A novel homozygous missense mutation of the leptin gene (N103K) in an obese Egyptian patient

Mazen, Inas; Gammal, Mona El; Abdel‐Hamid, Mohamed S.; Amr, Khalda

doi:10.1016/j.ymgme.2009.04.002

Cited by 110 publications

(79 citation statements)

References 20 publications

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“…Leptin deficiency is a rare human disease which has so far been reported in only 15 patients worldwide [1,2,3,4,5,6,7,8,9]. Apart from gross obesity and severe metabolic disturbances it is associated with several endocrinological problems.…”

Section: Introductionmentioning

confidence: 99%

Leptin Substitution Results in the Induction of Menstrual Cycles in an Adolescent with Leptin Deficiency and Hypogonadotropic Hypogonadism

et al. 2012

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Background: Leptin deficiency leads to midluteal-phase defect or reduced testicular volume in adults, despite normal gonadotropin levels. All children documented to date with leptin deficiency were prepubertal with physiologically low gonadotropins prior to therapy. A direct effect of leptin on pubertal development in a leptin-naive adolescent has not yet been shown. Methods: In 2010, we reported the first connatal leptin-deficient adolescent girl with clinically and chemically proven hypogonadotropic hypogonadism. In this study, we evaluated the effect of recombinant methionyl human leptin substitution. Results: Initially, the patient had prepubertal basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, low growth hormone and insulin-like growth factor 1 (IGF1) levels and no pulsatile secretion of LH and FSH. After 11 weeks of therapy, basal and stimulated LH and FSH levels rose to pubertal values and nocturnal pulsatility was initiated. After 76 weeks of therapy, menstruation occurred at the age of 16.3 years. Pulsatile nocturnal growth hormone secretion, stimulated growth hormone secretion and IGF1 values also normalized. Conclusion: We describe here the first adolescent with hypogonadotropic hypogonadism due to connatal leptin deficiency. Leptin substitution led to a rapid induction of gonadotropin secretion and menarche. These data are further proof of the concept that leptin is needed for a timely maturation of the hypothalamic/pituitary/gonadal axis.

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Section: Introductionmentioning

confidence: 99%

Leptin Substitution Results in the Induction of Menstrual Cycles in an Adolescent with Leptin Deficiency and Hypogonadotropic Hypogonadism

et al. 2012

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“…Being aware of Friedman's work (Zhang et al 1994), we measured the serum leptin concentration in these children and found that they had undetectable leptin concentrations despite their severe obesity and were homozygous for a frameshift mutation in the LEP gene, which resulted in a truncated protein that was not secreted ). In 1998, three adults carrying a homozygous missense mutation in the LEP gene were reported in a family of Turkish origin (Strobel et al 1998) and since that time, several other affected individuals from consanguineous families (Farooqi et al 2002, Mazen et al 2009, Frank et al 2011, Saeed et al 2012and I S Farooqi, unpublished observations) have been studied. Clement et al (1998) identified the first patients with homozygous mutations in the gene encoding the leptin receptor (LEPR) in 1998.…”

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confidence: 99%

20 YEARS OF LEPTIN: Human disorders of leptin action

Farooqi¹,

O’Rahilly²

2014

Journal of Endocrinology

242

156

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The discovery of leptin has provided a robust framework upon which our current understanding of the mechanisms involved in energy homeostasis has been built. In this review, we describe how the identification of humans with mutations in the genes encoding leptin and the leptin receptor and the characterisation of the associated clinical phenotypes have provided insights into the role of leptin-responsive pathways in the regulation of eating behaviour, intermediary metabolism and the onset of puberty. Importantly, administration of recombinant human leptin in leptin deficiency represents the first mechanistically based targeted therapy for obesity and has provided immense clinical benefits for the patients concerned. In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signalling within the brain.

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“…In contrast to the ob/ob mouse, among the 35 leptin-deficient patients reported so far in the literature [1,21,22,23,24,25,26], only our patient and a 3-year-old boy from Egypt [24] have been shown to suffer from hepatic steatosis.…”

Section: Introductionmentioning

confidence: 66%

“…With the exception of one Egyptian boy [24], transaminases levels are not reported for the other published leptin-deficient patients [1,21,22,23,24,25,26,34] or for the published patients with leptin receptor mutation [35,36]. Given the fact that ob/ob mice typically develop hepatic steatosis [3], it is surprising that this has not been reported for the other leptin-deficient patients.…”

Section: Discussionmentioning

confidence: 99%

Rapid Improvement of Hepatic Steatosis after Initiation of Leptin Substitution in a Leptin-Deficient Girl

Schnurbein¹,

Heni²,

Moß³

et al. 2013

Horm Res Paediatr

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Background: Leptin deficiency is associated with severe obesity and metabolic disturbances. Increased liver fat content has been reported in only one case beforehand, even though hepatic steatosis is a typical comorbidity of common obesity. It is also frequent in patients with lipodystrophy where it resolves under leptin therapy. Subject and Methods: In 2010, we reported a leptin-deficient patient with a novel homozygous mutation in the leptin gene and severe hepatic steatosis. We have now studied serum changes and changes in liver fat content during the substitution with recombinant methionyl human leptin. Results: After 23 weeks of leptin substitution, elevated transaminases, total cholesterol and low-density lipoprotein levels normalized. After 62 weeks, homeostasis model assessment of insulin resistance improved from 10.7 to 6.0 and body fat mass dropped from 50.2 to 37.8%. Liver fat content was drastically reduced from 49.7 to 9.4%. The first changes in liver fat content were detectable after 3 days of therapy. Conclusion: Our patient showed a remarkable reduction of liver fat content during the treatment with recombinant methionyl human leptin. These changes occurred rapidly after initiation of the substitution, which implies that leptin has a direct effect on hepatic lipid metabolism in humans as it is seen in rodents.

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A novel homozygous missense mutation of the leptin gene (N103K) in an obese Egyptian patient

Cited by 110 publications

References 20 publications

Leptin Substitution Results in the Induction of Menstrual Cycles in an Adolescent with Leptin Deficiency and Hypogonadotropic Hypogonadism

Leptin Substitution Results in the Induction of Menstrual Cycles in an Adolescent with Leptin Deficiency and Hypogonadotropic Hypogonadism

20 YEARS OF LEPTIN: Human disorders of leptin action

Rapid Improvement of Hepatic Steatosis after Initiation of Leptin Substitution in a Leptin-Deficient Girl

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