Early Onset Obesity (MC4R)

Introduction

MC4R is expressed in the hypothalamus. Stimulation of MC4R by α-MSH binding triggers the activation of anorexigenic signals, which, through a series of further steps, are believed to reduce food intake by creating the perception of satiety. In cell culture studies, many of the obesity-linked MC4R mutations have been shown to render the receptor protein dys- or non-functional (4, 5, 6). Thus, mutations in MC4R appear to prevent the activation of anorexigenic signals in response to α-MSH binding, so that individuals with obesity-linked mutations in MC4R may not experience the feeling of satiety.

Early onset obesity first occurs in children under ten years of age, and is characterized by hyperphagia and a body mass index (BMI) approximately four standard deviations higher than age appropriate. In children as in adults, severe obesity leads to insulin resistance and, consequently, hyperinsulinemia. Approximately 30% of hyperinsulinemic individuals eventually develop pancreatic β-cell failure and type 2 diabetes. As severely obese children reach adulthood, other common complications of obesity begin to manifest themselves, including the metabolic syndrome with its attendant atherosclerotic cardiovascular disease, type 2 diabetes, nephropathy, retinopathy, and neuropathy. In addition, obese individuals are prone to developing hepatic steatosis, obstructive sleep apnea, orthopedic complications, and acanthosis nigricans.

In contrast to several other known monogenic causes of obesity, defects in MC4R lead to non-syndromic obesity. Symptoms linked to MC4Rrelated early onset obesity include binge eating behavior, severe hyperinsulinemia, an increase in bone minerals, a higher linear growth velocity, and an earlier than normal onset of puberty.

Symptoms accompanying MC4R-related early onset obesity are also seen with other types of obesity (12) and may become apparent only over extended periods of time. Thus, these symptoms do not permit the differential diagnosis of MC4R-related early onset obesity. In contrast, genetic testing allows a diagnosis of MC4R-related early onset obesity at any age.

Traditionally, childhood obesity has been managed by dietary approaches combined with efforts to increase physical activity. However, dietary management in general is often ineffective, and more and more older children and young adults are undergoing bariatric surgeries. These procedures are highly effective in promoting weight loss in the short term, but have their own attendant complications.

Several drugs for targeted therapy of MC4R-related obesity are presently undergoing clinical development. The therapeutic concept is based on the finding that most patients with MC4R-related obesity are heterozygous for the mutation in the MC4R gene. Studies in cell culture have indicated that the functionality of a normal MC4R protein is not affected by presence of a mutated receptor protein in the same cell (5, 13). Therefore, increased stimulation of the remaining healthy MC4R protein with specific drugs may be able to compensate for the loss of function in the mutated receptor.

MC4R-related early onset obesity is inherited in an autosomal dominant manner. While individuals with mutations in only one of the two MC4R gene copies (heterozygotes) can express the obesity phenotype, patients with mutations in both copies of the MC4R gene (homozygotes) demonstrate more severe obesity (1). In heterozygotes, expression of the obesity phenotype appears to be due to haploinsufficiency, i.e., insufficient amounts of intact MC4R protein are expressed from the remaining normal gene copy. Penetrance of the mutation varies within and between families, i.e., not all heterozygous individuals carrying an obesityassociated MC4R mutation are obese (3, 14). Within families, female carriers of obesity-linked MC4R mutations are often more severely affected than males with the same mutation.

The Early Onset Obesity (MC4R) Evaluation detects mutations in the gene coding for MC4R, which represent the most common monogenic cause of early onset obesity known to date.

How Is Genetic Testing for MC4R-Related Obesity Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of MC4R are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.

Order Athena's Early Onset Obesity Test.

Download this Disease Review as a Printable PDF.