Bardet-Biedl syndrome
Encyclopedia
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.
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" including
and Arthur Biedl
. 14 genetic forms have been currently identified.
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.
The gene products encoded by these BBS genes, called BBS proteins, are located in the basal body
and cilia of the cell
.
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. 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.
Genes involved include:
s, 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
.
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
human
Human
Humans are the only living species in the Homo genus...
genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that produces many effects
Pleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...
and affects many body systems. It is characterized principally by obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, retinitis pigmentosa
Retinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
, polydactyly
Polydactyly
Polydactyly or polydactylism , also known as hyperdactyly, is a congenital physical anomaly in humans, dogs, and cats having supernumerary fingers or toes....
, mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
, and renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
in some cases.
Summary of the syndrome
"Bardet–Biedl syndrome is a pleiotropic disorder with variable expressivityExpressivity
Expressivity is a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype. The term can be used to characterize qualitatively or quantitatively the extent of phenotypic variation given a particular genotype. The term is analogous to the...
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
Polydactyly
Polydactyly or polydactylism , also known as hyperdactyly, is a congenital physical anomaly in humans, dogs, and cats having supernumerary fingers or toes....
; 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" including
- Speech disorder/delay
- StrabismusStrabismusStrabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...
/cataracts/astigmatismAstigmatismAn optical system with astigmatism is one where rays that propagate in two perpendicular planes have different foci. If an optical system with astigmatism is used to form an image of a cross, the vertical and horizontal lines will be in sharp focus at two different distances... - "BrachydactylyBrachydactylyBrachydactyly , is a medical term which literally means "shortness of the fingers and toes" . The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an inherited, usually dominant trait...
/syndactylySyndactylySyndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and kangaroo, but is an unusual condition in humans.-Classification:...
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)"
- PolyuriaPolyuriaPolyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
/polydipsiaPolydipsiaPolydipsia is a medical symptom in which the patient displays excessive thirst. The word derives from the Greek πολυδιψία, which is derived from πολύς + δίψα...
(nephrogenic diabetes insipidus) - AtaxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
/poor coordination/imbalance - Mild hypertoniaHypertoniaHypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
(especially lower limbs) - Diabetes mellitusDiabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
- Dental crowding/hypodontiaHypodontiaIn dentistry, hypodontia is the condition at which the patient has missing teeth as a result of their failure to develop. Hypodontia describes a situation where the patient is missing up to 6 teeth, excluding the 3rd molars. Missing third molars occur in 9-30% of population...
/small dental roots; high-arched palate - Cardiovascular anomalies
- Hepatic involvement
- AnosmiaAnosmiaAnosmia is a lack of functioning olfaction, or in other words, an inability to perceive odors. Anosmia may be either temporary or permanent. A related term, hyposmia, refers to a decreased ability to smell, while hyperosmia refers to an increased ability to smell. Some people may be anosmic for one...
- Auditory deficiencies
- Hirschsprung disease
Eponym and classification
The syndrome is named after Georges BardetGeorges Bardet
Georges Bardet was a French physician who is known for first describing a rare genetic disease. In his graduation thesis at the University of Paris in 1920, Bardet wrote about a medical condition characterized by obesity, retinitis pigmentosa, polydactyly and hypogonadism...
and Arthur Biedl
Arthur Biedl
Arthur Biedl was an Hungarian pathologist born in what today is Comloşu Mic, Romania.He studied medicine at the University of Vienna, where in 1896 he received his habilitation...
. 14 genetic forms have been currently identified.
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
Paraplegia
Paraplegia is an impairment in motor or sensory function of the lower extremities. The word comes from Ionic Greek: παραπληγίη "half-striking". It is usually the result of spinal cord injury or a congenital condition such as spina bifida that affects the neural elements of the spinal canal...
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.
Major clinical features
- Eyes: Pigmentary retinopathyRetinopathyRetinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
, poor visual acuity, low visionLow visionLow vision is a subspecialty within the professions of optometry and ophthalmology dealing with individuals who have reduced vision even when using the best possible spectacle or contact lens correction available. It can be a result of either congenital disease Low vision is a subspecialty within...
, and/or blindnessBlindnessBlindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define blindness...
caused by an impaired photoreceptor transport mechanism in the retinaRetinaThe vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
. - Nose: Loss of, or reduced sense of, smell. (anosmiaAnosmiaAnosmia is a lack of functioning olfaction, or in other words, an inability to perceive odors. Anosmia may be either temporary or permanent. A related term, hyposmia, refers to a decreased ability to smell, while hyperosmia refers to an increased ability to smell. Some people may be anosmic for one...
). Some patients claim extra-sensitive sense of smell. - Hand and foot: PolydactylyPolydactylyPolydactyly or polydactylism , also known as hyperdactyly, is a congenital physical anomaly in humans, dogs, and cats having supernumerary fingers or toes....
(extra digitsDigit (anatomy)A digit is one of several most distal parts of a limb, such as fingers or toes, present in many vertebrates.- Names:Some languages have different names for hand and foot digits ....
) or syndactylySyndactylySyndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and kangaroo, but is an unusual condition in humans.-Classification:...
(webbing of fingers and toes). - Cardiovascular system: Hypertrophy of interventricular septumInterventricular septumInterventricular septum , abbreviated IVS, is the stout wall separating the lower chambers of the heart from one another....
and left ventricleLeft ventricleThe left ventricle is one of four chambers in the human heart. It receives oxygenated blood from the left atrium via the mitral valve, and pumps it into the aorta via the aortic valve.-Shape:...
and dilated cardiomyopathyCardiomyopathyCardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
. - Gastrointestinal system: FibrosisFibrosisFibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
. - Urogenital system: HypogonadismHypogonadismHypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
, renal failureRenal failureRenal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
, urogenital sinuses, ectopic urethra, uterus duplex, septate vagina, and hypoplasiaHypoplasiaHypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
of the uterusUterusThe uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, ovaries, and fallopian tubes. - Growth and development: Mental and growth retardationRetardationRetardation is the act or result of delaying; the extent to which anything is retarded or delayed; that which retards or delays. In particular, it can mean:-In engineering:* Negative acceleration in mechanics Retardation is the act or result of delaying; the extent to which anything is retarded...
. - 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-AutismAutismAutism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
." 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 mechanosensationSomatosensory systemThe somatosensory system is a diverse sensory system composed of the receptors and processing centres to produce the sensory modalities such as touch, temperature, proprioception , and nociception . The sensory receptors cover the skin and epithelia, skeletal muscles, bones and joints, internal...
. 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." - Additional features: ObesityObesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, possibly related to a decreased sensory function that would normally indicate satiation. Hyperphagia in some patients.
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.The gene products encoded by these BBS genes, called BBS proteins, are located in the basal body
Basal body
A basal body is an organelle formed from a centriole, and a short cylindrical array of microtubules. It is found at the base of a eukaryotic undulipodium and serves as a nucleation site for the growth of the axoneme microtubules...
and cilia of the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
.
Using the round worm C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
as a model system, biologists found that BBS proteins are involved in a process called Intraflagellar transport
Intraflagellar transport
Intraflagellar transport or IFT is a bidirectional motility along axonemal microtubules that is essential for the formation and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface...
(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. 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.
Genes involved include:
- BBsomeBBsomeThe BBSome is a component of the basal body and is involved in formation of the primary cilium. The BBSome is a complex of seven Bardet–Biedl syndrome proteins: BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9. In addition the BBSome contains the BBIP10 protein. The BBSome was first identified in 2007...
: BBS1BBS1Bardet-Biedl syndrome 1 protein is a protein that in humans is encoded by the BBS1 gene.-External Links:* -Further reading:...
, BBS2BBS2Bardet-Biedl syndrome 2 protein is a protein that in humans is encoded by the BBS2 gene.-External Links:* -Further reading:...
, BBS4BBS4Bardet-Biedl syndrome 4 protein is a protein that in humans is encoded by the BBS4 gene.This gene encodes a protein which contains tetratricopeptide repeats , similar to O-linked N-acetylglucosamine transferase. Mutations in this gene have been observed in patients with Bardet-Biedl syndrome type 4...
, BBS5BBS5Bardet-Biedl syndrome 5 protein is a protein that in humans is encoded by the BBS5 gene.-External Links:* -Further reading:...
, BBS7BBS7Bardet-Biedl syndrome 7 is a protein that in humans is encoded by the BBS7 gene.Mutations in this gene are associated with the Bardet-Biedl syndrome.- External links :*...
, TTC8TTC8Tetratricopeptide repeat domain 8 also known as Bardet-Biedl syndrome 8 is a protein that in humans is encoded by the TTC8 gene.- Function :TTC8 is associated with gamma-tubulin, BBS4, and PCM1 in the centrosome...
/BBS8, BBS9BBS9Bardet-Biedl syndrome 9 is a protein that in humans is encoded by the BBS9 gene.The expression of the Bardet-Biedl syndrome 9 protein is downregulated by parathyroid hormone in osteoblastic cells, and therefore, is thought to be involved in parathyroid hormone action in bones.Mutations in this gene...
- chaperone: BBS6, BBS10BBS10Bardet-Biedl syndrome 10, also known as BBS10 is a human gene.- Function :The Bardet-Biedl syndrome 10 protein has distant sequence homology to type II chaperonins. As a molecular chaperone, this protein may affect the folding or stability of other ciliary or basal body proteins...
, BBS12BBS12Bardet-Biedl syndrome 12 is a protein that in humans is encoded by the BBS12 gene.Mutations in this gene are associated with the Bardet-Biedl syndrome.- External Links :*...
- Other: ARL6ARL6ADP-ribosylation factor-like protein 6 is a protein that in humans is encoded by the ARL6 gene.-External Links:* -Further reading:...
/BBS3, TRIM32TRIM32Tripartite motif-containing protein 32 is a protein that in humans is encoded by the TRIM32 gene. Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.- Structure :...
/BBS11
Relation to other rare genetic disorders
Recent findings in genetic research have suggested that a large number of genetic disorderGenetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
s, both genetic syndromes
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
and genetic diseases
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
root cause of the widely-varying, phenotypically
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
-observed disorders. BBS is one such syndrome that has now been identified to be caused by defects in the cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
ciliary structure
Cilium
A cilium is an organelle found in eukaryotic cells. Cilia are slender protuberances that project from the much larger cell body....
. Thus, BBS is a ciliopathy
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
. Other known ciliopathies include primary ciliary dyskinesia
Primary ciliary dyskinesia
Primary ciliary dyskinesia , also known as immotile ciliary syndrome or Kartagener Syndrome ', is a rare, ciliopathic, autosomal recessive genetic disorder that causes a defect in the action of the cilia lining the respiratory tract and fallopian tube, and also of the flagella of sperm in...
, polycystic kidney
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
and liver disease
Polycystic liver disease
Polycystic liver disease usually describes the presence of multiple cysts scattered throughout normal liver tissue, in association with polycystic kidney disease.-Pathophysiology:Associations with PRKCSH and SEC63 have been described....
, nephronophthisis
Nephronophthisis
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease.The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure.It is a form of...
, Alstrom syndrome
Alstrom syndrome
Alström syndrome is a rare genetic disorder caused by mutations in the gene ALMS1. It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and over 501 known cases in 47 countries. It was first described by Carl-Henry Alström in...
, Meckel–Gruber syndrome and some forms of retinal degeneration
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
.
Hereditary characteristics
The syndrome is familial and is transmitted as an autosomal recessive trait.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 InstituteHoward Hughes Medical InstituteHoward Hughes Medical Institute is a United States non-profit medical research organization based in Chevy Chase, Maryland. It was founded by the American businessman Howard Hughes in 1953. It is one of the largest private funding organizations for biological and medical research in the United...
on the importance and extensive use of cilia and basal bodiesBasal bodyA basal body is an organelle formed from a centriole, and a short cylindrical array of microtubules. It is found at the base of a eukaryotic undulipodium and serves as a nucleation site for the growth of the axoneme microtubules...
in many organ systems of human physiology. Includes multiple specific mentions of BBS. - BBS and loss of the sense of smell at Johns Hopkins UniversityJohns Hopkins UniversityThe Johns Hopkins University, commonly referred to as Johns Hopkins, JHU, or simply Hopkins, is a private research university based in Baltimore, Maryland, United States...
- Overview at United States National Library of MedicineUnited States National Library of MedicineThe United States National Library of Medicine , operated by the United States federal government, is the world's largest medical library. Located in Bethesda, Maryland, the NLM is a division of the National Institutes of Health...
- 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