Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016

Abstract

Obesity results from a synergistic relationship between genes and the environment. The phenotypic expression of genetic factors involved in obesity is variable, allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. This is mainly due to autosomal recessive mutations in genes of the leptin-melanocortin pathway which plays a key role in the hypothalamic control of food intake. Melanocortin 4 receptor(MC4R)-linked obesity is characterized by the variable severity of obesity and no notable additional phenotypes. Mutations in the MC4R gene are involved in 2-3% of obese children and adults; the majority of these are heterozygous. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. Additional genes participating in the development of hypothalamus and central nervous system have been regularly identified. But to date, not all involved genes have been identified so far. New diagnostic tools, such as whole-exome sequencing, will probably help to identify other genes. Managing these patients is challenging. Indeed, specific treatments are available only for specific types of monogenic obesity, such as leptin deficiency. Data on bariatric surgery are limited and controversial. New molecules acting on the leptin-melanocortin pathway are currently being developed.

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

“…Leptin treatment works in patients with leptin deficiency or with bioinactive leptin, but on the other hand, leptin treatment is useless in LEPR-deficient subjects, because the receptor mutations make it inactive [24,183].…”

“…A few studies have investigated the capacity of exogenous oxytocin to improve these PWS features, but other research is necessary [183].…”

“…Currently, data on bariatric surgery in children and adolescents with genetic obesity are limited and still controversial [183]. To date, bariatric surgery experience in treating children and adolescents with monogenic and syndromic forms of obesity is limited, and different bariatric procedures have been used with varying success [194].…”

“…To date, bariatric surgery experience in treating children and adolescents with monogenic and syndromic forms of obesity is limited, and different bariatric procedures have been used with varying success [194]. Some studies have demonstrated the efficacy of bariatric surgery (in terms of weight loss and reduction of comorbidities such as obstructive sleep apnea, dyslipidemia, hypertension, diabetes mellitus and poor mobility) in patients with monogenic obesity (such as LEPR-deficient patients and patients with heterozygous MC4R mutations, but not in patients with homozygous MC4R mutation [195]) and syndromic obesity (such as PWS, BBS, Alström syndrome) but, due to the limited number of cases, the long-term efficacy and safety of bariatric surgery in genetic forms of obesity need further evaluation [183].…”

Monogene Adipositas

“…Allerdings kann bisher bei Patienten mit extremer frühkindlicher Adipositas nur bei einer Minderheit eine monogene Stö-rung nachgewiesen werden [39]. Selbst wenn nicht alle Formen der extremen frühkindlichen Adipositas durch monogene Störungen ausgelöst werden, legt dies nahe, dass noch lange nicht alle monogenen Störungen bekannt sind.…”