Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia.

INTRODUCTION/AIMS: Traditional exercise is often difficult for individuals with Friedreich ataxia (FRDA), and evidence is limited regarding how to measure exercise performance in this population. We evaluated the feasibility, reliability, and natural history of adaptive cardiopulmonary exercise test (CPET) performance in children and adults with FRDA. METHODS: Participants underwent CPET on either an arm cycle ergometer (ACE) or recumbent leg cycle ergometer (RLCE) at up to four visits (baseline, 2 weeks, 4 weeks, and 1 year). Maximum work, oxygen consumption (peak VO2), oxygen (O2) pulse, and anaerobic threshold (AT) were measured in those who reached maximal volition. Test-retest reliability was assessed with intraclass coefficients, and longitudinal change was assessed using regression analysis. RESULTS: In our cohort (N = 23), median age was 18 years (interquartile range [IQR], 14-23), median age of FRDA onset was 8 years (IQR 6-13), median Friedreich Ataxia Rating Scale score was 58 (IQR 54-62), and GAA repeat length on the shorter FXN allele (GAA1) was 766 (IQR, 650-900). Twenty-one (91%) completed a maximal CPET (n = 8, ACE and n = 13, RLCE). Age, sex, and GAA1 repeat length were each associated with peak VO2. Preliminary estimates demonstrated reasonable agreement between visits 2 and 3 for peak work by both ACE and RLCE, and for peak VO2, O2 pulse, and AT by RLCE. We did not detect significant performance changes over 1 year. DISCUSSION: Adaptive CPET is feasible in FRDA, a relevant clinical trial outcome for interventions that impact exercise performance and will increase access to participation as well as generalizability of findings.

Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Predictors of outcome in children with disorders of mitochondrial metabolism in the pediatric intensive care unit.

BACKGROUND: The aim of this study was to identify factors predicting outcome in patients with mitochondrial disease admitted to pediatric intensive care units (PICU). METHODS: Retrospective study of 2434 patients (age <21 years) admitted to a PICU from 1 January 2006 through 31 March 2016 and captured in the Virtual Pediatric Systems database with ICD9 diagnosis 277.87, disorders of mitochondrial metabolism. Factors influencing mortality and prolonged length of stay (≥14 days) were analyzed using logistic regression. RESULTS: Predictors independently affecting mortality (adjusted odds ratios and 95% confidence intervals, p < 0.05): age 1-23 months 3.4 (1.7-6.6) and mechanical ventilation 4.7 (2.6-8.6) were risk factors; post-operative 0.2 (0.1-0.6), readmission 0.5 (0.3-0.9), and neurologic reason for admittance 0.3 (0.1-0.9) were factors reducing risk. Predictors affecting prolonged length of stay: mechanical ventilation 7.4 (5.2-10.3) and infectious reason for admittance 2.0 (1.3-3.2) were risk factors, post-operative patients 0.3 (0.2-0.5) had lower risk. The utility of PRISM and PIM2 scores in this patient group was evaluated. CONCLUSIONS: The single most predictive factor for both mortality and prolonged length of stay is the presence of mechanical ventilation. Age 1-23 months is a risk factor for mortality, and infectious reason for admittance indicates risk for prolonged length of stay. IMPACT: Presence of mechanical ventilation is the factor most strongly associated with negative outcome in patients with mitochondrial disease in pediatric intensive care. Age 1-23 months is a risk factor for mortality, and infectious reason for admittance indicates risk for prolonged length of stay PRISM3 and PIM2 are not as accurate in patients with mitochondrial disease as in a mixed patient population.

Sitting Height to Standing Height Ratio Reference Charts for Children in the United States.

OBJECTIVE: To create reference charts for sitting height to standing height ratio (SitHt/Ht) for children in the US, and to describe the trajectory of SitHt/Ht during puberty. STUDY DESIGN: This was a cross-sectional study using data from the 1988-1994 National Health and Nutrition Examination Survey III, a strategic random sample of the US population. Comparison between non-Hispanic White (NHW), non-Hispanic Black (NHB) and Mexican American groups was performed by ANOVA to determine if a single population reference chart could be used. ANOVA was used to compare SitHt/Ht in pre-, early, and late puberty. RESULTS: NHANES III recorded sitting height and standing height measurements in 9569 children aged 2-18 years of NHW (n = 2715), NHB (n = 3336), and Mexican American (n = 3518) ancestry. NHB children had lower SitHt/Ht than NHW and Mexican American children throughout childhood (P < .001). In both sexes, the SitHt/Ht decreased from prepuberty to early puberty and increased in late puberty. Sex-specific percentile charts of SitHt/Ht vs age were generated for NHB and for NHW and Mexican American youth combined. CONCLUSIONS: SitHt/Ht assessment can detect disproportionate short stature in children with skeletal dysplasia, but age-, sex-, and population-specific reference charts are required to interpret this measurement. NHB children in the US have significantly lower SitHt/Ht than other children, which adds complexity to interpretation. We recommend the use of standardized ancestry-specific reference charts in screening for skeletal dysplasias and have developed such charts in this study.

Body Mass Index Is a Better Indicator of Body Composition than Weight-for-Length at Age 1 Month.

OBJECTIVE: To assess whether body mass index (BMI) provides a better assessment of measured adiposity at age 1 month compared with weight-for-length (WFL). STUDY DESIGN: Participants were healthy term-born infants in the Infant Growth and Microbiome (n = 146) and the Baby Peas (n = 147) studies. Length, weight, and body composition by air displacement plethysmography were measured at 1 month. World Health Organization-based WFL and BMI z-scores were calculated. Within-cohort z-scores of percent fat-Z, fat mass-Z, fat mass/length2-Z, fat mass/length3-Z, fat-free mass-Z, and fat-free mass/length2-Z were calculated. Correlation and multiple linear regression (adjusted for birth weight) analyses tested the associations between body composition outcomes and BMI-Z vs WFL-Z. Quantile regression was used to test the stability of these associations across the distribution of body compositions. RESULTS: The sample was 52% female and 56% African American. Accounting for birth weight, both BMI-Z and WFL-Z were strongly associated with fat mass-Z (coefficients 0.56 and 0.35, respectively), FM/L2-Z (0.73 and 0.51), and FM/L3-Z (0.79 and 0.58), with stronger associations for BMI-Z compared with WFL-Z (P < .05). Even after accounting statistically for birth weight, BMI-Z was persistently more strongly associated than WFL-Z with body composition outcomes across the distribution of body composition outcomes. CONCLUSIONS: We demonstrate in 2 distinct cohorts that BMI is a better indicator of adiposity in early infancy compared with WFL. Our findings support the preferred use of BMI for growth and nutritional status assessment in infancy.

Genetic Survey of Adult-Onset Idiopathic Intracranial Hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure of unknown cause. IIH has been shown to be associated with female sex as well as obesity. This genome-wide association study was performed to determine whether genetic variants are associated with this condition. METHODS: We analyzed the chromosomal DNA of 95 patients with IIH enrolled in the Idiopathic Intracranial Hypertension Treatment Trial and 95 controls matched on sex, body mass index, and self-reported ethnicity. The samples were genotyped using Illumina Infinium HumanCoreExome v1-0 array and analyzed using a generalized linear mixed model that accounted for population stratification using multidimensional scaling. RESULTS: A total of 301,908 single nucleotide polymorphisms (SNPs) were evaluated. The strongest associations observed were for rs2234671 on chromosome 2 (P = 4.93 × 10), rs79642714 on chromosome 6 (P = 2.12 × 10), and rs200288366 on chromosome 12 (P = 6.23 × 10). In addition, 3 candidate regions marked by multiple associated SNPs were identified on chromosome 5, 13, and 14. CONCLUSIONS: This is the first study to investigate the genetics of IIH in a rigorously characterized cohort. The study was limited by its modest size and thus would have only been able to demonstrate highly significant association on a genome-wide scale for relatively common alleles exerting large effects. However, several variants and loci were identified that might be strong candidates for follow-up studies in other well-phenotyped cohorts.

N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.

Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.

Headache Characteristics in Children With Pseudotumor Cerebri Syndrome, Elevated Opening Pressure Without Papilledema, and Normal Opening Pressure: A Retrospective Cohort Study.

BACKGROUND: Certain headache characteristics and associated symptoms are commonly attributed to increased intracranial pressure, but they have not been systematically studied among children in the context of revised diagnostic criteria for pseudotumor cerebri syndrome (PTCS). METHODS: We performed a retrospective cohort study of patients treated for suspected or confirmed PTCS. Charts were reviewed for PTCS and headache diagnostic criteria and associated characteristics. Chi-squared or Fisher's exact tests were used to compare the frequency of headache characteristics between groups. RESULTS: One hundred and twenty-seven individuals were identified: 61 had definite PTCS, 10 had probable PTCS, 31 had elevated opening pressure (OP) without papilledema, and 25 had normal OP without papilledema. Eleven children had no headache (6 with definite PTCS, 5 with probable PTCS). Headache pattern was episodic in 49% (95% CI: 34-64%) of those with definite PTCS, 18% (95% CI 6-37%) of those with elevated OP without papilledema, and 16% (5-36%) of those with normal OP without papilledema. Headache location was more likely to involve the head along with neck or shoulders in those with definite PTCS compared with elevated OP without papilledema (OR = 7.2, 95% CI: 1.9-27.6) and normal OP (OR = 4.5, 95% CI: 1.3-15.6) groups. DISCUSSION: While missing data and small cohort size are limitations, this study suggests that headache in PTCS is more likely to involve the head along with neck/shoulders, and that headache in PTCS may be episodic or constant. Headache is occasionally absent in PTCS.

A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius.

Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures, we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD (aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P < 5 × 10(-6) for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10(-11), ß =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10(-8), ß = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex.

Hospitalizations for mitochondrial disease across the lifespan in the U.S.

IMPORTANCE: Mitochondrial disease is being diagnosed with increasing frequency. Although children with mitochondrial disease often have severe, life-limiting illnesses, many survive into adulthood. There is, however, limited information about the impact of mitochondrial disease on healthcare utilization in the U.S. across the lifespan. OBJECTIVES: To describe the characteristics of inpatient hospitalizations related to mitochondrial disease in the U.S., to identify patient-level clinical factors associated with in-hospital mortality, and to estimate the burden of hospitalizations on individual patients. DESIGN: Cross-sectional and longitudinal observational studies. SETTING: U.S. hospitals. PARTICIPANTS: Individuals with hospital discharges included in the triennial Healthcare Cost and Utilization Project (HCUP) Kids Inpatient Database (KID) and the National Inpatient Sample (NIS) in 2012 (cross-sectional analysis); individuals with hospital discharges included in the HCUP California State Inpatient Database from 2007 to 2011, inclusive (longitudinal analysis). EXPOSURE: Hospital discharge associated with a diagnosis of mitochondrial disease. MAIN OUTCOME MEASURES: Total number and rate of hospitalizations for individuals with mitochondrial disease (International Classification of Diseases, 9th revision, Clinical Modification code 277.87, disorder of mitochondrial metabolism); in-hospital mortality. RESULTS: In the 2012, there were approximately 3200 inpatient pediatric hospitalizations (1.9 per 100,000 population) and 2000 inpatient adult hospitalizations (0.8 per 100,000 population) for mitochondrial disease in the U.S., with associated direct medical costs of $113million. In-hospital mortality rates were 2.4% for children and 3.0% for adults, far exceeding population averages. Higher socioeconomic status was associated with both having a diagnosis of mitochondrial disease and with higher in-hospital mortality. From 2007 to 2011 in California, 495 individuals had at least one admission with a diagnosis of mitochondrial disease. Patients had a median of 1.1 hospitalizations (IQI, 0.6-2.2) per calendar year of follow-up; infants under 2y were hospitalized more frequently than other age groups. Over up to five years of follow up, 9.9% of participants with any hospitalization for mitochondrial disease were noted to have an in-hospital death. CONCLUSIONS AND RELEVANCE: Hospitalizations for pediatric and adult mitochondrial diseases are associated with serious illnesses, substantial costs, and significant patient time. Identification of opportunities to prevent or shorten such hospitalizations should be the focus of future studies.

Risk factors for poor bone health in primary mitochondrial disease.

INTRODUCTION: Primary mitochondrial disease is caused by either mitochondrial or nuclear DNA mutations that impact the function of the mitochondrial respiratory chain. Individuals with mitochondrial disorders have comorbid conditions that may increase their risk for poor bone health. The objective of this retrospective electronic medical record (EMR) review was to examine risk factors for poor bone health in children and adults with primary mitochondrial disease. METHODS: Eighty individuals with confirmed clinical and genetic diagnoses of primary mitochondrial disease at the Children's Hospital of Philadelphia (CHOP) were included in this study. Risk factors and bone health outcomes were collected systematically, including: anthropometrics (low BMI), risk-conferring co-morbidities and medications, vitamin D status, nutrition, immobility, fracture history, and, where available, dual energy x-ray absorptiometry (DXA) bone mineral density (BMD) results. RESULTS: Of patients 73% (n = 58) had at least one risk factor and 30% (n = 24) had four or more risk factors for poor bone health. The median number of risk factors per participant was 2, with an interquartile interval (IQI 0-4). In the subset of the cohort who were known to have sustained any lifetime fracture (n = 11), a total of 16 fractures were reported, six of which were fragility fractures, indicative of a clinically significant decrease in bone strength. CONCLUSIONS: The prevalence of risk factors for poor bone health in primary mitochondrial disease is high. As part of supportive care, practitioners should address modifiable risk factors to optimize bone health, and have a low threshold to evaluate clinical symptoms that could suggest occult fragility fracture.

Pediatric Idiopathic Intracranial Hypertension: Age, Gender, and Anthropometric Features at Diagnosis in a Large, Retrospective, Multisite Cohort.

PURPOSE: To examine anthropometric and maturational characteristics at diagnosis in pediatric idiopathic intracranial hypertension (IIH). DESIGN: Retrospective, international, multisite study. PARTICIPANTS: Pediatric patients (2-18 years of age at diagnosis) with IIH. MAIN OUTCOME MEASURES: Body mass index (BMI), height, and weight Z-scores; sexual maturation. METHODS: Cases of IIH were identified retrospectively based on diagnostic code, pediatric neuro-ophthalmologist databases, or both and updated diagnostic criteria (2013) were applied to confirm definite IIH. Anthropometric measurements were converted into age- and gender-specific height, weight, and BMI Z-scores CDC 2000 growth charts. When available, sexual maturation was noted. RESULTS: Two hundred thirty-three cases of definite IIH were identified across 8 sites. In boys, a moderate association between age and BMI Z-scores was noted (Pearson's correlation coefficient, 0.50; 95% confidence interval [CI], 0.30-0.66; P < 0.001; n = 72), and in girls, a weak association was noted (Pearson's correlation coefficient, 0.34; 95% CI, 0.20-0.47; P < 0.001; n = 161). The average patient was more likely to be overweight at diagnosis at age 6.7 years in girls and 8.7 years in boys, and obese at diagnosis at age 12.5 years in girls and 12.4 years in boys. Compared with age- and gender-matched reference values, early adolescent patients were taller for age (P = 0.002 in girls and P = 0.02 in boys). Data on Tanner staging, menarchal status, or both were available in 25% of cases (n = 57/233). Prepubertal participants (n = 12) had lower average BMI Z-scores (0.95±1.98) compared with pubertal participants (n = 45; 1.92±0.60), but this result did not reach statistical significance (P = 0.09). CONCLUSIONS: With updated diagnostic criteria and pediatric-specific assessments, the present study identifies 3 subgroups of pediatric IIH: a young group that is not overweight, an early adolescent group that is either overweight or obese, and a late adolescent group that is mostly obese. Data also suggest that the early adolescent group with IIH may be taller than age- and gender-matched reference values. Understanding these features of pediatric IIH may help to illuminate the complex pathogenesis of this condition.

Effects of genetic severity on glucose homeostasis in Friedreich ataxia.

INTRODUCTION: Friedreich ataxia (FRDA) leads to increased risk of diabetes. Less is known regarding the dynamics of glucose homeostasis in FRDA, the influence of disease features, and the utility of oral-based metrics for capturing metabolic dysfunction. METHODS: To examine these dynamics, we analyzed oral and intravenous glucose tolerance test data in 42 non-diabetic patients with FRDA. RESULTS: Patients showed high insulin responsiveness to glucose and low insulin sensitivity. Genetic severity predicted overall metabolic impairment: individuals with longer guanine-adenine-adenine (GAA) repeats on the shorter allele showed a lower disposition index. Genetic severity did not predict any other variables. Measures of disposition index from intravenous and oral glucose tolerance testing did not correlate well, possibly reflecting divergent responses to oral and intravenous glucose loads. CONCLUSIONS: FRDA patients demonstrate abnormal compensatory activity for managing glucose. Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient to patient. Muscle Nerve 54: 887-894, 2016.

An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics.

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.

A Pilot Randomized Clinical Trial of Intranasal Oxytocin to Promote Weight Loss in Individuals With Hypothalamic Obesity.

Context: Hypothalamic obesity is a rare, treatment-resistant form of obesity. In preliminary studies, the hypothalamic hormone oxytocin (OXT) has shown promise as a potential weight loss therapy. Objective: To determine whether 8 weeks of intranasal OXT (vs 8 weeks of placebo) promotes weight loss in children, adolescents, and young adults with hypothalamic obesity. Methods: This randomized, double-blind, placebo-controlled, crossover pilot trial (NCT02849743), conducted at an outpatient academic medical center, included patients aged 10 to 35 years with hypothalamic obesity from hypothalamic/pituitary tumors. Participants received intranasal OXT (Syntocinon, 40 USP units/mL, 4 IU/spray) vs excipient-matched placebo, 16 to 24 IU 3 times daily at mealtimes. Weight loss attributable to OXT vs placebo and safety (adverse events) were assessed. Results: Of 13 individuals randomized (54% female, 31% pre-pubertal, median age 15.3 years, IQR 13.3-20.6), 10 completed the entire study. We observed a nonsignificant within-subject weight change of -0.6 kg (95% CI: -2.7, 1.5) attributable to OXT vs placebo. A subset (2/18 screened, 5/13 randomized) had prolonged QTc interval on electrocardiography prior to screening and/or in both treatment conditions. Overall, OXT was well-tolerated, and adverse events (epistaxis and nasal irritation, headache, nausea/vomiting, and changes in heart rate, blood pressure, and QTc interval) were similar between OXT and placebo. In exploratory analyses, benefits of OXT for anxiety and impulsivity were observed. Conclusion: In this pilot study in hypothalamic obesity, we did not detect a significant impact of intranasal OXT on body weight. OXT was well-tolerated, so future larger studies could examine different dosing, combination therapies, and potential psychosocial benefits.

Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. OBJECTIVE: To evaluate safety and efficacy of intranasal carbetocin in PWS. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. SETTING: Twenty-four ambulatory clinics at academic medical centers. PARTICIPANTS: A total of 130 participants with PWS aged 7 to 18 years. INTERVENTIONS: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. MAIN OUTCOME MEASURES: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). RESULTS: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. CONCLUSIONS: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. CLINICAL TRIALS REGISTRATION NUMBER: NCT03649477.

A Survey of Patient-Relevant Outcomes in Pediatric Craniopharyngioma: Focus on Hypothalamic Obesity.

Context: Individuals treated for pediatric craniopharyngioma, a rare, grade 1 brain tumor, frequently develop hypothalamic obesity, a complication often recalcitrant to intervention. Although hypothalamic obesity is known to adversely impact quality of life, less is known about how caregivers and patients experience this condition. Objective: Our goal was to examine the approaches that families take towards weight management and the impact on social function in individuals with craniopharyngioma and obesity. Individuals with craniopharyngioma without obesity were included as a comparison. Subjects and Methods: Adult caregivers of children <18y with craniopharyngioma completed a web-based survey posted by a patient advocacy organization between February and July 2020. Questions related to the child's diagnosis, medications, lifestyle modifications, and social function along with research priorities. Descriptive statistics were generated. Linear regression was used to assess the independent effects of obesity and other covariates on social function. Results: Of 106 respondents, 60 (57%) reported their child had obesity at the time of survey completion. In contrast, only 6 (5.7%) had obesity prior to craniopharyngioma diagnosis. A majority (92%) of those with obesity had tried limiting calories or carbohydrates; 31% and 69% found these helpful, respectively. Thirty-eight percent had tried weight loss medications (stimulants, metformin, GLP1R-agonists, and topiramate) and 48% found at least one helpful. Both stimulant and anti-depressant use were reported more frequently with obesity. An index (T-score) reflecting social function was lower in the cohort than a population reference, 41 (SD 11) vs. 50 (SD 10), p<0.001. In a linear model, both older age and obesity were independently associated with greater social impairment. Ninety-four percent of respondents caring for a child with obesity (and 79% of all respondents) identified "improving treatments and prevention for hypothalamic obesity" as a key research priority. Conclusions: Only a minority of individuals with hypothalamic obesity had trialed medication, even though many reported that lifestyle modification was inadequate. Furthermore, social function was significantly impaired overall in survivors compared to a reference cohort, and even more so in individuals with obesity. These findings highlight the opportunity to improve social functioning as an additional potential benefit of improved treatments for hypothalamic obesity.

Bone Mineral Density and Current Bone Health Screening Practices in Friedreich's Ataxia.

Introduction: Friedreich's Ataxia (FRDA) is a progressive neurological disorder caused by mutations in both alleles of the frataxin (FXN) gene. Impaired bone health is a complication of other disorders affecting mobility, but there is little information regarding bone health in FRDA. Methods: Dual energy X-ray absorptiometry (DXA) scan-based assessments of areal bone mineral density (aBMD) in individuals with FRDA were abstracted from four studies at the Children's Hospital of Philadelphia (CHOP). Disease outcomes, including the modified FRDA Rating Scale (mFARS), were abstracted from the FRDA Clinical Outcomes Measures Study (FACOMS), a longitudinal natural history study. A survey regarding bone health and fractures was sent to individuals in FACOMS-CHOP. Results: Adults with FRDA (n = 24) have lower mean whole body (WB) (-0.45 vs. 0.33, p = 0.008) and femoral neck (FN) (-0.71 vs. 0.004, p = 0.02) aBMD Z-scores than healthy controls (n = 24). Children with FRDA (n = 10) have a lower WB-less-head (-2.2 vs. 0.19, p < 0.0001) and FN (-1.1 vs. 0.04, p = 0.01) aBMD than a reference population (n = 30). In adults, lower FN aBMD correlated with functional disease severity, as reflected by mFARS (R = -0.56, p = 0.04). Of 137 survey respondents (median age 27 y, 50% female), 70 (51%) reported using wheelchairs as their primary ambulatory device: of these, 20 (29%) reported a history of potentially pathologic fracture and 11 (16%) had undergone DXA scans. Conclusions: Low aBMD is prevalent in FRDA, but few of even the highest risk individuals are undergoing screening. Our findings highlight potential missed opportunities for the screening and treatment of low aBMD in FRDA.

Friedreich's Ataxia related Diabetes: Epidemiology and management practices.

AIMS: Friedreich's Ataxia (FRDA) is a progressive neuromuscular disorder typically caused by GAA triplet repeat expansions in both frataxin gene alleles. FRDA can be complicated by diabetes mellitus (DM). The objective of this study was to describe the prevalence of, risk factors for, and management practices of FRDA-related DM. METHODS: FACOMS, a prospective, multi-site natural history study, includes 1,104 individuals. Extracted data included the presence of DM and other co-morbidities, genetic diagnosis, and markers of disease severity. We performed detailed medical record review and a survey for the subset of individuals with FRDA-related DM followed at one FACOMS site, Children's Hospital of Philadelphia. RESULTS: FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk. FRDA-related DM was generally well-controlled, as reflected by HbA1c, though diabetic ketoacidosis did occur. Insulin is the mainstay of treatment (64-74% overall); in adults, metformin use was common and newer glucose-lowering agents were used rarely. CONCLUSIONS: Clinical factors identify individuals at increased risk for FRDA-related DM. Future studies should test strategies for FRDA-related DM screening and management, in particular the potential role for novel glucose-lowering therapies in preventing or delaying FRDA-related cardiac disease.