scholarly journals Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Stefanie Zorn ◽  
Julia von Schnurbein ◽  
Katja Kohlsdorf ◽  
Christian Denzer ◽  
Martin Wabitsch
Keyword(s):  
Bariatric Surgery ◽  
Early Onset ◽  
Weight Control ◽  
Leptin Receptor ◽  
Case Reports ◽  
Receptor Gene ◽  
Melanocortin Receptor ◽  
Genetic Diagnostics ◽  
Compound Heterozygous ◽  
Wide Range

Abstract Background Rare genetic variations in the leptin-melanocortin signalling pathway can severely impair appetite regulation and cause extreme obesity in early childhood. Case presentation Our case reports describe the diagnostic and therapeutic procedures in a girl as well as in a non-related boy of non-consanguineous, German parents with severe early-onset obesity, pronounced hyperphagia, and permanent food-seeking behaviour. Excessive weight gain within the first year of life initiated extensive diagnostics without finding a causal diagnosis. Furthermore, a wide range of intensive, interdisciplinary, and behavioural therapies for weight control were unsuccessful. Prior to bariatric surgery, the 18-year-old girl and the 14-year-old boy reached a BMI of 67.7 kg/m2 and 55.2 kg/m2, respectively. However, even surgical outcomes were unsatisfactory. A subsequently initiated genetic analysis including sequencing of the leptin receptor gene revealed compound heterozygous variants as a cause of the severe early-onset obesity in both patients (c.2598-3_2607delTAGAATGAAAAAG and c.2227 T>C; c.1874G>A and c.2051A>C). Both patients were enrolled in the clinical study RM-493-015 and treated with melanocortin receptor agonist setmelanotide. Currently, they are still on setmelanotide treatment in the extension trial RM-493-022. Conclusion Our case report illustrates the urgent necessity of early genetic diagnostics in children with severe early-onset obesity to avoid frustrating and potentially damaging therapies. Thus, genetic examination should precede bariatric surgery. In the future, several pharmacological therapies will be available for some forms of monogenetic obesity.

scholarly journals Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review

2020 ◽  
Vol 21 (20) ◽  
pp. 7783
Author(s):  
Tai-Heng Chen ◽  
Yan-Zhang Wu ◽  
Yung-Hao Tseng
Keyword(s):  
Muscular Dystrophy ◽  
Early Onset ◽  
Case Reports ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Clinical Severity ◽  
Genetic Diagnostics ◽  
Rapid Decline ◽  
Novel Treatments ◽  
D4z4 Repeat ◽  
History Of

Facioscapulohumeral muscular dystrophy (FSHD)—the worldwide third most common inherited muscular dystrophy caused by the heterozygous contraction of a 3.3 kb tandem repeat (D4Z4) on a chromosome with a 4q35 haplotype—is a progressive genetic myopathy with variable onset of symptoms, distribution of muscle weakness, and clinical severity. While much is known about the clinical course of adult FSHD, data on the early-onset infantile phenotype, especially on the progression of the disease, are relatively scarce. Contrary to the classical form, patients with infantile FSHD more often have a rapid decline in muscle wasting and systemic features with multiple extramuscular involvements. A rough correlation between the phenotypic severity of FSHD and the D4Z4 repeat size has been reported, and the majority of patients with infantile FSHD obtain a very short D4Z4 repeat length (one to three copies, EcoRI size 10–14 kb), in contrast to the classical, slowly progressive, form of FSHD (15–38 kb). With the increasing identifications of case reports and the advance in genetic diagnostics, recent studies have suggested that the infantile variant of FSHD is not a genetically separate entity but a part of the FSHD spectrum. Nevertheless, many questions about the clinical phenotype and natural history of infantile FSHD remain unanswered, limiting evidence-based clinical management. In this review, we summarize the updated research to gain insight into the clinical spectrum of infantile FSHD and raise views to improve recognition and understanding of its underlying pathomechanism, and further, to advance novel treatments and standard care methods.

Linkage study of early-onset obesity to leptin receptor gene in Italian children

2000 ◽  
Vol 20 (8) ◽  
pp. 1059-1063 ◽  
Author(s):  
Emanuele Miraglia del Giudice ◽  
Laura Perrone ◽  
Paola Forabosco ◽  
Marcella Devoto ◽  
Maria Teresa Carbone ◽  
...  
Keyword(s):  
Early Onset ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Linkage Study ◽  
Italian Children

scholarly journals Phenotype: Genotype Relationships in Growth Hormone Insensitivity Syndrome1

1997 ◽  
Vol 82 (11) ◽  
pp. 3529-3535 ◽  
Author(s):  
Katie A. Woods ◽  
Florence Dastot ◽  
Michael A. Preece ◽  
Adrian J. L. Clark ◽  
Marie-Catherine Postel-Vinay ◽  
...  
Keyword(s):  
Binding Protein ◽  
Receptor Gene ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Gh Receptor ◽  
Ghr Gene ◽  
Wide Range ◽  
Growth Hormone Insensitivity ◽  
Igf Binding ◽  
Igfbp 3

GH insensitivity syndrome (GHIS) is associated with many different mutations of the GH receptor (GHR) gene. We examined the phenotypic and biochemical features in 82 GHIS patients from 23 countries, each fulfilling diagnostic criteria of GHIS. There were 45 males and 37 females [mean age, 8.25 yr; mean height, −6.09 sd score, and mean insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3),− 7.99 sd score]. Sixty-three were GH-binding protein (GHBP) negative; 19 were GHBP positive (>10% binding). The mean height in GHBP-negative subjects was −6.5 sd score, and that in GHBP-positive patients was −4.9 sd score (P = <0.001). Clinical and biochemical heterogeneity was demonstrated by the wide range of height (−2.2 to− 10.4 sd score) and IGFBP-3 (−1.4 to −14.7 sd score) values, which were positively correlated (r2 = 0.45; P = <0.001). This contrasted with the lack of correlation between mean parental height sd score and height sd score (r2 = 0.01). Fifteen different GH receptor gene mutations were identified in 27 patients. All had homozygous defects, except 1 who had a compound heterozygous defect. The mutations were 5 nonsense, 2 frame shift, 4 splice, 4 missense, and 1 compound heterozygote. There was no relationship between mutation type or exon of the GHR gene involved and height or IGFBP-3 sd score. In conclusion, GHIS is associated with wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene. Other genetic and/or environmental factors must, therefore, contribute to phenotype in GHIS.

Association between leptin receptor gene polymorphisms and early-onset prostate cancer

2003 ◽  
Vol 92 (1) ◽  
pp. 109-112 ◽  
Author(s):  
Z. Kote-Jarai ◽  
R. Singh ◽  
F. Durocher ◽  
D. Easton ◽  
S.M. Edwards ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Early Onset ◽  
Gene Polymorphisms ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Receptor Gene Polymorphisms

scholarly journals Severe Early-Onset Obesity in Three Adult Patients Harboring Inactivating Mutations of the Leptin Receptor Gene

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A37-A37
Author(s):  
Carolina Marques Chaves ◽  
Teresa Kay ◽  
Joao Anselmo
Keyword(s):  
Early Onset ◽  
Leptin Receptor ◽  
Reference Range ◽  
Receptor Gene ◽  
Pubertal Development ◽  
Genetic Diagnosis ◽  
The Body ◽  
Homozygous Mutation ◽  
Genetic Sequencing ◽  
Lepr Gene

Abstract Background: Leptin is secreted by white adipocytes in response to fat storage and binds to leptin receptors (LEPR) expressed all over the body particularly in hypothalamic neurons. This hormone regulates several physiologic functions including energy expenditure and appetite. Clinical Case: We describe the clinical and hormonal findings in 3 adult brothers with body mass index (BMI) of 36.7, 50.7, and 46.1 kg/m2, respectively. There is no history of consanguinity in the family and none of the patients exhibited dysmorphic features. A rapid weight gain was noticed during their first few months of life, associated with permanent hyperphagia. At 2 years old, their BMI was already above 25 kg/m2 (> +3SD), and at 10 years old, it was over 40 kg/m2 (> +3SD). The linear growth was within the expected target heights for their parents. They did not seem to present cognitive impairment. The pubertal development began at 16 to 18 years old, and since then they maintained levels and FSH and LH above the upper limit of normal (15.6±3.7mUI/mL and 12.3±2.2mUI/mL, reference range 1.5–12.4 and 1.7–8.6, respectively), but with normal sexual steroids (estradiol 36.4±16.1pg/mL and total testosterone 445±401ng/dL, reference range 11–44 and 249–836, respectively). The thyroid function was normal and none of the patients suffered from dyslipidemia or diabetes, despite high serum insulin levels 26.4±15.8 mU/L (normal 5–10). Genetic sequencing identified a homozygous mutation of the leptin receptor gene in the 3 brothers: c.2357T> C, p. (Leu786Pro). Their parents were heterozygous for the mutation as well as the patients’ daughters. Homozygous carriers of the mutation presented a significantly higher BMI than their heterozygous family members, 44.5±7.1 Kg/m2 vs 32.2±1.7 Kg/m2 (p=0.023), a significantly increased leptin levels, 80±36.4 ng/ml vs 26.3±9.3 ng/ml (p=0.028), and significantly higher weight, 134.6±16.9 vs 89.2±15,2 kg (p=0.021), respectively. Women had higher BMI than men (42.0 ±12.2 Kg/m2 vs 37.9±7.5 Kg/m2, p=0.496) and also higher percentage of fat (46.4±3.1% vs 34.9±6.8%, p=0.108). Serum levels of leptin in homozygous patients were not significantly higher than those measured in 10 patients with adult-onset morbid obesity, 80± 36.4 ng/ml vs 53.8±24.1 ng/ml, respectively (p=0.149). Therefore, serum leptin is not a useful discriminative maker of LEPR gene mutations. Conclusion: Patients with severe early-onset obesity should have a genetic diagnosis workup. Firstly, because clinical trials with MC4R-agonists have raised expectations regarding the treatment of patients with mutations of the LEPR gene. Secondly, and in contradiction to other reports in the literature, our patients were fertile. Therefore, identification of the mutation allows genetic counseling of these patients and their families, including the possibility of Pre-Natal Diagnosis or Pre-Implantation Genetic Diagnosis.

scholarly journals Promoter Methylation of LEP and LEPR before and after Bariatric Surgery: A Cross-Sectional Study

Obesity Facts ◽  
2021 ◽  
pp. 1-7
Author(s):  
Julia Wilhelm ◽  
Anna Birkenstock ◽  
Vanessa Buchholz ◽  
Astrid Müller ◽  
Sherif Adel Aly ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Dna Methylation ◽  
Promoter Methylation ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Serum Levels ◽  
Cross Sectional Study ◽  
Feedback Mechanism ◽  
Epigenetic Mechanism ◽  
Cross Sectional

<b><i>Introduction:</i></b> DNA methylation constitutes one important epigenetic mechanism that regulates gene expression in human cells. With regard to obesity, bariatric surgery-induced weight loss has been associated with promoter methylation changes in several genes. Hyperleptinemia is a characteristic feature of obesity. The underlying regulating mechanisms have not yet been completely elucidated. <b><i>Methods:</i></b> We investigated the methylation of the promoters of the leptin gene (<i>LEP</i>) and the leptin receptor gene (<i>LEPR</i>) as well as leptin expression in pre- and postbariatric surgery patients using a comparative cross-sectional design. <b><i>Results:</i></b> Our results revealed significantly higher <i>LEP</i> promoter methylation patterns in prebariatric surgery patients compared to postoperatively. DNA methylation of the <i>LEPR</i> promoter was significantly higher in the postoperative group. Moreover, we found significantly higher leptin serum levels in patients before the bariatric surgery than afterwards. <b><i>Discussion:</i></b> These findings strengthen the suggestion that there is an association between LEP expression and <i>LEP</i> methylation in obesity. We suggest that the epigenetic profile of <i>LEP</i> might be influenced by leptin serum levels in the form of a regulating feedback mechanism.

Association between leptin receptor gene polymorphism and quality of both meat and back fat in large white pigs of ukrainian breeding

2016 ◽  
Vol 3 (2) ◽  
pp. 42-48
Author(s):  
V. Balatsky ◽  
I. Bankovska ◽  
A. Saienko
Keyword(s):  
Gene Polymorphism ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Intramuscular Fat ◽  
Large White ◽  
Pig Breeds ◽  
Lepr Gene ◽  
Large White Breed ◽  
White Breed

Leptin receptor is one of the components of the system of regulating energy homeostasis of the organism. Leptin receptor gene (LEPR) polymorphism is associated with pig carcass index of the content of intramus- cular fat in its valuable parts, which is particularly important when assessing the quality of their carcasses for processing. Intramuscular fat is associated with meat fl avor characteristics and partly determines its tenderness, juiciness, and other parameters. Aim. To analyze LEPR gene (SNP NM001024587.1, p. 1987 C > T) polymor- phism in populations of various pig breeds and to establish its relationship with the quality of both meat and fat of pigs of Large White breed of Ukrainian breeding. Methods. Genetic-population analysis of nine pig breeds, associative analysis on the search connection of LEPR gene polymorphism with quality of both meat and fat of pigs of Large White breed of Ukrainian breeding. LEPR locus genotyping was performed by High Resolution Melting (HRM). Results. All the studied breeds are characterized by polymorphism of the leptin receptor gene (SNP NM001024587.1, p. 1987 C > T), signifi cant breed specifi city in the distribution of frequencies of alleles was established. Statistically confi rmed effect (p < 0.05) of genotypes LEPR on the content of intramuscular fat, total dry matter and moisture in the meat, as well as the moisture content in the back fat of pigs of Ukrainian Large White breed was revealed. Higher content of intramuscular fat was found in the animals with genotype TT, while a smaller amount of intramuscular fat and more moisture in fat was revealed in heterozygotes. Conclusions. Genetic marker LEPR SNP NM001024587.1, p. 1987 C > T can be used in the marker-assisted selection to predict and improve the performance quality of the meat of pigs of Large White breed of the Ukrainian breeding. These results suggest that porcine leptin receptor gene controls the quality of fat comp- lex – inside muscles and in the dorsal part of the carcass.

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