Bardet–Biedl syndrome


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
ICD-10 Q87.8
ICD-9 759.89
OMIM 209900
DiseasesDB 7286
MeSH D020788

The Bardet–Biedl syndrome is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism, and renal failure in some cases.[1]

Contents

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; 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)"
  • 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] 14 genetic forms have been currently identified.[5]

The first known case was reported by Laurence and Moon in 1866 at the Ophthalmic Hospital in South London. Laurence–Moon–Biedl–Bardet syndrome are no longer considered as valid terms in that patients of Laurence and Moon had paraplegia but no polydactyly and obesity, which are the key elements of the Bardet–Biedl the syndrome. Laurence–Moon syndrome is usually considered a separate entity. However, some recent research suggests that the two conditions may not be distinct.[6]

Major clinical features

  • Eyes: Pigmentary retinopathy, poor visual acuity, low vision, and/or blindness caused by an impaired photoreceptor transport mechanism in the retina.[7]
  • Nose: Loss of, or reduced sense of, smell. (anosmia). Some patients claim extra-sensitive sense of smell.[8]
  • 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: Mental and growth retardation.
  • Behavior and performance: a wide variety of socialization and social interaction problems have been identified with BBS. Some refer to it as a kind of "mild-Autism." Many children who are later (explicitly and formally) diagnosed with the syndrome have gone through an extended period of time where school and medical professionals have struggled to find a name for the child's problems over several years.
  • 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."[9]
  • Additional features: Obesity, possibly related to a decreased sensory function that would normally indicate satiation. Hyperphagia in some patients.[10]

Pathophysiology

The detailed biochemical mechanism that leads to BBS is still unclear. At this moment, twelve genes that are responsible for the disease when mutated, have been cloned.[citation needed]

The gene products encoded by these BBS genes, called BBS proteins, are located in the basal body and cilia of the cell.[11]

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 the formation and maintenance of cilia.[12] 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 functions, which, in turns, causes BBS.[citation needed]

Genes involved include:

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.[13]

Hereditary characteristics

The syndrome is familial and is transmitted as an autosomal recessive trait.[citation needed]

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. PMC 1734378. PMID 10874630. http://mlmorris.com/lmbbs/437.htm. 
  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. http://books.google.com/?id=SOvEYxO2V4AC&dq. 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. http://books.google.com/?id=SOvEYxO2V4AC&dq. Retrieved 2009-07-01. 
  4. ^ synd/3745 at Who Named It?
  5. ^ http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=209900
  6. ^ 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. GenetARRAY 132 (4): 352–60. doi:10.1002/ajmg.a.30406. PMID 15637713. 
  7. ^ Abd-El-Barr, MM; Sykoudis K, Andrabi S, Eichers ER, Pennesi ME, Tan PL, Wilson JH, Katsanis N, Lupski JR, Wu SM. (2007-12). "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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2661240. Retrieved 2008-11-17. 
  8. ^ Downer, Joanna (2004-09-13). "That Stinks: People with Rare Obesity Syndrome Can't Sense Odors". The JHU Gazette. Johns Hopkins University. http://www.jhu.edu/~gazette/2004/13sep04/13stinks.html. Retrieved 2008-07-14. 
  9. ^ 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. http://www.pnas.org/content/104/44/17524. Retrieved 2008-07-14. 
  10. ^ 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. 177. ISBN 978-0-19-530016-1. http://books.google.com/?id=SOvEYxO2V4AC&dq. Retrieved 2009-07-01. 
  11. ^ 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. 
  12. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=443524. 
  13. ^ 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. http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.genom.7.080505.115610. 

External links


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