Читать книгу Clinical Obesity in Adults and Children - Группа авторов - Страница 85

Mutations in MC4R have been reported in up ∼6% of patients with severe early‐onset obesity, and are found at a frequency of approximately 1 in 300 in the general population, making this the most common monogenic form of obesity. While we found a 100% penetrance of early‐onset obesity in heterozygous probands, others have described carriers who were not obese. Given a large number of potential influences on body weight, it is perhaps not surprising that both genetic and environmental modifiers will have important effects on some pedigrees. Taking account of all these observations, co‐dominance, with modulation of expressivity and penetrance of the phenotype, is the most appropriate descriptor for the mode of inheritance.

Figure 4.2 Changes in energy intake and expenditure in two children with congenital leptin deficiency treated with recombinant leptin. (a) Change in ad libitum energy intake in a 3‐year‐old boy (Child B) with congenital leptin deficiency, before and one month after the initiation of leptin therapy. (b) Changes in energy expenditure in Child A (9‐year‐old girl) and Child B (3‐year‐old boy) in response to leptin. BMR, basal metabolic rate; TEE, total energy expenditure expressed per kg lean body weight (LBW).

(Source: Based on Rosenbaum et al. [35].)

Figure 4.3 Leptin therapy is associated with pulsatile gonadotropin secretion at an appropriate developmental age in child (a) (age 11 years) compared to child (b) (age 5 years).

(Source: Modified from Farooqi et al. [30].)

Detailed phenotypic studies of patients with MC4R mutations reveal that this syndrome is characterized by an increase in lean body mass, increased linear growth throughout childhood, hyperphagia, and severe hyperinsulinemia [44]. Of particular note is the finding that the severity of receptor dysfunction seen in in vitro assays can predict the amount of food ingested at a test meal by the subject harboring that particular mutation [44]. An elevated respiratory quotient (ratio of carbohydrate to fat oxidation) in MC4R deficiency is consistent with an impaired ability to mobilize fat seen in MC4R knockout mice. Linear growth of these subjects is striking, with affected children having a height standard deviation score (SDS) of +2 compared to population standards and adults have an increased final height when compared to equally adults with obesity with a normal MC4R genotype. MC4R‐deficient subjects also have higher levels of fasting insulin compared to age‐ and BMI SDS‐matched children.

We have studied in detail the signaling properties of many of these mutant receptors and this information should help to advance the understanding of structure/function relationships and potentially provide in vitro support for the use of MC4R agonists in this group of patients [45].