 mmol/mol, P = 0.03). CONCLUSIONS: Adherence to treatment and a reduction in BMI appear key to better outcomes a year after T2DM diagnosis. Retention and clinic attendance are concerning. The prevalence of microalbuminuria has increased 4-fold in the year following diagnosis and was associated with higher HbA1c.

Using neuroimaging to investigate the impact of Mandolean® training in young people with obesity: a pilot randomised controlled trial.

BACKGROUND: Slowing eating rate using the Mandolean® previously helped obese adolescents to self-select smaller portion sizes, with no reduction in satiety, and enhanced ghrelin suppression. The objective of this pilot, randomised trial was to investigate the neural response to food cues following Mandolean® training using functional Magnetic Resonance Imaging (fMRI), and measures of ghrelin, PYY, glucose and self-reported appetite. METHOD: Twenty-four obese adolescents (11-18 years; BMI ≥ 95th centile) were randomised (but stratified by age and gender) to receive six-months of standard care in an obesity clinic, or standard care plus short-term Mandolean® training. Two fMRI sessions were conducted: at baseline and post-intervention. These sessions were structured as an oral glucose tolerance test, with food cue-reactivity fMRI, cannulation for blood samples, and appetite ratings taken at baseline, 30 (no fMRI), 60 and 90 min post-glucose. As this was a pilot trial, a conservative approach to the statistical analysis of the behavioural data used Cliff's delta as a non-parametric measure of effect size between groups. fMRI data was analysed using non-parametric permutation analysis (RANDOMISE, FSL). RESULTS: Following Mandolean® training: (i) relatively less activation was seen in brain regions associated with food cue reactivity after glucose consumption compared to standard care group; (ii) 22% reduction in self-selected portion size was found with no reduction in post-meal satiety. However, usage of the Mandolean® by the young people involved was variable and considerably less than planned at the outset (on average, 28 meals with the Mandolean® over six-months). CONCLUSION: This pilot trial provides preliminary evidence that Mandolean® training may be associated with changes in how food cues in the environment are processed, supporting previous studies showing a reduction in portion size with no reduction in satiety. In this regard, the study supports targeting eating behaviour in weight-management interventions in young people. However, given the variable usage of the Mandolean® during the trial, further work is required to design more engaging interventions reducing eating speed. TRIAL REGISTRATION: ISRCTN, ISRCTN84202126 , retrospectively registered 22/02/2018.

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.

A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype.

BACKGROUND: Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis. METHODS: Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed. RESULTS: We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (<9th centile) and similar facial features including a prominent forehead, smooth philtrum and deep-set eyes associated with a recurrent homozygous c.64T>C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly. CONCLUSIONS: Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features-particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry-should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations.

Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes.

BACKGROUND: Survivors of childhood acute lymphoblastic leukaemia (ALL) treated with haematopoietic stem cell transplantation and total body irradiation (HSCT/TBI) have a high cardiometabolic risk despite lacking overt clinical obesity. This study characterised body composition using different methodologies and explored associations with reduced insulin sensitivities in a group of ALL survivors treated with/without HSCT/TBI. PROCEDURE: Survivors of childhood ALL treated with HSCT/TBI (n = 20,10 M) were compared with Chemotherapy-only (n = 31), and an obese non-leukaemic controls (n = 30). All subjects (aged 16-26 years) were investigated with: auxology (BMI, waist and hip circumferences), DEXA (total and regional fat, fat-free mass), abdominal MRI (subcutaneous, visceral, intramuscular fat), oral glucose tolerance tests (impaired glucose tolerance or diabetes, insulin sensitivity) and serum adiponectin. RESULTS: HSCT/TBI Group displayed a higher prevalence of abnormal glucose tolerance (45%); lower insulin sensitivity; lower lean mass with higher prevalence of reduced fat-free mass index (from DEXA); higher visceral and intramuscular, and lower subcutaneous fat on MRI, compared with the Chemotherapy-only and Obese controls. BMI was lowest in HSCT/TBI Group. Waist-to-hip and android-to-gynoid ratios were similar between HSCT/TBI and Obese Groups. Insulin sensitivity adjusted for visceral fat mass was lower in the HSCT/TBI than the Chemotherapy-only and Obese groups. Adiponectin in the HSCT/TBI Group was lower than the Chemotherapy-only group, and correlated negatively with time post HSCT/TBI. CONCLUSIONS: HSCT/TBI survivors have an increased risk of abnormal glucose tolerance and reduced insulin sensitivity with reduced subcutaneous and increased visceral fat distribution, increased total fat mass and reduced lean mass.

The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a ß cell phenotype.

BACKGROUND: Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. METHODS AND RESULTS: We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. CONCLUSIONS: The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.

Longitudinal changes in body mass index following renal transplantation in UK children.

BACKGROUND: Childhood obesity is a significant health problem in the UK. To date, there is little known about the pattern of change in body mass index (BMI) following renal transplantation in UK paediatric patients. Our objectives in this study were to (i) describe trends in BMI seen in UK patients undergoing renal transplantation in the short and medium term and (ii) identify risk factors predisposing children to excessive weight gain following transplantation. METHODS: A retrospective case note review was performed across 12 of 13 paediatric nephrology centres in the UK, with BMI measurements recorded pre-transplantation and for 4 years thereafter. BMI% was used to assess changes in adiposity over time. International Obesity Taskforce definitions of overweight and obesity were used to identify the prevalence of excess weight pre- and post-renal transplantation. RESULTS: A total of 159 patients (113 boys) under the age of 18 with a functioning kidney transplant were included. Fifty-six patients (35.2%) were under the age of 5 at transplantation. Pre-transplantation, 31.4% of patients were classified as overweight or obese, which increased to 52.8% by the end of follow-up. The majority of patients experienced rapid increases in BMI% over the initial four months post-transplantation, which were sustained for the remainder of the follow-up period. The major risk factor for being overweight or obese at the end of follow-up was having excessive weight pre-transplantation. Four years following transplantation, the prevalence rate of overweight and obesity was much higher in our study cohort than the normal UK childhood population. CONCLUSIONS: The prevalence of patients classified as overweight or obese in the UK paediatric renal cohort is high pre-transplantation and rises subsequently. Those at risk can be identified by an unhealthy BMI pre-transplantation and will require timely intervention with close monitoring in the subsequent post-transplantation period.

Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome.

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.

Evaluating Eating Behaviour, Energy Homeostasis, and Obesity in Childhood-Onset Craniopharyngioma: A Feasibility Study.

INTRODUCTION: Craniopharyngiomas are rare brain tumours (incidence 1.1-1.7 cases/million/year). Although non-malignant, craniopharyngioma causes major endocrine and visual morbidities including hypothalamic obesity, yet mechanisms leading to obesity are poorly understood. This study investigated the feasibility and acceptability of eating behaviour measures in patients with craniopharyngioma to inform the design of future trials. METHODS: Patients with childhood-onset craniopharyngioma and controls matched for sex, pubertal stage, and age were recruited. After an overnight fast, participants received the following measures: body composition, resting metabolic rate, oral glucose tolerance test including magnetic resonance imaging (patients only), appetite ratings, eating behaviour, and quality of life questionnaires, ad libitum lunch, and an acceptability questionnaire. Data are reported as median ± IQR, with effect size measure (Cliff's delta) and Kendall's tau for correlations, due to the small sample size. RESULTS: Eleven patients (median age = 14 years; 5 F/6 M) and matched controls (median age = 12 years; 5 F/6 M) were recruited. All patients had received surgery, and 9/11 also received radiotherapy. Hypothalamic damage post-surgery was graded (Paris grading): grade 2 n = 6; grade 1 n = 1; grade 0 n = 2. The included measures were deemed highly tolerable by participants and their parent/carers. Preliminary data suggest a difference in hyperphagia between patients and controls (d = 0.5), and a relationship between hyperphagia with body mass index standard deviation score (BMISDS) in patients (τ = 0.46). DISCUSSION: These findings demonstrate that eating behaviour research is feasible and acceptable to craniopharyngioma patients and there is an association between BMISDS and hyperphagia in patients. Thus, food approach and avoidance behaviours may be useful targets for interventions to manage obesity in this patient group.