Bardet Biedl syndrome is a rare autosomal recessive genetic disorder affecting approximately 1 in 250,000 people in the world.¹ It is caused by biallelic loss of function pathogenic variants (both copies of a specific gene in an individual are non-functional due to mutations) in at least 26 genes. This causes multisystem non-motile ciliopathy, where the nonmotile cilia on the surface of our cells become dysfunctional. This causes retinal cone-rod dystrophy (a problem with the light-sensitive cells of the eye called the cones and rods), cognitive impairment, hypogonadotropic hypogonadism( a failure of the testes to produce androgens and sperm), and or genitourinary malformation, renal (kidney) malformation, and renal parenchymal disease. It can also cause other dysfunctions in the eye like strabismus (crossed eyes), astigmatism (improper curvature of the cornea, lens, or retina causing blurred vision), and cataracts (a cloudy area that forms on the lens of the eye) as well as subtle craniofacial abnormalities, hearing loss, seizures and more.  It can also cause cardiovascular issues like congenital heart defects which are present at a significant rate in patients with Bardet Biedl syndrome, affecting 1.6-29% of all patients.¹

The genetics of bardet-biedl syndrome 

Bardet Biedl syndrome genes code for proteins that localize to the basal body of the cilium. These mutations lead to defective cilia which leads to various effects. Most pathogenic mutations are found in BBS1 and BBS10 accounting for 23.2% and 20% of cases in the population of northern European descent. In British patients, the most common mutation is M390R found in 82.5% of patients with the BBS1 mutation.

How do deformities in cilia cause cardiovascular issues?

Cilia function at the left-right organizer (an anatomical structure that breaks the left-right symmetry of the embryo) is essential for the establishment of cardiac left-right asymmetry. This asymmetry is critical for efficient oxygenation of the blood and the establishment of systemic and pulmonary circulation. The non-motile structural components of cilia such as centrosomal proteins, IFTS, and transition zone components also affect the cardiac left-right asymmetry establishment. Cilia-regulated signaling is also important for cardiac valve development, the cilia-regulated pathway ligand dessert hedgehog which is expressed within the cardiac valve regulates cytoskeletal organization during valve leaflet development.⁶

What is the prevalence and type of cardiovascular conditions in patients with bardet-biedl syndrome?

It is believed that 29.8% of patients with Bardet Biedl have heart abnormalities. 7% of these are congenital heart defects including aortic stenosis, patent ductus arteriosus, and unspecified cardiomyopathy. Bilateral persistent superior vena cava, the major vein that carries deoxygenated blood from the upper part of the body to the heart), interrupted inferior vena cava (a widened azygos vein), and hemizygous continuation, right-sided aorta (aortic arch is on the right side) and left-sided aorta ( aortic arch is on the left side) have also been reported, affecting males more so than females.²

In a study of 33 patients, 32% were found to have cardiac abnormalities ( three with congenital malformations and two with left ventricular hypertrophy). Dyslipidemia ( blood lipid levels that are abnormal) which is associated with low HDL cholesterol was found in nearly half of the patients and a third of the patients were already showing signs of hypertension despite their young age. None of these patients had a family history of cardiovascular disease.⁸ The majority of patients (795) had central obesity which puts them at a high risk of cardiovascular events in the future.

Experimental evidence of the link between bardet-biedl syndrome and cardiovascular issues

A study of 239 patients in the UK took place, participants had various combinations of mutations in the Bardet Biedl genes but the genes BBS1 and BBS10 were mainly studied (the genes responsible for most of the cases of the syndrome in patients of European descent) found that patients with the BBS10 variation of Bardet Biedl had significantly worse levels of C reactive protein, a protein made by the liver that seems to predict the chances that someone may have cardiovascular issues. C peptide is a marker for cardiovascular resistance,  also significantly high in these patients. Patients with homozygous truncating mutations (mutations in both genes that cause the coding sequence of a gene to be shortened) were more likely to have raised triglyceride levels which is associated with an increased risk of cardiovascular disease. There was also a statistically significant increase in gamma-glutamyltransferase in patients with homozygous truncating mutation which correlates with cardiovascular disease and is an independent marker of cardiovascular risk.³

The link between obesity and cardiovascular issues

89% of patients with Bardet Biedl syndrome have obesity.¹⁰ This is because the syndrome causes hyperphagia, a feeling of extreme and insatiable hunger. This is due to mutations that cause an impairment in primary cilia which leads to an impairment of the leptin-melanocortin-4-receptor pathway which disrupts energy regulation and leads to increased hunger.¹¹ Obesity can cause several different cardiovascular issues including:

• Atherosclerosis: A buildup of plaque ( fats, cholesterol, and other substances) in and on the artery walls. This can cause the arteries to narrow, blocking blood flow which could lead to serious health conditions like a stroke, heart attack, or dementia. The development of obesity and atherosclerosis overlap as both involve lipids, oxidized LDL particles, and free fatty acids which activate the inflammatory processes and trigger the disease. Inflammation is responsible for all of the steps that lead to the development of atherosclerosis and is caused by obesity because fatty tissue releases adipocytokines which induce systemic inflammation which facilitates the atherosclerotic process
• Coronary artery disease: A heart condition that involves atherosclerotic plaque formation in the vessel lumen which leads to impaired blood flow and oxygen delivery to the heart's muscle. At least  2 decades of obesity is likely to be an independent risk factor for developing coronary artery disease 
• Heart failure: A condition where the heart cannot pump blood around the body as well as it should. 32%-42% of patients suffering from heart failure are obese and after 20 years of obesity, the prevalence of heart failure grows by 70% and then 90% after 30 years. This is because obesity increases aldosterone levels as well as mineralocorticoid receptor expression which promotes interstitial cardiac fibrosis, platelet aggregation, and dysfunction of blood vessels. Inflammatory cytokines like tumour necrosis factor-alpha whose production is increased in obesity also play a crucial role in the development of heart failure as they cause myocardial fibrosis which increases the stiffness of the heart muscle and leads to heart failure.  A build-up of triglycerides in the cardiac muscles also leads to the death of heart cells
• Atrial fibrillation: An irregular heart rhythm that begins in the heart's upper chamber. Obese patients have a 1.52 times higher risk of developing atrial fibrillation compared to the normal-weight population¹²

FAQs

What is the life expectancy of someone with bardet-biedl syndrome?

Bardet Biedl syndrome does not necessarily decrease a patient's life expectancy but they will require specialist care and be dependent on the help of others in their everyday lives.

What drugs treat bardet-biedl syndrome?

Bardet Biedl syndrome is currently treated symptomatically with a focus on managing diabetes, hypertension, and metabolic syndrome to minimize the secondary impact that these conditions have on vulnerable organ systems like the eyes and kidneys. Medications like Imcivree (Setmelanotide) are used for weight management as a melanocortin-4 receptor agonist.¹³

At what age do major symptoms of bardet-biedl syndrome become evident?

Rod cone dystrophy is present in 90-100% of patients with Bardet Biedl syndrome, the average age of onset is 8 years. Obesity manifests at ages 2-5, postaxial polydactyly is perinatal and hypogonadism is diagnosed in adolescence.¹⁴

What is the difference between laurence moon syndrome and bardet-biedl syndrome?

Like Bardet Biedl syndrome, Laurence Moon syndrome is an inherited disorder associated with learning difficulties, diminished sex hormones, and stiffness of the muscles and joints. The main difference between Laurence Moon syndrome and Bardet Biedl syndrome is that Laurence Moon syndrome patients do not have extra digits or obesity in their abdomen.¹⁵

What ethnicity is most likely to get bardet-biedl syndrome?

Bardet Biedl syndrome can occur in individuals of all races and ethnicities, however, it is more common in the Bedouin population of Kuwait on the island of Newfoundland.¹⁶

What are the facial features of patients with bardet-biedl syndrome?

The characteristic facial features of someone with Bardet Biedl syndrome are deep widely spaced eyes, a flat nasal bridge, a prominent forehead, and a small jawline.¹⁷

Who is a carrier of bardet-biedl syndrome?

An individual who inherits one mutation in a BBS gene is a carrier but they are not expected to have health-related problems.¹⁸

Summary

Bardet Biedl is a rare genetic disorder caused by dysfunction in the cilia. It can cause a myriad of symptoms including various cardiovascular issues which can be a result of the syndrome also causing obesity.