Editors Note: Ophanet is a European website providing information about orphan drugs and rare diseases‘. It annually publishes the prevalence of rare diseases; this report series begins with the most prevalent.
Melanocortin 4 receptor (MC4R) deficiency is the commonest form of monogenic obesity identified so far. The prevalence in the general population is probably around 1 in 2000. MC4R deficiency is characterised by severe obesity, an increase in lean body mass and bone mineral density, increased linear growth in early childhood, hyperphagia beginning in the first year of life and severe hyperinsulinaemia, in the presence of preserved reproductive function. MC4R is a G protein-coupled receptor involved in the hypothalamic leptin-melanocortin signalling pathway. Activation of the MC4R plays a key role in the maintenance of energy homeostasis and is associated with suppression of food intake. MC4R deficiency is transmitted in a codominant manner, with expressivity and penetrance varying between ethnic groups. The majority of patients described so far are carriers of heterozygous mutations in the MC4R gene (18q22). Rare homozygous carriers have been described and display a more severe phenotype. However, one homozygous patient with complete absence of MC4R function has been reported and did not display hyperinsulinaemia. The prevalence of MC4R mutations has been estimated at between 0.5 and 1% in obese adults (body mass index >30) with higher values among populations with severe childhood-onset obesity and variability between ethnic groups. The majority of MC4R deficient cases reported so far have been identified through genetic screening of large cohorts of obese patients, however, diagnosis may be suspected on the basis of the clinical features of the disorder and confirmed by detection of a MC4R mutation. At present, there is no specific treatment for MC4R deficiency. However, future development of small molecule MC4R agonists might lead to the generation of highly effective treatments for this disorder. As with other forms of obesity, the prognosis is dependent on the complications present, with obese patients being at increased risk of cardiovascular disease, cancer and type 2 diabetes. Age of Onset:Infancy.
Estimated prevalence 50 per 100,000