Underlying medical causes of obesity (endocrine disorders, genetic obesity disorders, cerebral or medication-induced obesities) are thought to be rare. Even in specialized pediatric endocrinology ...clinics, low diagnostic yield is reported, but evidence is limited. Identifying these causes is vital for patient-tailored treatment.
To present the results of a systematic diagnostic workup in children and adolescents referred to a specialized pediatric obesity center.
This is a prospective observational study. Prevalence of underlying medical causes was determined after a multidisciplinary, systematic diagnostic workup including growth charts analysis, extensive biochemical and hormonal assessment and genetic testing in all patients.
The diagnostic workup was completed in n = 282 patients. Median age was 10.8 years (IQR 7.7-14.1); median BMI +3.7SDS (IQR +3.3-+4.3). In 54 (19%) patients, a singular underlying medical cause was identified: in 37 patients genetic obesity, in 8 patients cerebral and in 9 patients medication-induced obesities. In total, thirteen different genetic obesity disorders were diagnosed. Obesity onset <5 years (p = 0.04) and hyperphagia (p = 0.001) were indicators of underlying genetic causes, but only in patients without intellectual disability (ID). Patients with genetic obesity with ID more often had a history of neonatal feeding problems (p = 0.003) and short stature (p = 0.005). BMI-SDS was not higher in patients with genetic obesity disorders (p = 0.52). Patients with cerebral and medication-induced obesities had lower height-SDS than the rest of the cohort.
To our knowledge, this is the first study to report the results of a systematic diagnostic workup aimed at identifying endocrine, genetic, cerebral or medication-induced causes of pediatric obesity. We found that a variety of singular underlying causes were identified in 19% of the patients with severe childhood obesity. Because of this heterogeneity, an extensive diagnostic approach is needed to establish the underlying medical causes and to facilitate disease-specific, patient-tailored treatment.
Drug Repurposing for Rare Diseases Roessler, Helen I.; Knoers, Nine V.A.M.; van Haelst, Mieke M. ...
Trends in pharmacological sciences,
April 2021, 2021-Apr, 2021-04-00, 20210401, Volume:
42, Issue:
4
Journal Article
Peer reviewed
Open access
Currently, there are about 7000 identified rare diseases, together affecting 10% of the population. However, fewer than 6% of all rare diseases have an approved treatment option, highlighting their ...tremendous unmet needs in drug development. The process of repurposing drugs for new indications, compared with the development of novel orphan drugs, is a time-saving and cost-efficient method resulting in higher success rates, which can therefore drastically reduce the risk of drug development for rare diseases. Although drug repurposing is not novel, new strategies have been developed in recent years to do it in a systematic and rational way. Here, we review applied methodologies, recent accomplished progress, and the challenges associated in drug repurposing for rare diseases.
The awareness and interest of the public, media and legislative bodies in the field of rare diseases has been growing consistently.Researchers continue to successfully uncover the molecular and genomic drivers, as well as the clinical course of many rare conditions, due to advances in DNA sequencing technologies and big data analysis, resulting in high expectations for new and optimized treatments.Due to cost effectiveness and a reduced timeline, the process of repurposing drugs for new indications represents an alternative method for finding rare disease treatments with compelling advantages over traditional drug development.The development of systematic approaches to repurpose compounds has led to the identification of promising candidate drugs, some of which are in advanced stages of clinical trials or already approved, with the potential for use in the treatment of rare diseases.
We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in ...the first subjects tested.
We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings).
Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis.
This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder of the cilia, often resulting in a phenotype of obesity, rod-cone dystrophy, a variable degree of intellectual disability, ...polydactyly, renal problems, and/or hypogonadism in males or genital abnormalities in females. We here report the case of an 11-year-old girl who presented with postaxial polydactyly, retinal dystrophy, and childhood obesity, suggesting Bardet-Biedl syndrome. She had no renal problems, developmental delay, or intellectual disability. Genetic testing revealed compound heterozygous variants in the IFT74 gene (c.371_372del p.Gln124Argfs*9 and c.16850-1G>T p.?). We here report the second patient with Bardet-Biedl syndrome due to biallelic IFT74 variants. Both patients have obesity, polydactyly, retinal dystrophy, and no renal abnormalities. The present case however, has normal intellect, whereas the other patient has intellectual disability. We hereby confirm IFT74 as a BBS gene and encourage diagnostic genetic testing laboratories to add IFT74 to their BBS gene panels.
Introduction
Pathogenic heterozygous
MC4R
variants are associated with hyperphagia and variable degrees of obesity. Several research groups have reported short-term weight loss outcomes after ...bariatric surgery in a few patients with
MC4R
variants, but lack of longer-term data prevents evidence-based clinical decision-making.
Materials and Methods
Bariatric surgery patients with heterozygous (likely) pathogenic
MC4R
variants, from three collaborating centers in the Netherlands, France, and the UK, were compared to matched controls (matched 2:1 for age, sex, preoperative BMI, surgical procedure, and diabetes mellitus, but without
MC4R
mutations). Weight loss and regain outcomes up to 6 years of follow-up were compared.
Results
At 60 months of follow-up after RYGB, cases with
MC4R
variants showed weight regain with a mean of 12.8% (± 10.4 SD) total weight loss (TWL) from nadir, compared to 7.9% (± 10.5 SD) in the controls (
p
= 0.062). Among patients receiving SG, the cases with
MC4R
variants experienced inferior weight loss (22.6% TWL) during the first year of follow-up compared to the controls (29.9% TWL) (
p
= 0.010).
Conclusions
This multicenter study reveals inferior mid-term weight outcomes of cases with
MC4R
variants after SG, compared to RYGB. Since adequate weight loss outcomes were observed after RYGB, this procedure would appear to be an appropriate surgical approach for this group. However, the pattern of weight regain seen in cases with
MC4R
variants after both RYGB and SG highlights the need for pro-active lifelong management to prevent relapse, as well as careful expectation management.
Graphical abstract
Chromosomal microarray analysis is an important diagnostic tool to identify copy number variations (CNV). Some of the CNVs affect susceptibility regions, which means that deletions or duplications in ...these regions have partial penetrance and often give an increased risk for a spectrum of neurocognitive disorders. Not much is known about the impact of rare CNV susceptibility syndromes on the life of patients or their parents. In this study, we focus on one specific susceptibility CNV disorder, 16p11.2 deletion syndrome. This rare condition is characterised by an increased risk of mild intellectual disability, autism spectrum disorder, epilepsy, and obesity. We aimed to explore the impact of such a disorder on the family members involved in the daily care of children with this syndrome. Three focus group discussions were held with 23 Dutch (grand)parents. Thematic analysis was performed by two independent researchers. The following five themes emerged: (1) the end of a diagnostic odyssey and response to the diagnosis, (2) after the diagnosis-life with a child with 16p11.2 deletion syndrome, (3) access to medical care and support services, (4) nobody knows what 16p11.2 deletion syndrome is, and (5) future perspective-ideal care. The participants experienced a lack of knowledge among involved professionals. Together with the large variability of the syndrome, this led to fragmented care and unfulfilled needs regarding healthcare, social, and/or educational assistance. Care for children with a CNV susceptibility syndrome could be improved by a multidisciplinary approach or central healthcare professional, providing education and information for all involved professionals.
The pathogenesis of obesity Oussaada, Sabrina M.; van Galen, Katy A.; Cooiman, Mellody I. ...
Metabolism, clinical and experimental,
March 2019, 2019-Mar, 2019-03-00, 20190301, Volume:
92
Journal Article
Peer reviewed
Body fat mass increases when energy intake exceeds energy expenditure. In the long term, a positive energy balance will result in obesity. The worldwide prevalence of obesity has increased ...dramatically, posing a serious threat to human health. Therefore, insight in the pathogenesis of obesity is important to identify novel prevention and treatment strategies. This review describes the physiology of energy expenditure and energy intake in the context of body weight gain in humans. We focus on the components of energy expenditure and the regulation of energy intake. Finally, we describe rare monogenetic causes leading to an impairment in central regulation of food intake and obesity.
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•A chronic positive energy balance leads to weight gain and, ultimately, obesity.•Relative decreases in energy expenditure and increases in energy intake contribute to obesity.•The physiology, acquired pathophysiology, and genetics of energy metabolism are reviewed.•Central mechanisms include impaired homeostatic inhibition of food intake and reward deficiency.•Peripheral mechanisms include impaired nutritional feedback and neuroendocrine signaling.
The zebrafish (
) has become a popular vertebrate model organism to study organ formation and function due to its optical clarity and rapid embryonic development. The use of genetically modified ...zebrafish has also allowed identification of new putative therapeutic drugs. So far, most studies have relied on broad overexpression of transgenes harboring patient-derived mutations or loss-of-function mutants, which incompletely model the human disease allele in terms of expression levels or cell-type specificity of the endogenous gene of interest. Most human genetically inherited conditions are caused by alleles carrying single nucleotide changes resulting in altered gene function. Introduction of such point mutations in the zebrafish genome would be a prerequisite to recapitulate human disease but remains challenging to this day. We present an effective approach to introduce small nucleotide changes in the zebrafish genome. We generated four different knock-in lines carrying distinct human cardiovascular-disorder-causing missense mutations in their zebrafish orthologous genes by combining CRISPR/Cas9 with a short template oligonucleotide. Three of these lines carry gain-of-function mutations in genes encoding the pore-forming (Kir6.1,
) and regulatory (SUR2,
) subunits of an ATP-sensitive potassium channel (K
) linked to Cantú syndrome (CS). Our heterozygous zebrafish knock-in lines display significantly enlarged ventricles with enhanced cardiac output and contractile function, and distinct cerebral vasodilation, demonstrating the causality of the introduced mutations for CS. These results demonstrate that introducing patient alleles in their zebrafish orthologs promises a broad application for modeling human genetic diseases, paving the way for new therapeutic strategies using this model organism.
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