Bardet-Biedl Syndrome: An Overview

Euan MacInnes

Introduction

Bardet-Beidl syndrome (BBS) is an autosomal recessive ciliopathy (disorder of cilia) characterised by early development of retinal rod-cone dystrophy as well as renal abnormalities, obesity, polydactyly, obesity and learning difficulties.

Pathophysiology

BBS is cause by genetic mutation in one of any of the up to 26 Bardet-Beidl proteins (1). BBS genes code for proteins that make cilia and basal bodies (2). Cilia are microscopic hair like structures found on many cells within the body and can be separated into motile and non-motile categories (3). Motile cilia are involved with brushing fluid through the local environment. Non-motile cilia do not posses the ability to move and instead acts as antennas to regulate signalling pathways and modulate homeostasis. It is the nonmotile cilia that are primarily affected in BBS. Cilia in the rods and cones of the photoreceptor of the retina are defective and cause the classical rod-cone dystrophy and retinitis pigmentosa.


Diagnosis and Clincial Findings

Diagnosis is clinical and depends on features present. Table 1 demonstrates primary and secondary features present in BBS:

Primary featuresSecondary features
  1. Retinal degeneration
  2. Truncal obesity
  3. Cognitive impairment
  4. Postaxial polydactyly
  5. Hypogonadism/genitourinary anomalies
  6. Renal abnormalities
  1. Speech delay
  2. Developmental delay
  3. Diabetes mellitus
  4. Orodental abnormalities
  5. Cardiovascular anomalies
  6. Brachydactyly/syndactyly
  7. Ataxia/poor coordination
  8. Anosmia/hyposmia
Table 1. This table demonstrates the primary and secondary features of BBS (4)

To make a diagnosis of BBS, 4 primary features must be present or 3 primary features and 2 secondary features (5).

In a population survey by Beales et al, it was found mean age at diagnosis was 9 years old. Postaxial polydactyl was found in 69% of patients, retinopathy was not detected until a mean age of 8.5 years and truncal obesity developed at 2-3 years of age (5)

Ocular findings are the most highly penetrable defect found in BBS. These findings align with typical features consistent with retinitis pigmentosa (RP). With early cases of suspected BBS where retinal lesions may not have manifested to the point of being diagnosable on fundus examination, electroretinogram (ERG) testing may show early suggestion of RP.

Management and Prognosis

Patients with suspected BBS and their families should be referred to clinical genetics for genetic testing and counselling. BBS is inherited in an autosomal recessive (AR) fashion (6). In around 80% of cases, a mutation in a known BBS gene is found (4)

There is no treatment that targets the underlying cause of BBS. Instead, treatment is focussed on managing sequalae of the syndrome such as hypertension, metabolic syndrome and obesity to prevent further damage occurring to vulnerable organs such as the retina or kidneys.

There has been some evidence to suggest the melano-cortin 4 receptor agonist, Setmelanotide, which regulates appetite and bodyweight, was shown to significantly reduce the weight of patients with BBS over a 1 year periods (7)

There has also been a study looking at the effects of the ever more ubiquitus GLP-1 agonists on the effects on weight in mice with BBS, with results being promising (8)

Conclusion

In conclusion, BBS is a rare, autosomal recessive ciliopathy, characterised by retinopathy, renal disease, polydactyl and truncal obesity. Diagnosis is made based on the clinical features present in the patient and genetic testing. There is no treatment for the underlying cause but the sequalae, such as obesity and hypertension can be managed.

References

  1. Forsyth R, Gunay-Aygun M. Bardet-Biedl syndrome overview.
  2. Shoemaker A. Bardet‐Biedl syndrome: A clinical overview focusing on diagnosis, outcomes and best‐practice management. Diabetes, Obesity and Metabolism. 2024 Apr;26:25-33.
  3. Lee L, Ostrowski LE. Motile cilia genetics and cell biology: big results from little mice. Cellular and molecular life sciences. 2021 Feb;78(3):769-97.
  4. Forsythe E, Beales PL. Bardet–biedl syndrome. European journal of human genetics. 2013 Jan;21(1):8-13.
  5. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter F. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. Journal of medical genetics. 1999 Jun 1;36(6):437-46.
  6. Sahu JK, Jain V. Laurence-Moon-Bardet-Biedl syndrome. JNMA; Journal of the Nepal Medical Association. 2008 Oct 1;47(172):235-7.
  7. Haws R, Brady S, Davis E, Fletty K, Yuan G, Gordon G, Stewart M, Yanovski J. Effect of setmelanotide, a melanocortin‐4 receptor agonist, on obesity in Bardet‐Biedl syndrome. Diabetes, Obesity and Metabolism. 2020 Nov;22(11):2133-40.
  8. Singh A, Haq N, Yang M, Luckey S, Mansouri S, Campbell-Thompson M, Jin L, Christou-Savina S, de Lartigue G. Transcriptome-guided GLP-1 receptor therapy rescues metabolic and behavioral disruptions in a Bardet-Biedl syndrome mouse model. The Journal of Clinical Investigation. 2025 Apr 15.

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