Bardet-Biedl syndrome (BBS) is a rare autosomal recessive multisystem ciliopathy caused by mutations in genes involved in primary cilia function. It was independently described by Bardet in 1920 and Biedl in 1922 1, 6).
It is the second most common cause of syndromic retinitis pigmentosa (RP) after Usher syndrome, and along with Usher syndrome, BBS is one of the most prevalent syndromic hereditary retinal degenerations 9). The typical age of diagnosis is 8–9 years 2), and symptoms appear asynchronously and progress throughout life 9).
The prevalence is 1:140,000 to 1:160,000 in North America and Europe1, 8). It is higher in populations with a founder effect, reaching 1:3,700 in the Faroe Islands and 1:13,500 among the Bedouin in Kuwait7). Consanguinity increases the risk of homozygosity1), and in Saudi Arabia, 48% of BBS patients have a history of consanguineous marriage7).
Approximately 30 causative genes have been identified9), with BBS1 (23%), BBS10 (15%), and BBS2 (10%) being the most common, accounting for about 50% of all cases4). Inheritance is mainly autosomal recessive (biallelic loss-of-function), but oligogenic and triallelic inheritance may act as modifiers in some cases9).
Clinical diagnostic criteria require either 4 major findings or 3 major findings plus 2 minor findings1).
The major findings and their frequencies are as follows1):
| Major Findings | Frequency |
|---|---|
| Retinal degeneration | 93% |
| Truncal obesity | 72–92% |
| Postaxial polydactyly | 63–81% |
| Cognitive impairment | 61% |
| Hypogonadism | 59–98% |
| Renal abnormalities | 53% |
Secondary findings include speech disorders, strabismus, cataracts, iris coloboma, type 2 diabetes, dental abnormalities, heart malformations, and short stature.
Laurence-Moon syndrome (LMS) is characterized by spastic paraplegia, while BBS is characterized by polydactyly and renal abnormalities 5). They were once considered the same disease but are now treated as separate entities.
Night blindness is the first subjective symptom, and visual dysfunction appears within the first decade of life.
Legal blindness typically occurs in the 20s to 30s, but some reports indicate legal blindness at an average age of 15.5 years 3). Over 90% have rod-cone dystrophy (inherited retinal degeneration, IRD) 9).
Ophthalmic Findings
Macular atrophy: Atrophic changes in the macula occurring early.
Pigmentary degeneration: Pigmentary degeneration with vascular attenuation. Most commonly pigment spots without bone-spicule configuration.
Waxy disc pallor: Waxy optic disc pallor 1, 6)
Bull’s eye maculopathy: Bull’s eye maculopathy 1)
Vascular attenuation: Generalized arterial narrowing 1, 6)
Perivascular pigmentation: Bone-spicule pigment clumping 1, 6)
Systemic Findings
Early obesity: Normal birth weight, rapid weight gain within the first year 2)
Postaxial polydactyly: Present in 63–81% 1)
Cognitive impairment: IQ ≤79 in 44% 1)
Renal impairment: Structural or functional abnormalities, 30–50% 9)
Hypogonadism: More pronounced in males 9)
Autistic behaviors: observed in 77% of patients2)
Nystagmus is present in about 10% of patients, and strabismus, cataracts, severe corneal astigmatism, and chorioretinal coloboma may also occur. Electroretinography (ERG) shows a mixed rod-cone pattern with attenuation of both a- and b-waves in both scotopic and photopic conditions, with rods tending to be more severely affected than cones7).
Systemically, about 90% of patients exhibit hyperphagia and abnormal fat accumulation9), and rapid weight gain within the first 5 years of life can lead to metabolic syndrome9). Type 2 diabetes mellitus occurs in 6–48% of patients1). The average age at menarche in females is reported to be 13.8 years8).
Legal blindness usually occurs in the 20s to 30s, although some studies report legal blindness at an average age of 15.5 years3). The progression pattern varies among individuals and also depends on the genotype. Early introduction of low vision care is important.
The underlying cause of BBS is dysfunction of primary cilia. Primary cilia are present in almost all cells and are essential structures for receiving and transmitting extracellular signals9).
Approximately 30 causative genes have been identified9), and the encoded proteins are broadly classified into the following three groups.
The most common mutation type is single nucleotide variant (SNV), followed by small insertions/deletions and copy number variations9). Oligogenic and triallelic inheritance can act as modifiers of the phenotype9).
Consanguinity is the greatest risk factor1). If prenatal ultrasound reveals hyperechoic kidneys, renal cysts, hydronephrosis, or polydactyly, BBS should be considered in the differential diagnosis3).
BBS is an autosomal recessive disorder; if both parents are carriers, 25% of children will develop the condition. Prenatal genetic diagnosis is technically possible 9) and can provide useful information for family planning decisions.
Clinical diagnosis is possible with 4 major findings, or 3 major findings plus 2 minor findings 1). Polydactyly and kidney abnormalities can be identified prenatally and at birth 3).
It is necessary to differentiate from diseases that present with clinical features similar to BBS8).
| Disease | Key differentiating points |
|---|---|
| Alström syndrome | No polydactyly, hearing loss present |
| Usher syndrome | Hearing impairment is predominant |
| Joubert syndrome | Cerebellar vermis hypoplasia |
| Senior-Løken syndrome | Kidney and retina only |
| LCA | Severe visual impairment from early infancy |
There is no curative treatment for BBS, and multidisciplinary management by multiple specialists is essential9). Early intervention for each complication affects quality of life and life prognosis.
Setmelanotide (Imcivree) is a melanocortin 4 receptor (MC4R) agonist that acts on hypothalamic circuits to reduce hyperphagia and promote weight loss 9). It was approved for BBS-associated obesity in 2022 2).
In a phase 3 trial, patients aged 18 years and older experienced a mean weight reduction of −7.6%, while those under 18 years showed a mean decrease in BMI z-score of −0.75 2).
Dietary therapy recommends a combination of low-calorie, carbohydrate-restricted diet and aerobic exercise 6). A low-protein diet is considered effective for renal protection 8).
Regular ophthalmologic evaluation from early childhood is necessary. Correction of refractive errors 7) and early referral to low-vision services are important. Currently, there is no treatment to halt progression; utilization of visual aids and early planning for special education are essential.
Renal failure is a major cause of death in BBS, accounting for 25% of deaths by age 44 6). Renal replacement therapy (hemodialysis, peritoneal dialysis, kidney transplantation) is all applicable 6). Early renal function screening and regular follow-up are directly linked to life prognosis 6).
Surgical Interventions
Polydactyly excision: Surgical removal performed early after birth 6)
Intervention for gonadal abnormalities: Surgical management for conditions such as cryptorchidism 9)
Medical Management
Diabetes management: Monitor for development of type 2 diabetes and assess blood glucose regularly 1)
Cardiovascular management: Early screening for cardiovascular abnormalities 9)
Developmental support: Early intervention and educational support for cognitive and learning disabilities
Setmelanotide is an MC4R (melanocortin 4 receptor) agonist that acts on hypothalamic circuits to suppress hyperphagia and promote weight loss 9). It was approved for BBS-related obesity in 2022 2). Phase 3 trials reported significant improvements: weight −7.6% in adults and BMI z-score −0.75 in children 2).
The multi-organ dysfunction in BBS results from widespread impairment of signaling mediated by primary cilia.
The BBSome is an adapter complex for intraflagellar transport, and its main function is to transport G protein-coupled receptors (GPCRs) to cilia 9). Cargo includes MCH receptor, NPY receptor, somatostatin receptor 3 (SSTR3), etc. 9), and BBS1 plays a central role in cargo binding 9).
BBSome impairment disrupts intraflagellar transport of phototransduction proteins (e.g., rhodopsin), leading to progressive photoreceptor degeneration 9). In BBS mutant mice, rhodopsin accumulates in the inner segment and cell body rather than the outer segment. Altered lipid balance and protein mislocalization further exacerbate retinal degeneration 9).
Impaired transport of neuroreceptors (leptin receptor, NPY2R, 5-HT2CR) to cilia disrupts hypothalamic signaling, leading to hyperphagia and obesity 9). BBSome dysfunction reduces membrane expression of leptin receptors, resulting in dysfunction of appetite-suppressing signals 2). Suppression of BBS10/BBS12 expression weakens ciliogenesis and activates GSK3/PPARγ-related adipogenic pathways 2).
Mislocalization of polycystin 1/2 causes nephropathy 9), and renal structural and functional abnormalities occur in 30–50% of cases 9).
Alterations in Hedgehog signaling are involved in developmental abnormalities of the limbs and nervous system 9).
Primary cilia are signal-receiving structures present in almost all cells 9). Dysfunction of the BBSome impairs the transport of multiple receptors (GPCRs, leptin receptor, etc.), thereby disrupting signal transduction in a wide range of organs including the retina, kidneys, hypothalamus, limbs, and reproductive organs.
In animal models, gene therapy using AAV vectors (subretinal injection) has been shown to partially restore photoreceptor function. In early 2025, Viralgen and Axovia announced a partnership to manufacture AAV-9-based gene therapy drugs. Clinical development of gene therapy for retinal degeneration is ongoing.
The approval of setmelanotide (2022) is based on a phase 3 trial showing that intervention in the hypothalamic circuit with an MC4R agonist is effective for BBS obesity 2).
The potential application of GLP-1 receptor agonists (glucagon-like peptide-1 receptor agonists) for obesity and metabolic complications is also being studied.
Based on genetic diversity across approximately 30 genes, research on genotype-phenotype correlations is advancing9). The development of targeted therapies for specific genetic mutations is anticipated.
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