What is Bardet-Biedl Syndrome(BBS)?

Symptoms of BBS, an uncommon, ciliopathic and deadly genetic condition, that affects various parts of the body, include early onset obesity, inability to feel full, and hyperphagia. The estimated prevalence of BBS in North America and Europe is 1 in 100,000 to 160,000 people; however, certain locations have higher rates than others, such as Newfoundland and Labrador (1 in 16,000 to 18,000).¹

Setmelanotide (Imcivree™) is Recommended by CADTH(Canadian Agency for Drugs and Technologies in Health) for the management of weight in adult and paediatric patients with Bardet-Biedl Syndrome who are six years of age or older.

CADTH recommends Imcivree be included in public prescription programs if specific conditions are met. Imcivree is intended to help adults and children patients (6 years of age and older) with obesity caused by Bardet-Biedl syndrome (BBS) manage their weight. Imcivree should only be purchased with prescriptions issued by pediatric endocrinologists, endocrinologists, weight management experts, or obesity specialists.

An overview of Bardet-Biedl syndrome

The primary features of Bardet-Biedl syndrome (BBS), a multisystem non-motile ciliopathy, include retinal cone-rod dystrophy, obesity and its complications, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism and/or genitourinary malformations, renal malformations, and/or renal parenchymal disease.²

In addition, individuals with BBS may also have mild hypertonia, ataxia/poor coordination/imbalance, developmental delay(s), seizures, speech deviations, musculoskeletal abnormalities, dermatologic abnormalities, subtle craniofacial dysmorphisms, hearing loss, anosmia(loss of the ability to smell), oral/dental abnormalities (crowding, hypodontia, high-arched palate), and behavioral/psychiatric abnormalities.²

The features of Bardet-Biedl Syndrome can be separated into two groups, major and minor. 

Major features can be listed as:²

• Retinal cone-rod dystrophy
• Central obesity
• Postaxial polydactyly
• Cognitive impairment
• Hypogonadism & genitourinary abnormalities
• Kidney disease

Minor features can be listed as:²

• Neurological abnormalities, including DD and Epilepsy
• Olfactory dysfunction
• Oral or dental abnormalities
• Cardiovascular & thoraco-abdominal abnormalities
• Gastrointestinal abnormalities, including Hirschsprung disease, inflammatory bowel disease, celiac disease, and liver disease
• Endocrine/metabolic abnormalities, including Metabolic syndrome, Subclinical hypothyroidism, Subclinical hypothyroidism and polycystic ovary syndrome

Different genes can be responsible to consider due to the fact that they stimulate the generation of disorders in the differential diagnosis of Bardet-Biedl Syndrome. These disorders are:²

• Alström Syndrome
• McKusick-Kaufman Syndrome
• Meckel Syndrome
• Joubert Syndrome
• Senior-Løken Syndrome
• Leber Congenital Amaurosis / Early-onset severe retinal Dystrophy

These diseases all have both overlapping and distinguishing features from the BB. Therefore, differential diagnosis carries importance.²

Present opinions and clinical prospects for Bardet-Biedl Syndrome

It is crucial to comprehend how Bardet Biedl syndrome (BBS) proteins function in the primary cilium. The BBSome complex, comprising BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBIP1, is assembled with the assistance of chaperonin-like proteins (proteins that help proteins fold properly) BBS6, BBS10, and BBS12. Intraflagellar transport is dependent on the interaction between BBSome and the GTPase protein BBS3. On the other hand, the BBSome is kept at the level of the basal body via the BBS17 link. The IFT-A complex, which is propelled by dynein, promotes retrograde trafficking between the tips and bases of cilia. The IFT-B complex, which is made up of BBS19 and BBS20, not shown in the image, is propelled by kinesin and mediates anterograde trafficking. BBS11 supports the ubiquitination of proteins.³

Actually, BBS is caused by mutations in genes encoding proteins that are mainly located around the base of the cilium. Many clinical traits of other ciliopathies, especially autosomal recessive syndromic disorders, are shared by patients with BBS. Furthermore, mutations in cilia-related genes can result in unique clinical ciliopathy types.³

Bardet-Biedl Syndrome: the chaperonin-like BBS6, 10, and 12 Proteins' Pleiotropic role

BBS proteins share biological activities and unite to create multiprotein complexes. Numerous BBS gene mutations affect the same biological processes, including PC formation and functioning. This property is shared by other ciliopathy proteins that are present in the PC, basal body, and centrioles.⁴

Since BBS is a ciliopathy, defined as a pleiotropic condition(a genetic condition that affects multiple organs or tissues). Since the first BBS gene was cloned, several investigations into the genetics and molecular functions of BBS proteins have been carried out. The discovery of BBSome allowed for the clarification of its role in cilia biology as well as the identification of the condition's molecular aetiology. It is important to evaluate the functions of BBS6, BBS10, and BBS12 to understand the mechanism of BBS greatly.⁴

BBS6 is responsible for the regulation of gene expression, cell division, cytoskeletal organisation, protein trafficking to plasma membrane (such as insulin receptors); BBS10 is responsible for regulation of gene expression, adipogenic differentiation, chaperon-mediated protein complex assembly, perception of visualisation, non-motile cilium assembly, folding or stability of ciliary of other basal proteins, and protein trafficking to plasma membrane (such as AQP2); and lastly BBS12 is responsible for regulation of adipogenesis, chaperon-mediated protein complex assembly, photoreceptor cell maintenance, leptin signalling, and infraciliary transportation.⁴

The function of the multidisciplinary team in the multidisciplinary management of BBS illness

Paediatrics, neurology, dentistry, ophthalmology, endocrinology, ENT, surgery, gastroenterology, nephrology, genetics, cardiology and psychology are the widespread study areas of BBS syndrome.⁵ A multi-tasking, multifunctional approach and team management can advance the development of novel therapy perspectives.⁵

Examining the major difficulties in determining the pathophysiology of kidney disease in Bardet-Biedl Syndrome

Much research has elucidated the fundamental functions of BBS proteins and provided some evidence to support hypotheses on the aetiology of kidney failure; nevertheless, further investigation is still needed to pinpoint the pathomechanism behind kidney disease. A research revealed that three genes, BBS1, BBS2, and BBS10, are responsible for over half of all diagnoses related to the condition. Patients with mutations in BBS1 are more likely to develop kidney disease due to truncating mutations rather than missense mutations, and their renal phenotype is less severe than that of patients with mutations in the other two most prevalent sites. Both clinically and genetically, the illness is diverse. There has been notable intrafamilial clinical variability, yet the cause of it is still unknown.⁶

Interestingly, BBS1 is the sole locus with basal overexpression in the kidney. In comparison, the Bbs gene is expressed far less in the kidneys of mice than it is in other frequently damaged organs, such as the retina. Kidney illness in mice does not always spread to all areas; when it does, the phenotype is age-dependent and resembles that of humans. BBS depletion affects signalling pathways that are involved in kidney development and repair in embryos, based on in vitro study. It is unclear how important the systemic vs. local effects of Bbs dysfunction are in relation to one another.⁶

Neuroendocrine factors that induce and inhibit appetite and weight in Bardet-Biedl Syndrome

Bardet-Biedl disease is a syndrome associated with obesity.⁷ Ciliary dysfunction seems to be linked to the Bardet Biedl and Alstrom syndromes. It has been shown that mice cannot control their body weight without cilia. It is possible to induce the disruption of primary cilia that leads to obesity and hyperphagia by silencing the Alstrom syndrome gene in neurons that express POMC.^7,8

The role of Zeaxanthin supplements in eye health

I would like to conclude my sentences with a small emphasis on the benefits of zeaxanthin and lutein to retina. Strong evidence has been found to associate lutein and zeaxanthin with healthy eyesight and cognitive function throughout life. Several pieces of evidence suggest that zeaxanthin and lutein are involved in vision.

Only recently has the role of lutein in cognition been investigated. In ocular tissue, lutein and its isomer, zeaxanthin, are selectively absorbed. Lutein is the most prevalent carotenoid found in human brain tissue. Within brain tissue, lutein and zeaxanthin may have anti-inflammatory, antioxidative, and structural effects.

Furthermore, lutein and zeaxanthin may provide protection against eye sickness because they filter damaging blue light that enters the eye. Lutein accounts almost twice as much of the total carotenoids in juvenile brains as it does in adult brains, contributing more than half of the entire amount. The growing brain's higher lutein concentration suggests that lutein is also required for the development of new neurons. Higher lutein status in adults is associated with improved cognitive performance, and lutein supplementation improves cognitive function as well. Further study on the lifelong advantages of lutein and zeaxanthin for cognitive and visual health is warranted, as shown by the available evidence.⁹ 

Patients should always be alert and continue regular ophthalmology physician visits. The effects of Bardet-Biedl Syndrome on the eyes can have worsening scenarios, even results on the augmentation capacity have a capability to lead the patient to blindness. Therefore, sticking with scientific knowledge and relying on doctor's advice means a lot for disease management.

Summary

Bardet-Biedl Syndrome (BBS) is a rare and serious genetic disorder that affects many parts of the body due to problems with cilia (tiny structures in cells). Key symptoms include early-onset obesity, hunger issues, vision problems, extra fingers or toes, learning difficulties, and kidney and hormone problems. BBS is more common in some areas, like Newfoundland and Labrador.

Treatment for weight issues in BBS includes a medication called Setmelanotide (Imcivree™), which is recommended in Canada under certain conditions.

BBS is caused by mutations in specific genes that affect cilia function, and it shares similarities with other genetic conditions. Managing BBS requires a team of specialists due to its wide-ranging effects. Regular eye check-ups are important since vision loss can worsen over time. Supplements like lutein and zeaxanthin may help protect eye and brain health.