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- Bardet-Biedl syndrome: for patients
|Genes involved (OMIM No.)||21 causative genes identified to date with the most common being:|
|Molecular diagnosis||Next generation sequencing|
|Therapies under research|
BBS is a multisystemic disease caused by pathogenic mutations in 21 causative genes. Variable gene expressivity is typical of BBS, leading to marked intra- and interfamilial phenotypic heterogeneity. Overall, patients harbouring BBS1 variants tend to have less severe phenotypes while BBS10 variants are associated with more severe phenotypes.[3,4] The diagnosis of BBS tend to be missed at birth as most of the main features apart from polydactyly develop later in life.
1) Progressive retinal dystrophy
BBS patients tend to experience progressive visual impairment due to retinitis pigmentosa (RP) or less commonly cone-rod dystrophy. RP is observed in approximately 90% of BBS cases. Nyctalopia tend to manifest between the ages of 5 to 10 years with subsequent progressive visual field (VF) and visual acuity (VA) loss and dyschromatopsia. Patients usually display the typical RP phenotype with early macular involvement although there is variability in terms of the severity of visual dysfunction, rate of progression and macular abnormalities. Most patients are legally blind by the second or third decade but patients with BBS1 mutations generally have better residual visual function (cone and single-flash ERG amplitudes and VA) with later onset of visual symptoms, particularly in homozygotes of the common p.Met390Arg allele.[4,6]
Apart from progressive retinal dystrophy, other ocular abnormalities such as cataracts, refractive errors (typically myopia) are also prevalent among BBS patients.
Certain BBS genes are associated with non-syndromic retinal dystrophy. These include:
- BBS1 (autosomal recessive RP)
- BBS2 (autosomal recessive RP)
- CEP290 (BBS14) (autosomal recessive LCA/EOSRD)
- C8orf37 (BBS21) (autosomal recessive RP/cone-rod dystrophy)
Between 72-92% of patients develop truncal obesity in adulthood. While obesity in adulthood is generally truncal, it is more diffuse in childhood. Most patients are born with a birth weight in the normal range but one-third are classified as obese by age one. Type 2 diabetes mellitus and other metabolic syndromes are commonly observed alongside obesity in adolescence or adulthood.
3) Learning Difficulties
Two-thirds of BBS patients are reported to experience learning difficulties, the severity of which is highly variable but majority are mild to moderate.[5,7]
Several neurodevelopmental issues can also be observed such as:
- Obsessive-compulsive disorder
- Attention deficit hyperactivity disorder
- Autistic spectrum disorder
4) Post-axial polydactyly
Approximately 1 in 5 BBS cases involve all four limbs. In other cases, the hands (9%) or feet (21%) are affected alone with additional digits typically located on the ulnar side of the hand and fibular side of the foot. This is generally the only dysmorphic feature visible at birth and can occur along with syndactyly or brachydactyly.
Brachydactyly of the fingers and toes are common, as are partial syndactyly (generally between 2nd and 3rd toes), fifth-finger clinodactyly and a prominent ‘sandal gap’ between first and second toes.
5) Genital anomalies
Genital anomalies in males include:
- Delayed puberty
- Hypogonadism (micropenis, small-volume testes, atrophic seminiferous tubules)
- Infertility yet some rare cases of male fertility reported
Genital anomalies in females include:
- Hypoplastic fallopian tubes, uterus or ovaries
- Duplex uterus
- Partial/complete vaginal atresia
- Septate vagina
- Persistent urogenital sinus
- Vesico-vaginal fistula
- Absent vaginal and/or urethral orifice
- Low fertility rates
6) Renal anomalies
Renal dysfunction is highly prevalent among BBS patients (50-80%). Approximately 8% of these patients eventually progress to end-stage renal failure requiring dialysis or transplantation surgery. Majority of patients who develop end stage renal failure usually do so before the age of 5 years.
An American study monitoring BBS patients with renal disease over a 30 year period reported a similar percentage of patients receiving transplants and concluded that transplantation was a viable treatment option with favourable long-term outcomes despite the metabolic co-morbidities associated with these patients.
Both structural and/or functional renal anomalies may be observed in BBS. These include:
- Renal cysts
- Foetal lobulation (incomplete fusion of kidney lobules)
- Diffuse cortical scarring
- Renal agenesis/atrophy
- Renal dysplasia
- Urinary concentration defects (despite near-normal renal function and absence of major cysts)
As a result, these may lead to:
- Renal tubular acidosis
- Renal calculi
- Vesico-ureteric reflux (leading to recurrent urinary tract infections)
Furthermore, co-morbidities such as type 2 diabetes and hypertension may cause further renal insult as well.
1) Diabetes mellitus
Approximately 6% of BBS patients suffer from type 2 diabetes, which usually becomes evident in adolescence or adulthood.
2) Impaired speech
Estimates of roughly 60-84% of BBS patients have impaired speech, which often sounds high-pitched and nasally.[3,5] Impaired speech is compounded by hearing loss (sensorineural and conductive), which is experienced in roughly 1 in 5 BBS patients. Children generally do not develop intelligible 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 gross and fine motor skills and psychosocial skills (interactive play and ability to recognise social cues).
4) Dental anomalies
Dental crowding and a high-arched palate are commonly observed among BBS patients, while hypodontia, small dental roots, malocclusion and enamel hypoplasia are less commonly observed.
5) Congenital heart disease
Clumsiness and a wide-based gait are characteristic of BBS patients although there is no consensus as to when these features emerge.[5,7] Many cannot tandem walk (walk in a straight line with one toe abutting the other heel) and have dysdiadochokinesia. There is no indication that cerebellar dysfunction is the cause of ataxia, but rather an unknown defect in coordination or processing movements.
Loss of smell has been reported in some studies and may be attributed to defective ciliated olfactory epithelium. Subfertility patients are in part due to dysfunctional cilia in sperm or oocytes.[5,12]
This list of associated features is not exhaustive. Please visit the Bardet-Biedl Syndrome UK website for more information.
BBS is a ciliopathy due to defective ciliogenesis and ciliary protein trafficking as a result of pathogenic mutations in one of the 21 causative genes.
In the retina, proteins essential for phototransduction are trafficked from the inner photoreceptor segment to the outer segment via the connecting cilium. This process is primarily regulated by the BBSome, a protein complex in the cilia made up of 8 BBS proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, BBS18). Chaperone proteins (BBS6, BBS10, BBS12) are required to assemble the BBSome complex after which it is activated by the ARL6 (BBS3) protein. Apart from protein trafficking, the BBSome is also required for the morphogenesis and maintenance of the photoreceptor outer segments throughout life.
Other BBS proteins play a critical role in ciliary formation, protein transport and protein localisation.[15-18]
Of the 21 known causative genes, the most common are:
- BBS1 (28%)
- BBS10 (10%)
- BBS2, BBS12, ARL6 (8%)
|BBSome complex||BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, BBIP1 (BBS18)|
|BBS chaperonin complex||MKKS (BBS6), BBS10, BBS12|
|BBSome activation||ARL6 (BBS3)|
|Protein transport||WDPCP (BBS15), LZTFL1 (BBS17), IFT27 (BBS19/RABL4), IFT74 (BBS20)|
|Cilia formation||MKS1 (BBS13), CEP290 (BBS14), SDCCAG8 (BBS16)|
|Protein localisation||TRIM32 (BBS11)|
Full-field electroretinogram (ERG) may demonstrate a rod-cone dystrophy (common) or a cone-rod dystrophy pattern. Pattern ERG responses is reduced if there is macular involvement.
2) Fundus autofluorescence imaging (FAF)
FAF can be used to assess severity of retinal degeneration and monitor disease progression.
3) Optical coherence tomography (OCT)
Serial OCT scans of the outer retinal layers aid in monitoring disease progression and providing structural correlation to a patient’s visual function. Cystoid macular oedema (CMO) can also be identified easily and monitor the effectiveness of intervention.
Patients presenting with major features of BBS should be referred to a paediatrician for further investigations. This may include but not limited to:
- General physical examination including assessment of height, weight (BMI), head circumference and plotting of growth chart
- Blood tests (haematology and biochemistry profiles including renal and liver function, plasma glucose level, bone chemistry, cholesterol and triglycerides)
- MRI brain imaging
- Renal ultrasound
- Cardiac assessment
- Endocrinology assessment
- Developmental assessment
The diagnosis of BBS is based on the presence of at least 4 main features or 3 main and at least 2 secondary features. Antenatal diagnosis is rare except in cases with positive family history. Genetic testing is needed to confirm the diagnosis.
This can be achieved through a variety of next generation sequencing (NGS) methods:
- Targeted gene panels (BBS candidate genes)
- Whole exome sequencing (WES)
- Whole genome sequencing (WGS)
Targeted gene panels are currently the diagnostic method of choice and have up to an 80% diagnostic rate. Consideration is required before advancing with WES and WGS. These sequencing methods afford greater genome coverage and can detect novel genes or non-coding variants.
However, they are more expensive and may detect variants in non-BBS genes and/or variants of unknown significance in BBS genes. This may cause diagnostic complications, particularly when patients are only exhibiting one or two of the main BBS features.
Patients are managed symptomatically in a multidisciplinary setting with particular focus on aggressive management of diabetes, hypertension and metabolic syndrome to minimise damage on compromised end-organs such as the eyes or kidneys.
In the UK, children affected by BBS can be referred to one of the four national BBS multidisciplinary clinics. The clinics are based in London and Birmingham (2 centres in each city).
Management is mainly supportive which include:
- Correcting any refractive errors
- Referral to low vision services
- Tinted glasses/contact lens for photophobia
- Directing patients to supporting organisations
- Encourage a healthy diet consisting of fresh fruit and green leafy vegetables
- Encourage the use of assistive technology that may improve quality of life
- Monitoring and treating associated complications such as cataract and CMO
- UV protected sunglasses
- Blue light screen protectors on mobile devices or computer screens*
*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.
- Management of RP
- Management of cone-rod dystrophy
- Coping with sight loss
- Registration for sight impairment
Weight management is a pressing issue for many BBS patients. Although bariatric surgery or anti-obesity medications are options, dietetic input remains the safest and most effective approach.[3,21]
2) Diabetes Mellitus
This is usually managed based on standard protocols.
3) Genitourinary anomalies
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.
4) 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) is a structured early intervention programme designed to track developmental and vision progress 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
- Social workers
- Child and adolescent mental health service (CAMHS)
- Schools (see education support)
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.
5) 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. However, immunosuppressants required after transplantation may compound obesity issues. More information can be found on Kidney Care UK and BBSUK.
6) Hearing loss
Interventions such as hearing aids may recover some hearing loss associated with subclinical sensorineural hearing loss in adults while grommets are usually inserted for children with conductive hearing loss due to recurrent otitis media.
7) Dental crowding
For some patients, teeth removal is critical to relieve dental overcrowding.
The earliest and most frequent intervention for polydactyly is the removal of the accessory digit at an early age, often before the age of 2.
Family management and counselling
BBS is inherited in an autosomal recessive manner. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.
Emotional and social support
Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.
Referral to a specialist centre
In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.
Current research into BBS therapeutic developments can be split broadly into two categories: gene-specific and gene-independent therapies. Genetic therapies include gene therapy, nonsense-suppression therapies and gene editing. Gene-independent interventions include targeted therapies, drug repurposing and pharmacogenomic profiling.
There is an ongoing phase 2/3 trial (NCT 03013543) assessing the efficacy of a novel melanocortin receptor agonist called setmelanotide on syndromic forms of obesity including BBS. This is based on evidence suggesting that BBS causes defects in the hypothalamic leptin-melanocortin axis, which in turn leads to leptin resistance and eventually obesity.[23,24]
While no treatment is available, there have been some promising results in the development of gene therapy for BBS. These include:
- Restoration of BBS17/LZTFL1 expression with tamoxifen in a BBS mouse model with retinal degeneration
- Structural and functional rescue of a Cep290-LCA mouse model through subretinal injection of a truncated mouse Bbs14/Cep290 gene
- Restoration of mouse olfactory function with delivery of normal mouse Bbs1 gene
- Improvement in photoreceptor function and morphology in both Bbs1 and Bbs4 mouse models
Although nonsense suppression therapies have successfully restored full length functional proteins in some in vitro models of inherited retinal diseases associated with mutations in USH2A and RP2, this has not yet been reported in in vitro human cell models of BBS.[25-27]
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 novel therapies for BBS.
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
- Retina UK
- BBS UK
- Royal National Institute of Blind People (RNIB)
- Guide Dogs for the Blind Association
- Look UK
- Kidney Care UK
- 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)
- Tsang SH, Aycinena ARP, Sharma T. Ciliopathy: Bardet-Biedl Syndrome. Adv Exp Med Biol. 2018;1085:171-174
- Forsythe E, Kenny J, Bacchelli C, Beales PL. Managing Bardet–Biedl Syndrome—Now and in the Future. Frontiers in Pediatrics. 2018;6(23)
- Daniels AB, Sandberg MA, Chen J, Weigel-DiFranco C, Fielding Hejtmancic J, Berson EL. Genotype-phenotype correlations in Bardet-Biedl syndrome. Arch Ophthalmol. 2012;130(7):901-907
- Forsythe E, Beales PL. Bardet-Biedl syndrome. European journal of human genetics : EJHG. 2013;21(1):8-13
- Castro-Sánchez S, Álvarez-Satta M, Cortón M, Guillén E, Ayuso C, Valverde D. Exploring genotype-phenotype relationships in Bardet-Biedl syndrome families. J Med Genet. 2015;52(8):503-513
- Forsythe E, Beales PL. Bardet-Biedl Syndrome. In: GeneReviews®[Internet]. University of Washington, Seattle; 2015
- Beales P, Elcioglu N, Woolf A, Parker D, Flinter F. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. Journal of medical genetics. 1999;36(6):437-446
- Forsythe E, Sparks K, Best S, et al. Risk factors for severe renal disease in bardet–biedl syndrome. Journal of the American Society of Nephrology. 2017;28(3):963-970
- 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
- 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
- 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
- May-Simera H, Nagel-Wolfrum K, Wolfrum U. Cilia – The sensory antennae in the eye. Prog Retin Eye Res. 2017;60:144-180
- Hsu Y, Garrison JE, Kim G, et al. BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment. PLOS Genetics. 2017;13(10):e1007057
- Jiang J, Promchan K, Jiang H, et al. Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice. J Genet Genomics. 2016;43(6):381-391
- Xue B, Liu Y-X, Dong B, et al. Intraflagellar transport protein RABL5/IFT22 recruits the BBSome to the basal body through the GTPase ARL6/BBS3. Proceedings of the National Academy of Sciences. 2020;117(5):2496-2505
- Nozaki S, Araya RFC, Katoh Y, Nakayama K. Requirement of IFT-B–BBSome complex interaction in export of GPR161 from cilia. Biology open. 2019;8(9):bio043786
- Brown Jason M, Cochran Deborah A, Craige B, Kubo T, Witman George B. Assembly of IFT Trains at the Ciliary Base Depends on IFT74. Current Biology. 2015;25(12):1583-1593
- 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
- Forsythe E, Sparks K, Hoskins BE, et al. Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome. Clin Genet. 2015;87(4):343-349
- 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
- Kenny J, Forsythe E, Beales P, Bacchelli C. Toward personalized medicine in Bardet-Biedl syndrome. Per Med. 2017;14(5):447-456
- Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet. 2009;18(7):1323-1331
- Mason K, Page L, Balikcioglu PG. Screening for hormonal, monogenic, and syndromic disorders in obese infants and children. Pediatr Ann. 2014;43(9):e218-224
- Samanta A, Stingl K, Kohl S, Ries J, Linnert J, Nagel-Wolfrum K. Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations. International Journal of Molecular Sciences. 2019;20(24):6274
- Schwarz N, Carr A-J, Lane A, et al. Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells. Human molecular genetics. 2015;24(4):972-986
- Shahi PK, Hermans D, Sinha D, et al. Gene augmentation and readthrough rescue channelopathy in an iPSC-RPE model of congenital blindness. The American Journal of Human Genetics. 2019;104(2):310-318