Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene

Wabitsch, Martin; Funcke, Jan-Bernd; Schnurbein, Julia von; Denzer, Friederike; Lahr, Georgia; Mazen, Inas; Gammal, Mona El; Denzer, Christian; Moß, Anja; Debatin, Klaus‐Michael; Gierschik, Peter; Mistry, Vanisha; Keogh, Julia M.; Farooqi, I. Sadaf; Moepps, Barbara; Fischer‐Posovszky, Pamela

doi:10.1210/jc.2015-2263

Cited by 88 publications

(96 citation statements)

References 10 publications

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“…Despite their severe obesity, both children had undetectable levels of serum leptin and a mutation in the gene encoding leptin mapped at 7q32.1. The disease is caused by mutations in the LEP gene (OMIM *164160) typically leading to defects in protein synthesis or secretion, and therefore to the absence or very low blood levels of this hormone [21][22][23].…”

Section: Congenital Leptin Deficiency (Omim #614962)mentioning

confidence: 99%

“…However, recently the first cases of functional leptin deficiency have been described [23,24]. This entity is characterized by detectable immunoreactive levels of circulating leptin, but bioinactivity of the hormone due to defective receptor binding [23,24].…”

Section: Congenital Leptin Deficiency (Omim #614962)mentioning

confidence: 99%

“…This entity is characterized by detectable immunoreactive levels of circulating leptin, but bioinactivity of the hormone due to defective receptor binding [23,24].…”

Section: Congenital Leptin Deficiency (Omim #614962)mentioning

confidence: 99%

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New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

Stagi¹,

Bianconi²,

Sammarco³

et al. 2017

Adiposity - Omics and Molecular Understanding

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Historically, some genetic syndromes and monogenic forms of obesity have been identified by clinical features and by sequencing candidate genes in patients with severe obesity. The phenotypic expression of genetic factors involved in obesity is variable, thereby allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. Many of the findings emerged from studying families who displayed a classical Mendelian pattern of inheritance. On the contrary, patients with syndromic obesity show a various degree of intellectual disability, different dysmorphic features, and organ-specific abnormalities. But to date, not all involved genes have been identified so far. New diagnostic tools, such as genome-wide studies, array CGH, and whole-exome sequencing, have highlighted more complex models of inheritance, and even more candidate genes were identified. This increase of knowledge may provide insights into the mechanisms involved in the regulation of body weight and finally lead to specific treatments. In these patients, hyperphagia is often a primary phenotypic component. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present today with a lack of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. We have evaluated retrospectively the literature data on weight, body mass index (BMI), clinical features, treatments, and treatment response in pediatric patients with forms of genetic obesity. However, this chapter provides an updated picture of emerging knowledge outlined by the more comprehensive genetic approaches, trying to outline more candidate genes for these forms of genetic obesity. Relevant papers will be identified through systematic searches of the PubMed, EMBASE and Cochrane databases. All published studies in the English language concerning these disorders will be evaluated. Keywords in the

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Section: Congenital Leptin Deficiency (Omim #614962)mentioning

confidence: 99%

Section: Congenital Leptin Deficiency (Omim #614962)mentioning

confidence: 99%

See 1 more Smart Citation

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

Stagi¹,

Bianconi²,

Sammarco³

et al. 2017

Adiposity - Omics and Molecular Understanding

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“…The most common form is caused by heterozygous mutations in the melanocortin 4 receptor gene ( MC4R ) . Other causes are, eg, biallelic mutations in the leptin gene ( LEP ), leptin receptor gene ( LEPR ), or proopiomelanocortin gene ( POMC ) …”

Section: Introductionmentioning

confidence: 99%

Methylphenidate in children with monogenic obesity due to LEPR or MC4R deficiency improves feeling of satiety and reduces BMI‐SDS—A case series

Brandt¹,

Schnurbein²,

Lennerz

et al. 2019

Pediatric Obesity

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Summary Background The clinical phenotype of patients with monogenic obesity due to mutations in the leptin receptor (LEPR) or melanocortin 4 receptor (MC4R) gene is characterized by impaired satiety and hyperphagia, leading to extreme, sometimes life‐threatening weight gain. Subjects/methods In a case series, we analysed the effect of an off‐label methylphenidate (MPH) use for 1 year as an individual treatment approach on eating behaviour (Child Eating Behaviour Questionnaire [CEBQ]), appetite (visual analogue scales) and body mass index (BMI) trajectories in five patients with severe obesity due to mutations in the LEPR (n = 3) or MC4R (n = 2) gene. Results After 1 year use of MPH (20 mg/day divided in two to three doses), BMI (Δ BMIT0−T1 truex¯: −0.7 ± 0.9 kg/m2), BMI standard deviation score (SDS) (Δ BMI‐SDST0−T1 truex¯: −0.32 ± 0.20), and %BMIP95 (Δ %BMIP95T0−T1 truex¯: −6.6 ± 7.8%) decreased. BMI‐SDS velocity decreased from +0.17 ± 0.22 to −0.30 ± 0.20. Appetite and CEBQ subscale scores for “food responsiveness” and “enjoyment of food” decreased. We observed adverse effects with increase in self‐reported frequency of disordered sleep, nervousness, hyperactivity, and tics. Conclusions The observed decrease in BMI trajectories with MPH use for one year is clinically meaningful in this group of patients, since the natural course would have been associated with a pronounced increase in BMI, leading to comorbidities and complications over time.

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“…It is located on chromosome 7q31.3 in humans and consists of three exons spanning 650 kb [9]. Mutations of the LEP gene have been associated with different degrees of obesity in the human population [10,11]. Moreover, in obese families, recent studies have shown an association of different single nucleotide polymorphisms (SNPs) in the LEP gene with serum leptin levels, obesity and metabolic biomarkers, including anthropometric parameters, levels of glucose, insulin and lipid profile [12,13].…”

Section: Introductionmentioning

confidence: 99%

Mismatch Amplification Mutation Assay Real-Time PCR Analysis of the Leptin Gene G2548A and A19G Polymorphisms and Serum Leptin in Infancy: A Preliminary Investigation

Savino¹,

Rossi²,

Stasio

et al. 2016

Horm Res Paediatr

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Leptin is a hormone that regulates food intake and energy metabolism. Its coding gene (LEP) is one of the most promising candidates for obesity. Although some studies have detected associations of different single nucleotide polymorphisms (SNPs) in the LEP gene with serum leptin levels and obesity-related traits, the results are still conflicting. We investigated two SNPs to find relationships with leptin concentrations. Thirty healthy Caucasian infants younger than 6 months were genotyped for the SNPs G2548A and A19G with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system-mismatch amplification mutation assay (ARMS- MAMA) real-time PCR, and serum leptin concentrations were measured with a radioimmunoassay method. Considering the significant linkage disequilibrium observed between the two SNPs, we divided the sample according to the number of GG haplotypes and observed that individuals homozygous for the GG haplotype had higher serum leptin levels in early infancy than the others. Although these preliminary results are based on a limited sample, they suggest that the genetic background seems to play a role in modulating leptin levels in infancy, but changes in leptin levels over infancy and their correlation with obesity need to be further explored. We describe an ARMS-MAMA real-time PCR procedure which could be profitably applied in routine genetic screening.

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Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene

Cited by 88 publications

References 10 publications

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

Methylphenidate in children with monogenic obesity due to LEPR or MC4R deficiency improves feeling of satiety and reduces BMI‐SDS—A case series

Mismatch Amplification Mutation Assay Real-Time PCR Analysis of the Leptin Gene G2548A and A19G Polymorphisms and Serum Leptin in Infancy: A Preliminary Investigation

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