Introduction

Bardet-Biedl syndrome (BBS) is a rare ciliopathic disorder that affects multiple body systems. Symptoms include truncal obesity, visual impairments, polydactyly (extra fingers or toes), and renal abnormalities. It is caused by mutations in multiple genes, which result in defective cilia, and tiny hair-like structures that are crucial for cell function. Understanding the underlying genetics and inheritance patterns of BBS is crucial for accurate diagnosis, disorder management, and genetic counselling. This knowledge helps make informed decisions and supports ongoing research into treatments and therapies.

Genetic basis of bardet-biedl syndrome

Mutations in multiple genes cause BBS, with each mutation contributing to the syndrome's development. These genes are named the BBS genes and are crucial in the normal functioning of cilia. 

BBS1 and BBS10 are the most frequently mutated genes accounting for most cases. Some mutations are more prevalent in certain ethnicities, even if not found to be exclusive. 

BBS1 and BBS10 mutations are more frequent among Northern Europeans, while mutations in BBS4, BBS5, and BBS8 are mostly observed in patients with Middle Eastern and North African lineage.¹

How do genetic mutations cause bardet-biedl syndrome?

Cilia are small, hair-like projections found on cell surfaces. They are necessary for various cellular processes, such as the movement of fluids, signalling pathways, and sensory functions. 

They are classified into motile and immotile (primary) cilia. BBS affects primary cilia, which is found in most cells, except for blood cells. They act as sensory organelles in cells and are also important in signal transmission within cells and between the cell and its environment.²

BBS genes produce proteins that are essential for the formation and maintenance of primary cilia. Due to their role in sensory perception, mutations in BBS genes lead to sensory defects such as vision loss, and loss of sense of smell. The mutations also lead to physiological effects such as obesity, polydactyly and hypogonadism due to the involvement of cilia in cell signalling.³

Inheritance patterns of bardet-biedl syndrome

BBS is inherited in an autosomal recessive manner. Humans have 23 pairs of chromosomes, each pair consisting of one chromosome from each parent. Out of the 23, one pair is called the sex chromosome, which determines the gender of the individual and the rest are named the autosomes. BBS genes are located on the autosomal chromosomes.

Each gene has two copies, one inherited from each parent. To present symptoms, both copies of the BBS genes must be mutated. If only one copy is mutated, the individual becomes a carrier who does not present symptoms. This is due to the normal gene making up for the mutated gene. However, the carrier could end up passing the gene to their children.

In rare cases, gene mutation can occur spontaneously without being inherited. This mutation arises during the initial stages of embryonic development. Here, the affected individual will have no family history of BBS.

Families affected by BBS or at risk of it should seek genetic counselling. They can acquire detailed information on genetic testing and the implications of the results. This helps parents to understand the patterns of inheritance, analyse the risk of passing down the genes and make informed reproductive decisions.⁷

Signs and symptoms of bardet-biedl syndrome 

BBS exhibits a wide range of symptoms which can vary on an individual basis. The most common features are:

Truncal obesity

Disproportionate distribution, especially in the abdomen and chest, in comparison to limbs is common in BBS. It typically begins within the first year of life and affects 72 - 86% of patients. It can lead to complications such as type II diabetes, and cardiac defects. Management of weight through diet, exercise and medical care is crucial to prevent further conditions.

Vision defects

Most BBS patients lose the function of certain cells in the retina which often leads to retinitis pigmentosa. Early signs exhibit night blindness leading to progressive vision deterioration and can result in blindness. Additionally, BBS can also cause a lazy eye (strabismus), the formation of a cloudy layer covering the eye (cataract), and glaucoma. This can hinder mobility and ability to perform daily tasks, thereby making the patient dependent on those around them. Visual aids and support therapy can help to deal with the effects.⁴

Postaxial polydactyly

Development of an extra digit near the outermost finger or toe is commonly seen in BBS. It affects approximately 70% of people diagnosed. There is also a possible presence of webbing between fingers and toes. Polydactyly causes difficulties with fine motor skills and may require surgery.

Hypogonadism

Hypogonadism can be explained as the under-functioning of sexual organs. In males, this manifests as the presence of a small penis, undescended testicles, and delayed onset of puberty. In females, the reproductive system could show underdevelopment in organs, such as the uterus, fallopian tubes or ovaries. Menstrual cycles may have a delayed onset and follow an irregular pattern.¹

Kidney abnormalities 

Renal defects present in BBS patients are highly varied. Some of the more common ones include:

• Hydronephrosis: Urine accumulation in the kidney causing dilation of structures, which could lead to bacterial infections
• Pyelonephritis: Inflammation of kidneys due to infection
• Polycystic kidney: Fluid-filled cysts form on or around kidneys

These can all lead to renal failure, which could be fatal, if not remedied by kidney transplantation and dialysis.⁵

Cognitive impairment 

Learning difficulties can be present due to BBS or as a result of vision loss. Symptoms also include speech delay, poor muscle coordination and developmental delay.⁶

Diagnosis and management of bardet-biedl syndrome 

Diagnosis of the BBS involves clinical evaluation, and genetic testing to confirm findings.

The clinical evaluation considers six major features:

• Rod cone dystrophy
• Obesity
• Genital anomalies
• Renal anomalies
• Postaxial polydactyly
• Cognitive impairment

If an individual exhibits four of the six major features, they are diagnosed with BBS. Alternatively, a diagnosis can be made if an individual exhibits only three of the major features and two minor features. These minor features could be ataxia, speech delay, dental anomalies, heart disease, or developmental delay.

To further confirm findings, genetic testing is performed to determine if the individual carries mutated BBS genes. Genetic testing is recommended, especially if obesity is observed before 5 years of age. Early diagnosis is vital to manage and treat the syndrome, as it can potentially improve results and enhance the quality of life. 

The challenges in diagnosing bardet-biedl syndrome

BBS is a rare disorder and its symptoms are not localised to one organ, but rather are spread over the body and affect various organs. In isolation, the symptoms such as obesity and vision loss could be misdiagnosed for more common conditions.

Moreover, BBS has a significant overlap with other ciliopathies, both physiologically and genetically. It shares symptoms with several other syndromes such as Alstrom syndrome and Prader-Willi syndrome. This could also lead to misdiagnosis of the condition.

Awareness of BBS and thorough genetic and clinical analysis are crucial to identifying BBS as early as possible.

Management of bardet-biedl syndrome

BBS affects multiple organs and requires management by a multidisciplinary team. The team is generally led by geneticists, endocrinologists or nephrologists. They are involved in the diagnosis and management of the initial stages. The team can then widen to include ophthalmologists, paediatrics, and/or dietitians. Management of BBS requires extensive lifestyle changes such as a healthy diet and routine exercise. 

Regular medical check-ups are important to monitor the condition so that any complications that arise can be addressed quickly and effectively. Support systems including support groups and counselling, can provide valuable information and support for those affected and their families.⁸

Research and future directions

Significant progress has been made in treating genetic diseases. Research has identified several genes associated with BBS, which could be targeted for treatment to cure the disease. The eye is an ideal target for gene therapy due to its easy access and delayed onset of symptoms. Ongoing research aims to develop gene therapy for rod-cone dystrophy, which is a major sign of BBS.⁹ 

Non-genetic therapies are also being developed to help manage symptoms of BBS. Drugs are being tested to handle obesity in BBS. These drugs aim to bridge the disrupted molecular pathways in the body, such that weight gain due to BBS can be prevented. Setmelanotide is one such drug undergoing clinical trials for BBS-linked obesity.¹⁰ 

Pre-existing drugs that are already approved are being tested in the early stages to treat kidney issues in BBS. This can be an economical way and is time-saving as it is already exposed to the market.¹¹

The complexity of BBS and the variation in number of the diseases causing genes make therapy development challenging. However, several avenues are being explored in genetic and non-genetic therapies for BBS and other ciliopathies. With eventual progress in these therapies and personalised medicine, there is a high potential of being able to correct genetic defects and prescribe patient-specific treatments to individuals.¹²

Summary

Bardet-Biedl syndrome is a complex genetic disorder impacting multiple body systems due to defective cilia. Understanding its genetic basis and inheritance patterns is crucial for diagnosis, management, and future research. Advances in genetic and non-genetic therapies offer hope for improved treatments, emphasising the need for continued research and multidisciplinary care.