Study reveals new information on obesity in achondroplasia and the soluble FGFR3

A recent study by Celine Saint-Laurent, Stephanie Garcia and

others, from Elvire Gouze research team, published "Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia". 

The soluble FGFR3 is being developed as a potential treatment for achondroplasia by Therachon, under the designation TA-46.

As stated in the abstract of this study and we here highlight the major concerns related to obesity in achondroplasia:  "Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients and is associated with life-threatening complications including increased risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication"

 

Image 1: Abrão M et al., 2008 "Anesthesia for bariatric surgery in an achondroplastic dwarf with morbid obesity"

Obesity augments the morbidity associated with lumbar lordosis as well as the severity of orthopedic complications, increasing, for example, bearing weight on already fragile knees. It can also increase the risk of serious complications such as cardiovascular risks, obstructive sleep apnea or restrictive lung disease (Trotter T and Hall J, 2005)

Before this new study, several papers indicated that obesity in ACH was related to excessive food intake for a small and shorter body as in this paper from Owen et al.,1990 "Resting metabolic rate and body composition of achondroplastic dwarfs". It stated the following: "... dwarfs had distinctly greater resting metabolic rates (RMR) per kg fat-free mass by densitometry than adults with average stature... Body mass indices were worthless, and skinfold thicknesses and other anthropometric measurements were of very limited value in predicting the body fat of dwarfs. Although our new and specific equations for estimating RMR and body composition give reasonable values, we recommend that the caloric requirements and body compositional variables be measured if nutritional therapy is needed to induce weight loss or gain in Little People"

 

In this study, the researchers observed that obese patients with achondroplasia seem to suffer from associated metabolic complications: apparent dyslipidemia and low insulin levels and also a tendency to glucose intolerance (Alatzoglou KS el at., 2009)

Dyslipidemia occurs when there are unhealthy levels of one or more kinds of lipid (fat) in the blood. Insulin is a hormone that regulates the metabolism of sugars, fats, and protein by promoting the absorption of, especially, glucose from the blood into liver, fat and skeletal cells. Glucose intolerance occurs in metabolic conditions which result in higher than normal blood glucose levels or hyperglycemia.

 

Relevant points presented in this study:

1. The researchers tried to understanding whether and how obesity and metabolic complications are also consequences of the FGFR3 mutation;

2. They verified that the metabolic disturbances in children with achondroplasia led to the preferential development of atypical abdominal obesity;

3. They observed metabolic disturbances in children with achondroplasia leading to the preferential development of atypical abdominal obesity that is unexpectedly not associated with the concurrent development of diabetes or hypercholesterolemia.

 

What did the researchers do in this study?

1. The team conducted a longitudinal, retrospective study in children with achondroplasia separated in 3 age groups ranging from [0–3], [4–8] and [9–18]. 

2. The team studied a mouse model with achondroplasia (mutation Fgfr3ach/+) and they observed that alterations in glucose metabolism lead to similar visceral obesity development.

 

 

Image 2. Mice with different sizes: WT - wild-type mouse (without mutation) an FGFR3 ach+ -Mouse model with achondroplasia. Adapted from Garcia S et al., 2013 "Postnatal Soluble FGFR3 Therapy Rescues Achondroplasia Symptoms and Restores Bone Growth in Mice"

 

 What did the researchers observe in this study?

A. Achondroplasia patients develop an excess of abdominal adipose tissue without classical complications

B. In the Fgfr3ach/+ mice (the ones with achondroplasia mutation) alterations in glucose metabolism lead to similar visceral obesity development.

B. Metabolic alterations occur in lean and obese Fgfr3ach/+ mice and are corrected by sFGFR3 treatment

 

What are the conclusions?

The paper presents the following: "Body mass index and precise growth curves have been established for children with achondroplasia for several decades. Our data are in accordance with them but also establish that:

 

1. The development of a nonconforming obesity is preferentially abdominal and appears to be triggered by the FGFR3 mutation. Even though there is no correlation with increased risk of diabetes, it is necessary to monitor the development of obesity in these patients as it leads to increased severe co-morbidities and cardiovascular risks.

2. If administered early in life, the soluble FGFR3 appears to be a promising treatment for achondroplasia, targeting together bone growth and preventing the development of this atypical obesity.

 

So, the soluble FGFR3 (or TA-46, currently in clinical trial, phase 1)  beside increasing growth rate, can potentially reduce obesity in achondroplasia.