Hyperphagia in Bardet-Biedl syndrome: Pathophysiology, burden, and management

Abstract

Bardet-Biedl syndrome (BBS) is a rare, genetically heterogeneous, and highly pleiotropic autosomal recessive ciliopathy. Patients typically present with early loss of vision, hyperphagia, severe obesity, learning difficulties, and renal dysfunction. In patients with BBS, dysfunction of the immotile primary cilia in the hypothalamic melanocortin-4 receptor (MC4R) pathway responsible for controlling energy balance, hunger, and satiety results in severe hyperphagia manifesting in food-seeking behaviors that drive the development of obesity early in childhood. These behaviors have negative impacts on many areas of the lives of patients with BBS and their families/caregivers, including sleep, mood, school/work, and social/family relationships. Additionally, many patients feel stigmatized due to their hyperphagia-associated food-seeking behaviors and the resulting obesity, which exacerbates the impacts of hyperphagia on quality of life. Early identification and management of hyperphagia in patients with BBS is key: mitigating food-seeking and weight gain can improve quality of life and reduce the risk of metabolic and cardiovascular diseases that is increased in patients with BBS. Until recently, the only treatment strategies available were lifestyle and diet modifications. However, targeted treatment with the novel MC4R agonist setmelanotide now offers an effective management option to reduce hyperphagia and weight in patients with BBS, improving overall health and quality of life.

Keywords: Bardet–Biedl syndrome; MC4R pathway; hyperphagia; obesity.

FIGURE 1

The role of the primary cilia in leptin signaling and control of hyperphagia. The BBSome is involved in cilia function and leptin receptor signaling. Patients with BBS have an impaired MC4R pathway, which can be caused by a variant of one or more of the genes that encode the BBSome proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, BBS18). This can cause both dysfunction of the cilia and disruption of leptin receptor signaling. BBS6, BBS10, and BBS12 are thought to be chaperone proteins involved in BBSome assembly, while the role of other proteins has yet to be determined. α‐MSH, alpha‐melanocyte‐stimulating hormone; BBS, Bardet–Biedl syndrome; LEPR, leptin receptor; MC4R, melanocortin‐4 receptor; POMC, pro‐opiomelanocortin.