Bardet-Biedl Syndrome (BBS) is a rare disease which interferes with cell motility, resulting in blindness and developmental abnormalities such as polydactyly and learning disability. In addition, BBS is strongly linked to obesity and metabolic abnormalities that increase the risk of cardiovascular disease, this is potentially related to dysfunctions in Leptin signalling which can reduce satiety and promote adipogenesis. To minimise risks and improve health, it is fundamental to tackle obesity through weight monitoring, lifestyle changes and potentially pharmacotherapy for Diabetes and weight loss.

Introduction

Bardet-Biedl Syndrome (BBS) is a rare genetic condition that affects the formation and maintenance of a structure called “cilia” in cells across the body. Cilia play a crucial role in cell movement, which is necessary for the detection of sensory signals, reproductive function and cell migration during development. As such, Bardet-Biedl Syndrome results in a vast array of health problems, particularly progressive vision loss, due to an inability of photoreceptor cells in the ocular retina to pick up light signals. In addition, many individuals experience hypogonadism, developmental delay, kidney disease, as well as obesity and Diabetes.¹

Obesity is a common complication of BBS, which can negatively impact health outcomes.² Patients are also at a higher risk of metabolic syndrome, which is a combination of factors such as hypertension, Diabetes, high abdominal perimeter and elevated blood cholesterol levels, which greatly increase the risk of cardiovascular disease.³ The underlying mechanisms behind obesity in BBS are poorly understood, but researchers believe that a deficiency in ciliary function may promote adipogenesis and affect the way the satiety hormone Leptin interacts with its receptors.⁴

Obesity, abdominal fat deposition, hypercholesteremia and high blood sugar levels can lead to cardiovascular complications such as stroke, heart attack and congestive heart failure, increasing mortality and reducing life expectancy. As a result, patients with BBS should undergo weight diet monitoring, as well as be offered lifestyle or medical interventions to reduce body weight and prevent metabolic disturbances.

What is bardet-biedl syndrome

Bardet-Biedl Syndrome is a rare disease that results from a mutation or combination of mutations in different genes that encode proteins involved in the genesis and maintenance of ciliary structures in cells. These allow for the movement of cells, which is necessary for normal development and cell migration in the brain and body, as well as normal function of different organ systems and specialised sensory cells.¹ Diagnosis of BBS is based on the presence of a combination of characteristic primary and secondary features. These include:

• Retinal dystrophy, which typically results in childhood-onset vision abnormalities such as progressive loss of night vision, colour perception and visual acuity, eventually culminating in full legal blindness by early adulthood
• Polydactyly (having more than five fingers), which is often corrected with surgery
• Hypogonadism presents as delays in puberty and infertility and/or genitourinary abnormalities, such as undescended testis, penile atrophy and uterine malformations
• Anatomical and functional kidney abnormalities, greatly increase the risk of Chronic Kidney Disease
• Learning disability and delays in intellectual development
• Obesity, elevated blood lipids and metabolic syndrome
• Endocrine abnormalities such as hypothyroidism and, in females, Polycystic Ovaries Disease:
  • Other sensory issues such as disturbances in hearing and olfaction
  • Gastrointestinal disorders such as Liver Disease, Celiac Disease and Inflammatory Bowel Syndrome

There is no known cure for Badelt-Biedl Syndrome, instead, management involves continuous monitoring of renal, reproductive and cardiovascular health, as well as lifestyle interventions to promote independence and prevent obesity. Nevertheless, the average life expectancy for individuals with BBS is 63 years old, therefore lower than that of the general population. Patients also have a greater risk of premature mortality before middle age, most frequently due to renal or cardiovascular complications. In addition, virtually all individuals with BBS experience debilitating vision loss which cannot be prevented or treated and must therefore be managed with social and living accommodations.⁵

The link between obesity and bardet-biedl syndrome

Obesity is present in 72-92% of patients with Bardet-Biedl Syndrome and typically appears during the first three years of life. Several mechanisms have been proposed to explain this association. Leptin is a hormone that is released by fat cells and enterocytes to signal that the body is in a fed state, modulating activity in certain parts of the hypothalamus to promote satiety and calorie expenditure. Individuals with BBS have been shown to have Leptin resistance, which can increase appetite and slow down metabolism leading to adipogenesis. Other studies indicate that a deficiency in ciliary proteins may have a direct effect on adipocyte differentiation and fatty tissue formation. Mice with mutations mimicking BBS also have hypothalamic expression of the Serotonin 5HT2C receptor which normally is involved in suppressing appetite.⁵

Obesity and excessive food intake due to genetic factors can also lead to Metabolic Syndrome which is present in 56% of individuals with BBS. This is a combination of health parameters such as high abdominal perimeter, hypertension and elevations in blood sugar and lipids, which are associated with Insulin resistance and higher cardiovascular risk.³

Complications of obesity and metabolic syndrome

Obesity and metabolic syndrome are major risk factors for atherosclerosis, this is the buildup of fat plaques and subsequent endothelial inflammation in arteries across the body. Atherosclerosis in the coronary arteries can reduce blood flow to the heart and cause chronic complications such as angina and congestive heart failure. In addition, a Myocardial Infarction (or heart attack) can occur if these plaques rupture, which leads to the formation of a blood clot that fully obstructs coronary arteries, causing acute and potentially fatal ischaemic damage to the heart tissue. Similarly, atherosclerosis affecting the cerebral arteries can result in a similar thrombotic event in the brain (stroke), which can result in cognitive decline, neurological deficits or even death, depending on the area of the brain affected by ischaemia.⁶

Other serious complications of obesity include:

• Type 2 Diabetes which can cause vascular and nerve damage
• Poor mental health and low self-esteem
• Non-alcoholic fatty liver disease
• Obstructive Sleep Apnoea that can lead to poor sleep quality and daytime fatigue
• Chronic Kidney Disease
• Osteoarthritis
• And increased risk of several cancers⁷

Treatment of obesity and metabolic disturbances in bardet-biedl syndrome

Besides regular monitoring of body weight, blood pressure and tests to assess blood lipid sugar and levels, educating patients and carers on adequate dietary and lifestyle habits is fundamental to both prevent and treat obesity. In many cases, weight loss can be achieved through a caloric deficit by implementing regular exercise, controlling food portions and respectively increasing and decreasing the consumption of fibre and high-fat-content foods. Bariatric surgery to increase satiety and pharmacotherapies may also be useful for some individuals. (8) GLP-1 agonists such as Semaglutide (Ozempic) have been shown to be particularly effective at correcting hypothalamic appetite regulation abnormalities in people with Bardet-Biedl Syndrome.⁹

Guidelines also recommend therapies to tackle specific metabolic abnormalities such as Diabetes and hypercholesteremia. These include common drugs such as blood sugar lowering agents like Metformin and statin medication.⁵

Conclusion

Bardet-Biedl Syndrome is a genetic condition that affects the structure and motility of cells by interfering with the formation and maintenance of cilia. This results in visual impairment as well as developmental abnormalities such as polydactyly, kidney deformities and learning disability. In addition, obesity and metabolic syndrome are also highly prevalent in BBS patients, potentially due to increased adipogenesis and abnormalities in signalling molecules involved in hunger and satiety.

Obesity, diabetes and hyperlipidaemia are important risk factors for the development of chronic cardiovascular disease and potentially life-threatening events such as stroke and myocardial infarction, which are more frequent in individuals with Bardet-Biedl Syndrome. In order to prevent these complications, patients´ weight and metabolic status should be regularly monitored and different interventions should be used to reduce abdominal fat and promote health. These can include lifestyle changes such as regular exercise and a balanced diet, as well as new promising pharmacological therapies.

FAQs

What is bardet-biedl syndrome?

Bardet-Biedl Syndrome is a genetic disease that affects the formation and function of cell cilia. This results in visual impairment, developmental abnormalities, obesity and hypogonadism.¹

What is the link between BBS and obesity?

Studies have shown that the genetic mutations associated with BBS can affect the function of biochemical modulators of satiety and energy expenditure, potentially leading to adipocyte formation, slower metabolism and increased appetite.⁵

How can obesity and metabolic syndrome be managed in individuals with BBS?

Patients must have regular weight and metabolic assessments as well as be educated and aided in implementing healthy lifestyle choices such as regular exercise, balanced diet and avoidance of foods high in fat and calories. Pharmacological interventions such as GLP-1 antagonists and weight loss surgery may be necessary in some individuals with metabolic syndrome and high risk of cardiovascular disease.⁸

What are the complications of obesity and metabolic syndrome in BBS?

Obesity is a major risk factor for atherosclerosis, which can lead to coronary heart disease, congestive heart failure, angina and acute cardiovascular events such as Myocardial Infarction and stroke. (6) It can also lower quality of life through complications of Diabetes, poor mental health/self-esteem and increased risk of chronic liver and kidney disease.⁷

What is the prognosis of BBS?

The life expectancy of individuals with BBS is 63 years due to premature mortality from renal and cardiovascular complications. Some anatomical abnormalities such as polydactyly can be corrected with surgery and psychosocial interventions can accommodate for learning difficulties. However, retinal dystrophy, the hallmark feature of BBS, is untreatable and always leads to blindness.⁵