Congenital Leptin Deficiency Due to Homozygosity for the Δ133G Mutation: Report of Another Case and Evaluation of Response to Four Years of Leptin Therapy

Department of Biochemistry, University of Cambridge, Cambridge, England, United Kingdom
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 11/2004; 89(10):4821-6. DOI: 10.1210/jc.2004-0376
Source: PubMed


Congenital leptin deficiency is a rare, but treatable, cause of severe early-onset obesity. To date, two United Kingdom families of Pakistani origin carrying a frameshift/premature stop mutation, c.398delG (Delta133G), and one Turkish family carrying a missense mutation, c.313C>T (Arg(105)Trp), have been described. Affected subjects are homozygotes and manifest severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction. The effects of recombinant leptin therapy have been reported in three children with the Delta133G mutation, and in all cases this has led to a dramatic resolution of clinical and biochemical abnormalities. We now report a Canadian child, of Pakistani origin but unrelated to the previously reported subjects, presenting with severe hyperphagia and obesity, who was found to be homozygous for the Delta133G mutation. In this child, 4 yr of therapy with sc injections of recombinant leptin provided additional evidence for the sustained beneficial effects of leptin replacement on fat mass, hyperinsulinemia, and hyperlipidemia. In addition, leptin administration corrected abnormal thyroid biochemistry and allowed the withdrawal of T(4) treatment, providing additional support for the role of leptin in the regulation of the human hypothalamic-pituitary-thyroid axis.

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Available from: William T Gibson, Dec 12, 2014
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    • "This homozygous single base deletion at codon 133 in the gene coding for leptin caused a frameshift mutation resulting in a truncated protein and undetectable serum leptin levels. Since then several other severely obese patients with missense mutations (p.L72S, p.N103K, p.R105W, p.H118L, p.S141C) and deletion mutations (c.104_106delTCA, c.135del 3 bp, c.398delG and c.481_482delCT) [3] [4] [5] [6] [7] [8] [9] [10] [11] in LEP have been reported. All of these mutations were found in patients from Pakistan, Turkey, Turkmenistan, Egypt, Europe and China where consanguineous marriages are more prevalent. "
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    ABSTRACT: Congenital leptin deficiency is a rare recessively inherited condition due to homozygous mutations in the LEP gene. To date, only nine mutations have been identified in the LEP gene (p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, c.104_106delTCA, c.135del3bp, c.398delG and c.481_482delCT). In this study we present a novel homozygous nonsense mutation (W121X) in LEP in a twelve year old obese male and his severely obese sister. As this disorder is treatable with recombinant leptin, it is intriguing to report a novel homozygous nonsense mutation in LEP in two obese children of consanguineous parents. These patients showed features in accordance with leptin deficiency.
    Full-text · Article · Nov 2014 · Molecular Genetics and Metabolism Reports
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    • "Leptin receptors expressed elsewhere in the body mediate a plethora of non-metabolic functions, including regulation of the immune system, (Taleb et al., 2007), angiogenesis (Park et al., 2001), fetal lung function (Torday & Rehan, 2006), bone mass (Ducy et al., 2000) and a number of extra-hypothalamic neurological functions (Lieb et al., 2009). In mice and humans, absence of leptin signalling caused either by inactivating mutations of the leptin gene (ob/ob) or the leptin receptor (db/db) leads to severe obesity due to uncontrolled eating (Ingalls et al., 1950; Gibson et al., 2004). "
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    • "Ozata et al. (1999) have reported abnormalities of sympathetic nerve function in leptin-deficient adults consistent with defects in the efferent sympathetic limb of thermogenesis. Evidence from rodents and humans suggests that leptin is necessary for the normal biosynthesis and secretion of thyrotropin-releasing hormone and that complete leptin deficiency is associated with a moderate degree of hypothalamic hypothyroidism characterized by low free thyroxine and high serum thyroid-stimulating hormone, which is bio-inactive (Gibson et al. 2004). "
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    ABSTRACT: Body weight is a highly heritable trait across species. In humans, genetic variation plays a major role in determining the inter-individual differences in susceptibility or resistance to environmental factors which influence energy intake and expenditure. In this review, I discuss how genetic studies have contributed to our understanding of the central pathways that govern energy homeostasis. The study of individuals harboring highly penetrant genetic variants that disrupt the leptin-melanocortin pathway has informed our understanding of the physiological pathways involved in mammalian energy homeostasis.
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