“One in five children who are severely overweight is probably …

Ulm – Conservative treatment methods are often unsuccessful in overweight children and adolescents. It showed a survey in 2014 Deutsches Ärzteblatt (DAE). Especially young people with extreme obesity could benefit from genetic diagnosis. For the reason that not all children gain weight equally and that certain therapies work less well lies in a different biological disposition.

Body weight is regulated by two main systems: the homeostatic system, which operates on the subconscious level, and the hedonic system, which operates on the conscious level. DÄ spoke with Martin Wabitsch from Ulm University Hospital about how obesity can be treated.

Five questions to Martin Wabitsch, Head of the Center for Rare Endocrine Diseases and the Endocrinological Research Laboratory at Ulm University Hospital.

THE: They offer consultation hours for children and adolescents with obesity and especially with extreme obesity in children. What types of obesity do you encounter?
Martin Wabitsch: Our office hours are very popular. Criteria for inclusion are extreme obesity in early childhood (onset before school age) with signs of hyperphagia or age under 14 years and a body mass index (BMI) greater than 35 kg / m2.

These patients have a strong biological predisposition to obesity. Patients who meet the latter criteria often gain 10 to 15 kg in weight per year. This is inevitable. These young people have a clear, central nervous system disorder of energy regulation (hunger-saturation regulation). We estimate that around 100,000 people in Germany are affected.

THE: Which children have also been genetically examined and in how many are genetic causes found? Which genes are affected?
Wabitsch: The Department of Human Genetics at Ulm University Hospital is one of the few university diagnostic laboratories that has offered next-generation sequencing (NGS) -based gene panel testing for several years. Here, more than 150 molecular genetic analyzes are performed each year on extremely obese children. One in five severely obese children is likely to be genetically obese. This figure matches with results from other European university centers.

The affected genes in which we find pathogenic variants often play a role in the leptin-POMC-MCR4 regulatory pathway (examples: leptin receptor (LEPR), proopiomelanocortin (POMC), steroid receptor coactivator 1 (SRC1), prohomon convertase (PC) 1 / 3 (PCSK1), SH2B adapter protein 1 (SH2B1).

THE: What therapy options do you offer children with and without genetic causes?
Wabitsch: Patients with extreme obesity and hyperphagia with and without genetic causes respond little or not at all to purely behavioral therapy interventions. You can not correct the biologically caused regulatory disorder through voluntary control. This is why new drugs and bariatric surgery procedures play a role in the treatment of these patients.

Researchers have recently been able to find a number of genetic causes that work in the homeostatic system of obesity in its extreme form. Some of these can be treated specifically (causally) (J Endocr Soc. 2022, 10.1210 / jendso / bvac057).

Liraglutide, an incretin mimetic approved for all adolescents 12 years of age and older with obesity, and setmelanotide, an MC4 receptor agonist approved for the treatment of patients with pathogenic variants in the genes for LEPR, POMC and PCSK1, are suitable for this .

THE: How successful are these therapy options? When should obesity surgery be considered?
Wabitsch: Liraglutide works well in adolescent obesity as well as in various forms of genetic obesity, as the active substance unfolds its effect in part independently of the leptin-POMC-MCR4 regulatory pathway. Obese young people will usually gain between 10 and 15 kg per year.

If we use liraglutide for normal obesity or Setmelanotide for genetic obesity, then those affected lose weight for the first time in their lives. On average, there is a weight loss of 5 kg per year. In some cases, the weight can also be reduced by more than ten kilos. With the genetic forms of obesity, weight loss is even more pronounced.

The other incretin mimetics, including dual and multiple receptor agonists, which are currently in clinical trials (Phase 2 and 3), are likely to allow for further treatment options after their approval.

In addition to the effect of these drugs (setmelanotide, liraglutide) on body weight, patients report a markedly marked reduction in hyperphagia and thus an improvement in quality of life (doi: 10.1007 / s12325-022-02059-8). The young people say that the feeling of satiety is back and the desire for evening snacks is gone.

Obesity surgery in children and adolescents is a last resort, and the working group on obesity in children and adolescents has clearly formulated the criteria for such therapy.

THE: How well cared for overweight children and young people in Germany?
Wabitsch: Children and young people with obesity are very poorly cared for in Germany. There is no structured treatment for childhood obesity in Germany. There are hardly any special consultation times. Most patients undergo an odyssey of diagnostic and therapeutic trials. Here we have an urgent need for a solution, also with the help of the targeted DMP obesity for children and young people.

According to the evidence-based S3 guidelines (AWMF) from 2019, every child with obesity must have access to a therapeutic training program (with the involvement of the parents). This is the basis of all therapeutic efforts.

Less than one percent of those affected receive such care. Offers for such programs have declined in recent years due to funding problems. Pediatricians in private practice can not undertake the treatment on their own, as it is time consuming and requires the involvement of other disciplines.

The knowledge now available about the genetic causes of extreme obesity in children shows that appropriate genetic diagnosis makes sense and that the results have a significant impact on therapy decisions (personalized medicine). © gie / aerzteblatt.de

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