• Endocrine parameters [ Time Frame: Before and every 6 months after treatment is initiated, during 5 years ] [ Designated as safety issue: Yes ]
• Bone mineral density [ Time Frame: Before and every 6 months after treatment is initiated, during 5 years ] [ Designated as safety issue: Yes ]
• Immune function [ Time Frame: Before and every 6 months after treatment is initiated, during 5 years ] [ Designated as safety issue: Yes ]

We will assess the endocrine and immune effects of leptin replacement in leptin-deficient children, from a consanguineous Turkish family. We hypothesize that leptin replacement will have significant effects on immune and endocrine function.

The proposed study of the treatment of a child with congenital leptin deficiency will permit to elucidate key aspects of human endocrine and immune function, and will give new insights on the role of leptin in human endocrine regulation.

Leptin administration in leptin-deficient children will possibly increase energy and fat metabolism by increasing sympathetic nervous system activity. To test this hypothesis, we will measure food intake, energy expenditure, body composition and sympathetic nervous system activity in patients homozygous due to a leptin gene mutation, before and throughout the leptin replacement therapy.

Leptin modulates T-cell function and affects the phagocytic activity of macrophages. Immune function will be assessed during the course of this study. Specifically, tests for antibody, complement and phagocytic function, tests for T-cell immunity, flow cytometry, TREC PCR, thymus imaging studies will be performed. Antibody levels for pathogen organisms will be checked and the child will be vaccinated if needed.

Leptin also has important roles on thyroid, adrenal and gonadal functions. Morevover, leptin is correlated with levels of lipids, glucose and insulin. To test the effects of leptin replacement in leptin-deficient humans, endocrine and metabolic parameters will be measured, before and during treatment.

Leptin determines changes on bone mineral density. To evaluate these changes, bone function and densitometry will also be assessed in this leptin deficient child.

Finally, leptin may have a role in brain growth and development. We will conduct volumetric brain imaging studies in this patient during the course of leptin replacement, ensuring safe exposure to radiation. Neuropsychological evaluation will also be undertaken.

• Obesity
• Metabolic Syndrome
• Diabetes

• Baicy K, London ED, Monterosso J, Wong ML, Delibasi T, Sharma A, Licinio J. Leptin replacement alters brain response to food cues in genetically leptin-deficient adults. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18276-9. Epub 2007 Nov 6.
• Licinio J, Ribeiro L, Busnello JV, Delibasi T, Thakur S, Elashoff RM, Sharma A, Jardack PM, Depaoli AM, Wong ML. Effects of leptin replacement on macro- and micronutrient preferences. Int J Obes (Lond). 2007 Dec;31(12):1859-63. Epub 2007 Aug 7.
• Licinio J, Milane M, Thakur S, Whelan F, Yildiz BO, Delibasi T, de Miranda PB, Ozata M, Bolu E, Depaoli A, Wong ML. Effects of leptin on intake of specific micro- and macronutrients in a woman with leptin gene deficiency studied off and on leptin at stable body weight. Appetite. 2007 Nov;49(3):594-9. Epub 2007 Apr 6.
• Williamson DA, Ravussin E, Wong ML, Wagner A, Dipaoli A, Caglayan S, Ozata M, Martin C, Walden H, Arnett C, Licinio J. Microanalysis of eating behavior of three leptin deficient adults treated with leptin therapy. Appetite. 2005 Aug;45(1):75-80.
• Matochik JA, London ED, Yildiz BO, Ozata M, Caglayan S, DePaoli AM, Wong ML, Licinio J. Effect of leptin replacement on brain structure in genetically leptin-deficient adults. J Clin Endocrinol Metab. 2005 May;90(5):2851-4. Epub 2005 Feb 15.
• Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4531-6. Epub 2004 Mar 9.
• Mantzoros CS, Ozata M, Negrao AB, Suchard MA, Ziotopoulou M, Caglayan S, Elashoff RM, Cogswell RJ, Negro P, Liberty V, Wong ML, Veldhuis J, Ozdemir IC, Gold PW, Flier JS, Licinio J. Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans. J Clin Endocrinol Metab. 2001 Jul;86(7):3284-91.
• Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab. 1999 Oct;84(10):3686-95. Erratum in: J Clin Endocrinol Metab 2000 Jan;85(1):416.
• Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998 Mar;18(3):213-5. No abstract available.
• Paz-Filho GJ, Babikian T, Asarnow R, Esposito K, Erol HK, Wong ML, Licinio J. Leptin replacement improves cognitive development. PLoS ONE. 2008 Aug 29;3(8):e3098.

Inclusion Criteria:

• Children with a functional leptin gene mutation from a consanguineous Turkish family. Only one leptin-naïve child from this family is alive and eligible.

Exclusion Criteria:

• N/A