Bardet–Biedl syndrome

Laurence-Moon-Biedl syndrome and Laurence-Moon-Biedl-Bardet redirect here. See below for an explanation.

Bardet–Biedl syndrome
Classification and external resources
Specialty	medical genetics
ICD-10	Q87.8
ICD-9-CM	759.89
OMIM	209900
DiseasesDB	7286
MeSH	D020788
GeneReviews	Bardet-Biedl Syndrome
Orphanet	110

Bardet–Biedl syndrome (BBS) is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity, retinitis pigmentosa, polydactyly, hypogonadism, and renal failure in some cases.^[1] Historically, slower mental processing has also been considered a principal symptom but is now not regarded as such.

Summary of the syndrome

Bardet–Biedl syndrome is a pleiotropic disorder with variable expressivity and a wide range of clinical variability observed both within and between families. The main clinical features are rod–cone dystrophy, with childhood-onset visual loss preceded by night blindness; postaxial polydactyly; truncal obesity that manifests during infancy and remains problematic throughout adulthood; specific learning difficulties in some but not all individuals; male hypogenitalism and complex female genitourinary malformations; and renal dysfunction, a major cause of morbidity and mortality. There is a wide range of secondary features that are sometimes associated with BBS^[2] including^[3]

• Speech disorder/delay
• Strabismus/cataracts/astigmatism
• "Brachydactyly/syndactyly of both the hands and feet is common, as is partial syndactyl (most usually between the second and third toes)"
• "Developmental delay: Many children with BBS are delayed in reaching major developmental milestones including gross motor skills, fine motor skills, and psychosocial skills (interactive play/ability to recognize social cues)". However these delays are treatable with therapy.
• Polyuria/polydipsia (nephrogenic diabetes insipidus)
• Ataxia/poor coordination/imbalance
• Mild hypertonia (especially lower limbs)
• Diabetes mellitus
• Dental crowding/hypodontia/small dental roots; high-arched palate
• Cardiovascular anomalies
• Hepatic involvement
• Anosmia
• Auditory deficiencies
• Hirschsprung disease

Eponym and classification

The syndrome is named after Georges Bardet and Arthur Biedl.^[4]

The first known case was reported by Laurence and Moon in 1866 at the Ophthalmic Hospital in South London. Laurence–Moon–Biedl–Bardet syndrome is no longer considered as valid terms in that patients of Laurence and Moon had paraplegia but no polydactyly or obesity, which are the key elements of the Bardet–Biedl syndrome. Laurence–Moon syndrome is usually considered a separate entity. However, some recent research suggests that the two conditions may not be distinct.^[5]

As of 2012, 14^[6] (or 15)^[7] different BBS genes had been identified.

Major clinical features

• Eyes: Pigmentary retinopathy, poor visual acuity, low vision, and/or blindness caused by an impaired photoreceptor transport mechanism in the retina.^[8]
• Nose: Loss of, or reduced sense of, smell (anosmia). Some patients claim extra-sensitive sense of smell.^[9]
• Hand and foot: Polydactyly (extra digits) or syndactyly (webbing of fingers and toes).
• Cardiovascular system: Hypertrophy of interventricular septum and left ventricle and dilated cardiomyopathy.
• Gastrointestinal system: Fibrosis.
• Urogenital system: Hypogonadism, renal failure, urogenital sinuses, ectopic urethra, uterus duplex, septate vagina, and hypoplasia of the uterus, ovaries, and fallopian tubes.
• Growth and development: Developmental delay, especially of fine and gross motor skills
• Behavior: a wide variety of socialization and social interaction problems have been identified with BBS.
• Defective thermosensation or mechanosensation. New finding reported in October 2007: "hitherto unrecognized, but essential, role for mammalian basal body proteins in the acquisition of mechano- and thermosensory stimuli [highlight potential] clinical features of ciliopathies in humans."^[10]
• Additional features: Obesity, possibly related to a decreased sensory function that would normally indicate satiation. Hyperphagia in some patients.^[11]

Pathophysiology

The detailed biochemical mechanism that leads to BBS is still unclear.

The gene products encoded by these BBS genes, called BBS proteins, are located in the basal body and cilia of the cell.^[12]

Using the round worm C. elegans as a model system, biologists found that BBS proteins are involved in a process called Intraflagellar transport (IFT), a bi-directional transportation activity within the cilia along the long axis of the ciliary shaft that is essential for ciliogenesis and the maintenance of cilia.^[13] Recent biochemical analysis of human BBS proteins revealed that BBS proteins are assembled into a multiple protein complex, called "BBSome". BBSome is proposed to be responsible for transporting intracellular vesicles to the base of the cilia and to play an important role in the ciliary function.

Since abnormalities of cilia are known to be related to a wide range of disease symptoms including those commonly seen in BBS patients, it is now widely accepted that mutated BBS genes affect normal cilia function, which, in turns, causes BBS.

A theory that photoreceptor cells are nourished by the IFT of retinal cilia now offers a potential explanation for the retinal dystrophy common in BBS patients after their early years of life.^[14][15]

Genes involved include:

• BBsome: BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, TTC8/BBS8, BBS10, TRIM32/BBS11 BBS12, CCDC28B, CEP290, TMEM67, MKS1, MKKS^[6]
• chaperone: BBS6

Relation to other rare genetic disorders

Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely varying, phenotypically observed disorders. BBS is one such syndrome that has now been identified to be caused by defects in the cellular ciliary structure. Thus, BBS is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, polycystic kidney and liver disease, nephronophthisis, Alstrom syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.^[16]

References

1. Beales P, Elcioglu N, Woolf A, Parker D, Flinter F (1 June 1999). "New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey". J. Med. Genet. 36 (6): 437–46. doi:10.1136/jmg.36.6.437. PMC 1734378. PMID 10874630.
2. Ross, Allison; PL Beales; J Hill (2008). The Clinical, Molecular, and Functional Genetics of Bardet–Biedl Syndrome, in Genetics of Obesity Syndromes. Oxford University Press. pp. 147–148. ISBN 978-0-19-530016-1. Retrieved 2009-07-01.
3. Ross, Allison; PL Beales; J Hill (2008). The Clinical, Molecular, and Functional Genetics of Bardet–Biedl Syndrome, in Genetics of Obesity Syndromes. Oxford University Press. pp. 153–154. ISBN 978-0-19-530016-1. Retrieved 2009-07-01.
4. synd/3745 at Who Named It?
5. Moore S, Green J, Fan Y, et al. (2005). "Clinical and genetic epidemiology of Bardet–Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study". Am. J. Med.. Genet. 132 (4): 352–60. doi:10.1002/ajmg.a.30406. PMC 3295827. PMID 15637713.
6. Hamosh, Ada (2012-11-02). "OMIM entry #209900 Bardet-Biedl Syndrome; BBS". Online Mendelian Inheritance in Man. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine. Retrieved 2013-09-04.
7. Hereditary Retinopathies: Progress in Development of Genetic and Molecular Therapies. Springer. 2012. p. 15. Retrieved 2013-09-04.
8. Abd-El-Barr, MM; Sykoudis K; Andrabi S; Eichers ER; Pennesi ME; Tan PL; Wilson JH; Katsanis N; Lupski JR; Wu SM. (December 2007). "Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet–Biedl syndrome". Vision Res. 47 (27): 3394–407. doi:10.1016/j.visres.2007.09.016. PMC 2661240. PMID 18022666.
9. Downer, Joanna (2004-09-13). "That Stinks: People with Rare Obesity Syndrome Can't Sense Odors". The JHU Gazette. Johns Hopkins University. Retrieved 2008-07-14.
10. Tan PL, Barr T, Inglis PN, et al. (2007). "Loss of Bardet Biedl syndrome proteins causes defects in peripheral sensory innervation and function". Proc. Natl. Acad. Sci. U.S.A. 104 (44): 17524–9. doi:10.1073/pnas.0706618104. PMC 2077289. PMID 17959775. Retrieved 2008-07-14.
11. Ross, Allison; PL Beales; J Hill (2008). The Clinical, Molecular, and Functional Genetics of Bardet–Biedl Syndrome, in Genetics of Obesity Syndromes. Oxford University Press. p. 177. ISBN 978-0-19-530016-1. Retrieved 2009-07-01.
12. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N (October 2003). "Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome". Nature. 425 (6958): 628–33. doi:10.1038/nature02030. PMID 14520415.
13. Blacque OE, Reardon MJ, Li C, McCarthy J, Mahjoub MR, Ansley SJ, Badano JL, Mah AK, Beales PL, Davidson WS, Johnsen RC, Audeh M, Plasterk RH, Baillie DL, Katsanis N, Quarmby LM, Wicks SR, Leroux MR (2004). "Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport". Genes Dev. 18 (13): 1630–42. doi:10.1101/gad.1194004. PMC 443524. PMID 15231740.
14. Sedmak T, Wolfrum U (April 2010). "Intraflagellar transport molecules in ciliary and nonciliary cells of the retina". J. Cell Biol. 189 (1): 171–86. doi:10.1083/jcb.200911095. PMC 2854383. PMID 20368623. Retrieved 2014-01-22.
15. Orozco, JT; Wedaman KP; Signor D; Brown H; Rose L; Scholey JM (1999). "Movement of motor and cargo along cilia". Nature. 398 (6729): 674. doi:10.1038/19448. PMID 10227290.
16. Badano JL, Mitsuma N, Beales PL, Katsanis N (2006). "The ciliopathies: an emerging class of human genetic disorders". Annu Rev Genomics Hum Genet. 7: 125–48. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803.

External links

• Laurence Moon Bardet Biedl Society (UK-based)
• Bardet Biedl Syndrome Family Association a US-based non-profit providing education, support and resources for families affected by BBS
• Bardet Biedl Syndrome Center of Excellence Housed at the Marshfield Clinic, Wisconsin, USA
• The Importance of Being Cilia Accessible article at Howard Hughes Medical Institute on the importance and extensive use of cilia and basal bodies in many organ systems of human physiology. Includes multiple specific mentions of BBS.
• BBS and loss of the sense of smell at Johns Hopkins University
• Overview at United States National Library of Medicine
• Foundation Fighting Blindness
• Bardet–Biedl Syndrome Association francaise (France-based; in French language) Syndrome de Bardet-Biedl (BBS)
• Bardet–Biedl syndrome at GeneReview/UW/NIH