Endocrine Abstracts

We have established a cohort of 700 subjects with severe early-onset obesity. The average age of onset of clinical presentation of obesity is less than 5 years of age and the mean body mass index standard deviation score is >4. In this cohort, we have detected three independent probands with congenital leptin deficiency, and they and their families are currently undergoing a long-term therapeutic trial of leptin replacement therapy with beneficial effects on energy balance, neuroendocrine and metabolic profile and immuno function. 5.6% of our cohort have pathogenic mutations in the melanocortin 4 receptor that both cosegregate with obesity and show impaired signalling when studied ex vivo. The phenotype of melanocortin 4 deficiency is distinct from leptin deficiency with a greater increase in lean mass, no adverse effects on reproductive function and more severe hyperinsulinaemia. There is documented objective evidence for hyperphagia in the melanocortin 4 receptor deficient subjects but this is less severe than that seen in leptin deficiency. There is a remarkable correlation between the signalling properties of the MC4 mutant when studied ex vivo and measurements of food intake in vivo. While we have not found any children completely deficient in the POMC gene, we have detected a relatively common variant which impairs the processing between beta MSH and beta endorphin creating a mutant peptide with capacity to interfere with signalling at the MC4 receptor. Having described the first subject with prohormone convertase 1 deficiency, we have recently detected another obese subject with different compound heterozygous mutations in PC1, who also had evidence for severe gastrointestinal dysfunction. Further studies in our original proband revealed marked abnormalities of GI absorption. Thus, PC1 appears essential for normal gastrointestinal function in man. There are a number of other mutations in other key candidate genes. Ongoing work will be discussed.