Bardet–Biedl syndrome

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

The 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, mental retardation has 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 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 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 have 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: 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."^[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.^{[citation needed]}

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]}

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^{[citation needed]}

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

External links

• Laurence Moon Bardet Biedl Society (UK-based)
• LMBBS Association a US-based association promoting awareness of BBS
• 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