Understanding Unmet Needs in Bardet-Biedl Syndrome

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Significant advances in genetic research are enabling us to learn more about the complex factors that can influence the balance between energy intake and expenditure and ultimately contribute to obesity. While environment can play a substantial role, studies have shown that in rare cases highly impactful variants in just one gene can be sufficient to cause early-onset, severe obesity and an insatiable hunger drive known as hyperphagia. This development is especially important for improving the care of individuals living with rare genetic diseases that may lead to early-onset, severe obesity such as Bardet-Biedl syndrome.

Bardet-Biedl syndrome is an inherited disease characterized by multisystemic dysfunction. While severe obesity and hyperphagia can potentially affect individuals living with the disease, many other health problems are also associated with Bardet-Biedl syndrome, which can make management a challenge. This disease presents with multiple clinical characteristics and symptoms that affect individuals with Bardet-Biedl syndrome to varying degrees, including retinal degeneration, postaxial polydactyly, learning disabilities, hypogonadism, and renal dysfunction, as well as several other features including speech and developmental delays, congenital heart disease, and diabetes mellitus.

Bardet-Biedl syndrome has been linked to impaired function of the melanocortin-4 receptor (MC4R) pathway that regulates body weight and energy balance. Bardet-Biedl is an autosomal recessive inherited disorder caused by variants in BBS genes, of which more than 20 have been identified. Variants in BBS genes impair MC4R pathway signaling, as loss of BBS genes can disrupt localization of leptin receptors, among others, and this impairs activation of MC4R-expressing neurons. Individuals living with Bardet-Biedl syndrome are typically at a normal weight at birth, but some may exhibit behaviors associated with hyperphagia and can develop severe obesity in early childhood.

Ongoing research in Bardet-Biedl syndrome has helped inform healthcare providers and genetic counselors with much-needed guidance to support the development of individualized management plans to the meet the unique needs of people living with the condition. To diagnose Bardet-Biedl syndrome, doctors use the Beales Diagnostic Criteria to assess whether a person presents with specific clinical features associated with the condition. The Beales Diagnostic Criteria, developed by Dr. Philip Beales, outlines the primary and secondary characteristics of Bardet-Biedl syndrome. Doctors may also use genetic testing to confirm a clinical diagnosis or to identify which Bardet-Biedl syndrome gene is the cause. Early recognition and diagnosis may mitigate disease progression by allowing for better management of features including severe obesity and hyperphagia. Early diagnosis can also help alleviate the burden of blame felt by individuals and caregivers, prevent negative health perceptions, and reduce harmful stigmas surrounding obesity.

In recent years, genetic research has given us unprecedented insight on the environmental and genetic factors that can contribute to obesity. We now know that there is not a “one size fits all” approach to treating severe obesity and hyperphagia, especially in cases caused by rare genetic diseases such as Bardet-Biedl syndrome. As we improve our knowledge of underlying genetic variants and their influence on hunger and body weight, we continue to make critical progress in building a better understanding of the unmet needs of individuals living with Bardet-Biedl syndrome and the impact of severe obesity and hyperphagia.

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