Bardet–Biedl syndrome
A ciliopathic genetic disorder affecting multiple body systems.
Bardet–Biedl syndrome (BBS) is a genetic disorder caused by defects in cellular cilia, affecting multiple body systems. Its main features include rod-cone dystrophy, extra fingers or toes, central obesity, underdeveloped reproductive organs, and sometimes kidney problems. While learning difficulties were once considered a core symptom, this is no longer the case.
The condition varies widely in severity, even within the same family. The most common signs are childhood-onset night blindness that progresses to severe vision loss; extra digits on the hands or feet; obesity that starts in infancy and persists; varying degrees of intellectual disability; underdeveloped genitals in males and complex urinary tract malformations in females; and kidney dysfunction, which is a major cause of illness and death. Additional features can include crossed eyes, cataracts, astigmatism, retinal degeneration, and blindness due to faulty transport in the retina’s light-sensing cells. Short or fused fingers and toes are common, especially webbing between the second and third toes. Other possible issues include excessive thirst and urination, poor coordination, mild muscle stiffness (mainly in the legs), diabetes, liver problems, loss of smell, hearing loss, Hirschsprung disease, heart abnormalities, and speech or motor delays.
BBS is now recognized as a ciliopathy—a group of disorders linked to faulty cilia. Other ciliopathies include primary ciliary dyskinesia, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome, and some forms of retinal degeneration. The underlying biochemical mechanism is not fully understood. The proteins produced by BBS genes are located at the base and within cilia. Studies in roundworms showed these proteins are involved in intraflagellar transport (IFT), a process that moves materials along cilia and is essential for their formation and maintenance. In humans, these proteins form a complex called the BBSome, which is thought to shuttle vesicles to the cilia base and support ciliary function. Defects in cilia are known to cause many symptoms seen in BBS, so it is widely accepted that mutations in BBS genes disrupt normal cilia function. The retinal degeneration common in BBS may result from impaired IFT in the cilia of photoreceptor cells.
- Field
- Medical genetics
- Known for
- Pleiotropic ciliopathy with rod–cone dystrophy, polydactyly, truncal obesity, learning disabilities, hypogenitalism, and renal dysfunction
- Genes identified
- 26 as of 2024
- First reported cases
- Georges Bardet (1920) and Arthur Biedl (1922)
- Earliest known case
- Laurence and Moon (1866)
Lore & Background
Bardet–Biedl syndrome is a pleiotropic disorder with variable expressivity and a wide range of clinical variability observed both within and between families. The most common clinical features are rod–cone dystrophy, with childhood-onset night-blindness followed by increasing visual loss; postaxial polydactyly; truncal obesity that manifests during infancy and remains problematic throughout adulthood; varying degrees of learning disabilities; male hypogenitalism and complex female genitourinary malformations; and renal dysfunction, a major cause of morbidity and mortality. Secondary features include strabismus, cataracts, astigmatism, pigmentary retinopathy, poor visual acuity, low vision, and/or blindness caused by an impaired photoreceptor transport mechanism in the retina; brachydactyly, syndactyly of both the hands and feet; polyuria/polydipsia; ataxia/poor coordination/imbalance; mild hypertonia; diabetes mellitus; hepatic involvement; anosmia; auditory deficiencies; Hirschsprung disease; hypertrophy of interventricular septum and left ventricle; dilated cardiomyopathy; hypogonadism; kidney failure; urogenital sinuses; ectopic urethra; uterus duplex; septate vagina; hypoplasia of the uterus, ovaries, and fallopian tubes; speech disorder/delay; and developmental delay, especially of fine and gross motor skills.
Reader's Guide
Bardet–Biedl syndrome is significant as a ciliopathy, a class of disorders caused by defects in the cellular ciliary structure. Findings in genetic research published in 2006 suggested that many genetic disorders previously not identified as related may be highly related in their genotypical root cause, and BBS is one such syndrome. The gene products encoded by 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 intraflagellar transport (IFT), a bi-directional transportation activity within the cilia essential for ciliogenesis and the maintenance of cilia. Recent biochemical analysis of human BBS proteins revealed that BBS proteins are assembled into a multiple protein complex called 'BBSome,' proposed to be responsible for transporting intracellular vesicles to the base of the cilia. A theory that photoreceptor cells are nourished by the IFT of retinal cilia offers a potential explanation for the retinal dystrophy common in BBS patients. As of 2024, 26 different genes had been identified. There is currently no comprehensive treatment for all symptoms, but setmelanotide was approved for treatment of obesity and hunger control associated with genetically confirmed BBS by the European Medicines Agency in 2021 and for weight management in patients aged 6 or older by the FDA in 2022. Gene therapies for retinal degeneration are in development for at least two BBS genes.
Did You Know?
- Bardet–Biedl syndrome is a ciliopathic human genetic disorder that produces many effects and affects many body systems.
- The most common clinical features include rod–cone dystrophy, postaxial polydactyly, truncal obesity, varying degrees of learning disabilities, male hypogenitalism, and renal dysfunction.
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