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Bardet-Biedl Syndrome (BBS): for patients

Overview

Bardet-Biedl syndrome (BBS) is a rare, inherited condition that can affect most organs in the body. Approximately 1 in 125,000 to 1 in 170,000 people in USA and northern Europe are affected.[1-3] So far, mutations in 21 genes are known to cause this condition. These mutations lead to abnormal changes in a cellular structure called the primary cilium (plural: cilia). Primary cilia are thin hair-like projections present on the surface of most cells in the body. They act like antennae that allow cells to communicate with each other and are essential to the normal functioning of multiple organs.  

The main features of BBS include progressive sight loss due to retinitis pigmentosa (about 90% of BBS patients) or less commonly cone-rod dystrophy, extra fingers and/or toes (polydactyly), obesity, genital malformations, kidney abnormalities and learning difficulties. Additional symptoms might include diabetes, impaired speech, developmental delays, dental abnormalities, poor coordination (ataxia) and congenital heart disease. Not all patients with BBS have all of these features, and they often vary in severity.

The age at which symptoms of BBS become noticeable varies, but this usually occurs between 5 and 10 years old, when affected children often develop night blindness due to retinitis pigmentosa.[4] Currently, there is no cure for BBS, but treatments exist to alleviate the associated symptoms.

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The condition

Symptoms

Main features

1) Progressive retinal degeneration

Around 90% of people with BBS are affected by an eye condition called retinitis pigmentosa (RP).[3] RP is a type of inherited retinal dystrophy which affects the specialised photoreceptor cells in the retina, causing gradual but permanent visual impairment. Difficulty seeing in the dark (night blindness) is usually the first visual symptom experienced by patients which tends to occur between 5 and 10 years of age.[4] Over time, gradually enlarging blind spots appear in the peripheral (side) vision, leading to “tunnel vision’. The remaining central vision is eventually lost in the late stages of RP.

A person driving a car with normal peripheral vision is able to see the girl in a red dress on the left. If the driver has a loss of peripheral vision, the same girl is not noticeable.
Peripheral vision loss

A minority of patients develop the opposite sequence of events (initial central vision loss with progressive enlarging peripheral blind spots and night blindness) known as cone-rod dystrophy. The severity of visual impairment and rate of sight loss vary significantly among patients within and between families.

Both RP and cone-rod dystrophy are conditions that cause progressive degeneration of photoreceptor cells but are classified differently based on their initial symptoms.

Other eye conditions associated with BBS include cataracts and refractive errors (usually short-sightedness—unable to see distant objects) which require glasses to correct.[5]

2) Obesity

Between 72-92% of patients with BBS develop obesity in adulthood.[3] Most patients are born with a normal birthweight, but one-third are classified as obese by the age of one year.[5] Obesity may be accompanied by the development of type 2 diabetes, high blood pressure (hypertension) and high cholesterol levels in adolescence or adulthood.

3) Learning difficulties

About 60% of BBS patients may experience some degree of learning difficulties, the severity of which is highly variable, but most are mild to moderate in nature.[5]

In some children, certain behavioral and/or neurodevelopmental issues may occur, including:

  • Obsessive-compulsive disorder (OCD)
  • Attention deficit hyperactivity disorder (ADHD)
  • Autism spectrum disorder (ASD)
4) Polydactyly

Some patients will have extra fingers and/or toes at birth, known as polydactyly. About 1 in 5 BBS patients have extra digits on all four limbs.[3] In other cases, the hands (9%) or feet (21%) are affected in isolation.[3] Apart from polydactyly, other finger/toe abnormalities that are associated with BBS include:

  • Syndactyly (two or more digits are fused together)
  • Brachydactyly (short fingers/toes)
  • Clinodactyly (inwardly curved finger)
  • A prominent ‘sandal gap’ between the first and second toes[4]
5) Genital abnormalities

A range of genital abnormalities can occur in both male and female BBS patients, which usually lead to fertility issues. Some examples include:

  • Delayed onset of puberty and hypogonadism (small penis, small testes) due to reduced amount of sex hormones
  • Undescended testes (cryptorchidism)—A baby boy’s testes are normally developed in the abdomen during pregnancy before moving down into the scrotum about 1 to 2 months before birth. Cryptorchidism is associated with an increased risk of testicular cancer and should not be left unaddressed
  • Opening of the urethra on the underside of the penis (hypospadias) – Usually apparent from birth; It can be an isolated problem in many boys and may not be associated with BBS.
  • Delayed onset of the first menstrual cycle (menarche)
  • Underdeveloped fallopian tubes, uterus or ovaries
  • Infertility (normal fertility has been reported in some rare cases[6])
6) Kidney (renal) abnormalities

Renal diseases are one of the main causes of illness among BBS patients due to the development of end-stage renal failure. Developmental defects of the kidneys, cyst formation and excessive accumulation of urine can lead to a series of problems that predispose patients to renal failure. These include:

  • Failure of the kidney to filter toxins in the blood
  • Stretched and swollen kidneys due to excessive urine build-up (Hydronephrosis)
  • Recurrent infections
  • Kidney stones
  • High blood pressure

It is estimated that 50-80% of BBS patients will develop renal disease and around 8% progress to end-stage renal failure requiring dialysis or transplant surgery.[3] The development of type 2 diabetes and high blood pressure, both common medical conditions associated with BBS, can worsen kidney damage.

Secondary features

1) Diabetes mellitus

Approximately 6% of BBS patients suffer from type 2 diabetes, which usually begins in adolescence or adulthood.[7]

2) Impaired speech and hearing loss

Roughly 60-84% of people with BBS have impaired speech, which often sounds high-pitched and nasal.[3,4] Impaired speech is often accompanied by hearing loss, which is experienced in roughly 1 in 5 people with BBS.[4] Children generally do not develop understandable speech before the age of four and characteristically replace the first consonant of a word with another or longer repetition of syllables. However, speech therapy can stimulate speech improvements in children.

3) Developmental delays

In addition to learning difficulties, children with BBS often have delays in other development aspects as well, such as motor skills (sitting, standing and walking etc) and social skills (interactive play and ability to recognise social cues).[8]

4) Dental abnormalities

Crowding of the teeth and high-arched palate (roof of the mouth) are commonly seen in people with BBS, while small teeth (hypodontia), short dental roots, bite misalignment (malocclusion) and thin enamel (enamel hypoplasia) are less common.[4]

5) Congenital heart disease

Approximately 7% of patients have structural defects of the heart that are present from birth such as narrowing of the heart valves (and therefore obstructing blood flow) or a hole in the wall of the heart (atrial/ventricular septal defect). The severity of these abnormalities varies and some patients may only be mildly affected.  

6) Poor coordination (ataxia)

Many BBS patients report a significant degree of clumsiness and often walk with legs in a wide-based stance.[4,5] It is not clear yet why BBS patients have poor coordination.

7) Disturbance to the sense of smell

Loss of smell (anosmia) or reduced sense of smell (hyposmia) has been reported among individuals affected by BBS.[4,9]

This list of associated features is not exhaustive. Please visit the Bardet-Biedl Syndrome UK (BBSUK) website for more information.

Cause

Mutations in 21 genes so far have been identified as causing up to 80% of BBS cases.[3] This means that more genes have yet to be identified. These genes provide instructions to make proteins needed for the correct assembly and functioning of a cellular structure called the primary cilium (plural: cilia). Primary cilia are present in most cells in the body and are essential for multiple organs such as the eyes, ears and kidneys to function normally. Therefore, a defect in any of these genes can cause issues in various organs.

Of the 21 known causative genes, the most common are[10]:

  • BBS1 (28% of cases)
  • BBS10 (10% of cases)
  • BBS2, BBS12, ARL6 (8% of cases each)

These gens are usually identified through genetic testing. Currently, there is no clear link between the causative gene and disease severity, but some trends have been observed. Generally, patients with mutations in the BBS1 gene tend to develop less severe symptoms, whereas those with mutations in the BBS10 gene have more severe disease. However, these observations are highly variable where even patients who carry mutations in the same BBS genes may display very different symptoms and severity.  

How is it diagnosed?

A person is diagnosed with BBS if at least four of the main features are present, or three main and at least two secondary features.[6] Diagnosing a patient with BBS usually involves multiple specialists.

1) Eye examination

An ophthalmologist is often the first point of contact for many patients due to the early onset of visual symptoms. Patient are diagnosed with RP or cone-rod dystrophy based on their presenting symptoms, clinical examination and performing an electro-diagnostic test of the retina called electroretinogram (ERG). The ERG is used to assess the overall function of the photoreceptor cells in the retina.

Often, patients also undergo other more specialised tests so that the ophthalmologist can assess the retina in more detail and determine the level of visual function. These additional tests include:

  • Colour vision testing
  • Visual field testing for the detection of blind spots. Patients are asked to press a button when they detect flashing lights and a map of their visual field is created.
  • Optical coherence tomography (OCT), a camera that allows detailed visualisation of all the retinal layers and reveal abnormalities in the retinal structure if present.
  • Autofluorescence imaging (FAF) is another camera that can visualise and assess the health of the retina.

2) General medical assessment

Children with features suggestive of BBS are referred to a paediatrician and other relevant specialists for further investigations. This may include but not limited to:

  • General physical examination including assessment of height, weight (BMI), head circumference and overall development
  • MRI (magnetic resonance imaging) of the brain
  • Blood tests
  • Ultrasound scans of the kidneys and heart

The diagnosis is confirmed with genetic testing by identifying mutations in one of the 21 associated genes.

How is it inherited?

1) Autosomal recessive (AR) inheritance

In this type of inheritance, two faulty copies of a gene are required to have the condition. Both parents are usually unaffected carriers (only have one faulty gene copy) while the affected child has two faulty gene copies (one faulty copy inherited from each parent). This means that every newborn of the parents has the following risks regardless of gender:

  • 25% chance of being affected by BBS
  • 25% chance of being unaffected and not a carrier
  • 50% chance of being a carrier with no symptoms
If the mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
Autosomal recessive inheritance

If you or your child is affected by BBS, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

There is currently no treatment for the underlying genetic changes causing BBS. Treatment is therefore focused on managing and alleviating the symptoms of BBS. Patients require good control of weight, diabetes and hypertension with a combination of lifestyle changes (diet and exercise) and medications in order to minimise damage to affected organs such as the eyes and kidneys.[11] Individuals affected by BBS should be managed by a multidisciplinary team of healthcare professionals.

In the UK, children affected by BBS can be referred to one of the four national BBS multidisciplinary clinics that are based in London and Birmingham (two centres in each city).

1) Retinitis pigmentosa/ cone-rod dystrophy

Treatment is focused on alleviating visual symptoms and optimising remaining sight. These include:

  • Regular monitoring of visual function and prescribing glasses (if required)
  • Visual aids and assistive technology
  • Tinted glasses/contact lenses for light sensitivity
  • Wearing UV protective sunglasses
  • Blue light screen protectors on mobile devices or computer screens*
  • Regular check-ups to monitor for other eye conditions frequently associated with RP such as cataracts
  • A healthy diet consisting of fresh fruit and green leafy vegetables

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

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2) Obesity

As obesity is highly associated with the development of type 2 diabetes and high blood pressure (metabolic syndrome), weight management is a particularly important factor to address for many BBS patients. Although weight-loss (bariatric) surgery or anti-obesity medications are options, dietician input remains the safest and most effective approach.[3,12]

3) Diabetes Mellitus

This is treated with a combination of lifestyle changes (diet and exercise), tablets and occasionally insulin injections depending on how severe the condition is. Treatment is usually coordinated by GP and endocrinologist.

4) Genital abnormalities

This is usually managed by a combination of urologists, gynaecologists and endocrinologists. Various surgical and/or hormonal approaches can be explored on an individual basis. Of the genital abnormalities associated with BBS, undescended testes (cryptorchidism) is of particular concern as it can lead to testicular cancer if left untreated. An operation called orchidopexy is usually performed to move the undescended testes to the scrotum.

5) Learning difficulties, developmental delays and neurodevelopmental disorders

Visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI), developed by Great Ormond Street Hospital Developmental Vision team is a structured early intervention programme designed to track developmental and vision progress in children from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents. Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

In addition, patients may also require other forms of support in the community to cater to their complex health, developmental and social needs. These are usually delivered through specialist centres working alongside community paediatric services. A multitude of professionals might be involved such as:

  • Community nurses 
  • Speech and language therapists 
  • Occupational health therapists 
  • Physiotherapists 
  • Social workers 
  • Child and adolescent mental health service (CAMHS) 
  • Schools  (see education and learning)

As children may be seen by many different services, parents may find it helpful to speak to their paediatrician to help coordinate care.

This is based on current UK practice and might differ in other countries.

6) Chronic kidney disease

Early diagnosis of kidney disease and aggressive treatment with medications may preserve kidney function for long periods in some patients. When kidney function declines below the level needed to sustain life, dialysis or kidney transplant is required.[13] However, the medications required to prevent rejection of the transplanted kidney (known as immunosuppressants), which often have to be taken long-term may worsen obesity.[5] More information can be found on Kidney Care UK and BBSUK.

7) Polydactyly

Polydactyly is often addressed with surgery by removing the extra digit.

8) Other associated symptoms

Hearing aids may help some patients while grommets are inserted for children with hearing loss due to recurrent otitis media (middle ear infection). Tooth extraction and other dental work may be necessary for some patients. Those affected by congenital heart diseases may require surgery to repair the associated defects.

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Current research in BBS

1) Drug therapy

Setmelanotide is a newly developed medication with the potential to reduce weight and hunger in individuals affected by rare genetic disorders of obesity such as BBS. This medication is injected under the skin (subcutaneous injection) and is currently being investigated in a phase 2/3 trial (NCT 03013543).  

Related links

2) Gene therapy

Gene therapy aims to halt retinal degeneration by replacing the mutated gene with a normal healthy copy. This enables the affected cells to regain some of their function and produce functioning proteins.

While research has not advanced to human clinical trials yet, there have been some promising results from studying animal models of BBS. The following are links to scientific summaries of some of the studies:

There are other groups such as those of Dr Phillip Beales at University College London or Dr Helen May-Simera at Johannes Gutenberg University Mainz that are continually investigating mechanisms of cilia formation, function and disease involving the BBS proteins. This research will form the foundations of developing new therapies for BBS.

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How to see a genetic eye specialist?” page. 

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Further information and support

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A patient’s perspective

A patient talking about her personal experience with Bardet-Biedl syndrome

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References

  1.  Weihbrecht K, Goar WA, Pak T, et al. Keeping an eye on Bardet-Biedl syndrome: a comprehensive review of the role of Bardet-Biedl syndrome genes in the eye. Medical research archives. 2017;5(9)
  2.  Tsang SH, Aycinena ARP, Sharma T. Ciliopathy: Bardet-Biedl Syndrome. Adv Exp Med Biol. 2018;1085:171-174
  3.  Forsythe E, Kenny J, Bacchelli C, Beales PL. Managing Bardet–Biedl Syndrome—Now and in the Future. Frontiers in Pediatrics. 2018;6(23)
  4.  Forsythe E, Beales PL. Bardet-Biedl syndrome. European journal of human genetics : EJHG. 2013;21(1):8-13
  5.  Forsythe E, Beales PL. Bardet-Biedl Syndrome. In: GeneReviews®[Internet]. University of Washington, Seattle; 2015
  6.  Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999;36(6):437-446
  7.  Imhoff O, Marion V, Stoetzel C, et al. Bardet-Biedl syndrome: a study of the renal and cardiovascular phenotypes in a French cohort. Clinical journal of the American Society of Nephrology : CJASN. 2011;6(1):22-29
  8.  Baker K, Beales PL. Making sense of cilia in disease: the human ciliopathies. Am J Med Genet C Semin Med Genet. 2009;151c(4):281-295
  9.  Kulaga HM, Leitch CC, Eichers ER, et al. Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nature genetics. 2004;36(9):994-998
  10.  Niederlova V, Modrak M, Tsyklauri O, Huranova M, Stepanek O. Meta-analysis of genotype-phenotype associations in Bardet-Biedl syndrome uncovers differences among causative genes. Human Mutation. 2019;40(11):2068-2087
  11.  Forsythe E, Sparks K, Hoskins BE, et al. Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome. Clin Genet. 2015;87(4):343-349
  12.  Mujahid S, Huda MS, Beales P, Carroll PV, McGowan BM. Adjustable gastric banding and sleeve gastrectomy in Bardet-Biedl syndrome. Obes Surg. 2014;24(10):1746-1748
  13.  Kenny J, Forsythe E, Beales P, Bacchelli C. Toward personalized medicine in Bardet-Biedl syndrome. Per Med. 2017;14(5):447-456

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Updated on November 30, 2020
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