RARE DISEASE
Bardet-Biedl syndrome
Bardet-Biedl syndrome
Bardet-Biedl syndrome
Synonyms: BBS
Synonyms: BBS
Synonyms: BBS
Drug discovery
5
drugs
With orphan designations
Overview
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by rod-cone dystrophy, obesity, polydactyly, renal anomalies, learning disabilities, and hypogonadism. Caused by mutations in at least 24 genes affecting cilia function, it leads to multisystemic complications. Diagnosis relies on clinical criteria (four major features or three major plus two minor). Management requires a multidisciplinary approach addressing metabolic, renal, and visual impairments, with emerging therapies targeting underlying genetic mechanisms [1][5][12].
Burden
Leading morbidity: progressive vision loss, renal failure (30–50% develop chronic kidney disease), and obesity-related complications (e.g., type 2 diabetes) [1][5][12].
Caregiver burden: 53% of total costs stem from hyperphagia/obesity management, productivity loss, and emotional strain [4][9].
Lifetime societal cost: ~$5.2 million per patient, driven by medical care, reduced QALYs, and premature mortality [4][9].
Therapies
Categories: rare abdominal surgical diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare gastroenterological diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
243 drug discovery papers about Bardet-Biedl syndrome, with 1 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
243 drug discovery papers about Bardet-Biedl syndrome, with 1 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-10-17 | Effect of Tirzepatide in an Adolescent With Early-Onset Obesity, Hyperphagia, and Type 2 Diabetes
Early-onset severe obesity is rare and largely treatment-resistant to standard measures. Etiologies include syndromic disorders (Prader-Willi, Bardet-Biedl and Alström syndromes), monogenic defects of appetite-regulating pathways - most significantly melanocortin-4-receptor (MC4R) deficiency, but also leptin receptor (LEPR), pro-opiomelanocortin (POMC), and secondary hypothalamic injury, most commonly craniopharyngiomas. Most childhood obesity, however, is polygenic, arising from interactions of environmental and genetic factors. In many patients, no clear etiology is identified. Treatment remains challenging, particularly if hyperphagia and reduced satiety are predominant presenting features. We describe the case of a 19-year-old male with a history of autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), type 2 diabetes mellitus (T2DM) and morbid obesity, who showed a clinically significant response to tirzepatide therapy following failed conventional interventions. This case highlights the potential role of dual incretin therapy in adolescents with severe early-onset obesity and hyperphagia, even in the absence (based on present knowledge) of identifiable hypothalamic or genetic pathology.
2025-10-15 | Efficacy of Semaglutide in Pediatric Patients With Bardet-Biedl Syndrome and Alström Syndrome
Abstract Bardet-Biedl syndrome (BBS) and Alström syndrome (AS) are rare autosomal recessive ciliopathies characterized by severe multisystemic involvement, including metabolic, sensory, and developmental impairments. Both conditions result from primary cilia dysfunction, disrupting pathways such as leptin and insulin signaling, which leads to obesity and insulin resistance. While setmelanotide, a melanocortin-4 receptor agonist, may be an effective therapy for obesity in these conditions (especially BBS), its cost limits accessibility for many patients. We describe two pediatric cases (one with BBS and another with AS) demonstrating significant metabolic improvements with semaglutide, a glucagon-like peptide-1 receptor agonist. These observations suggest that some cases of BBS and AS may be treated with semaglutide.
2025-09-01 | OC29 - Genotype over phenotype: the road less travelled in diagnosing Bardet- Biedl syndrome
Abstract Introduction Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder classified under ciliopathies. It typically presents with a combination of features such as retinal dystrophy, polydactyly, renal abnormalities, hypogonadism, intellectual disability, and obesity. While obesity is a hallmark feature, its occurrence in isolation—without other classical manifestations—is uncommon. With advancements in molecular diagnostics, atypical presentations of BBS are being increasingly identified. Purpose This case report highlights a rare phenotype of BBS, where metabolic abnormalities appeared in the absence of traditional clinical signs. Case Summary A 19-year-old male presented with progressive weight gain beginning at age 5. At the time of evaluation, he weighed 135 kg and had a blood pressure of 158/108 mmHg. Clinical examination revealed acanthosis nigricans and multiple skin tags. Notably, he lacked typical BBS features such as polydactyly, retinal dystrophy, genital anomalies, or cognitive impairment. He had normal neurodevelopment and reported no visual issues. Given the early-onset severe obesity and metabolic features, genetic testing was pursued, which identified a pathogenic mutation in the IFT172 gene—associated with BBS20. This confirmed the diagnosis despite the absence of classical clinical features. Treatment and Follow-up Following genetic confirmation and absence of retinal involvement, the patient was initiated on lifestyle modification and oral semaglutide, starting at 3 mg daily with uptitration to 7 mg over six months. Follow-up at 3 months showed a weight reduction of 10 kg, and by 6 months, a total weight loss of 20 kg was achieved. The treatment was well tolerated with a favorable safety profile. Conclusion This case underscores a mild, atypical presentation of Bardet-Biedl Syndrome, manifesting solely with obesity and features of metabolic syndrome. It emphasizes the critical role of genetic testing in evaluating individuals with early- onset obesity, especially when phenotypic hallmarks are absent. Early diagnosis facilitates timely intervention, genetic counselling, and longitudinal monitoring, as additional features of BBS may develop over time.The positive metabolic response to semaglutide underscores its therapeutic potential in syndromic obesity, even in the absence of classical phenotypic markers.
2025-06-24 | Sudden acquired retinal degeneration syndrome may be an acquired primary ciliopathy, phenotypically similar to human Alström and Bardet-Biedl syndromes.
Sudden acquired retinal degeneration syndrome (SARDS) is an acquired canine disease that presents as rapidly progressive retinal degeneration, often accompanied by polyphagia, weight gain, polydipsia, polyuria, and hyposmia. Alström syndrome (AS) and Bardet-Biedl syndrome (BBS) are rare human autosomal recessive genetic disorders marked by progressive retinopathy, polyphagia, obesity, polydipsia, polyuria, and hyposmia, with varying degrees of phenotypic severity. While the etiology of AS and BBS is partially understood, the cause of acquired SARDS remains elusive. Historically, scientific inquiry has focused on an immunologic insult and/or endocrinopathy as the cause of SARDS. Clinicians have often pointed to these Cushingoid symptoms mentioned above in SARDS patients as evidence of a contributing endocrinopathy. However, systemic cortisol concentrations, both pre- and post-ACTH stimulation, typically do not differ appreciably between normal patients and those with SARDS. Blindness due to photoreceptor degeneration, along with the observed Cushingoid symptoms, may result from dysfunctional or absent primary cilia, as documented in human AS and BBS cases. Recognizing SARDS as a possible acquired ciliopathy may be the first step toward seeking effective treatments.
2025-06-16 | Should GLP-1 receptor agonist therapy be used to treat obesity in Bardet-Biedl syndrome?
Bardet-Biedl syndrome (BBS) is a complex genetic condition that can affect multiple organ systems, frequently causing pigmentary retinopathy, renal abnormalities, polydactyly, and obesity. Metabolic disturbances including obesity, unsuppressed appetite, and an increased risk of type 2 diabetes (T2D) present clinical management challenges. In this issue of the JCI, Singh et al. present a mouse model of a specific BBS subtype with genetic deletion of the Bbs5 gene. The model recapitulates many of the clinical features observed in patients living with BBS5 and sheds light on adipocyte biology, as well as the hypothalamic mechanisms driving hunger- and food-seeking behaviors that fuel the adverse metabolic phenotype. Importantly, exogenous GLP-1 receptor agonist treatment suppressed both appetite and weight, opening opportunities for direct translation into the clinical setting.
small molecules
2026-08-01 | Melanocortin-4 Receptor Regulation of Endocrine Axes and Clinical Effects of Setmelanotide.
Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood. In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time. After 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter. Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects. German Federal Ministry of Research and Education and Rhythm Pharmaceuticals.
2026-07-22 | Regulation and adaption of adenylyl cyclases and cAMP signaling networks in brown and beige adipose tissue
β-adrenergic stimulation of brown adipose tissue (BAT) via G-protein coupled receptors (GPCRs) promotes BAT activity by increasing cellular cAMP levels through activating adenylyl cyclase 3 (AC3). We recently demonstrated that upon cold exposure, BAT expresses a truncated AC3 isoform (AC3-AT). Loss of Adcy3-at increases energy expenditure and protects from obesity and ensuing metabolic imbalances. I revealed that AC3-AT is retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and in turn interacts and sequesters AC3, thereby limiting cAMP synthesis. Thus, these findings reveal that AC3-AT acts as a cold-induced rheostat in BAT, limiting cAMP synthesis during chronic BAT activation. To preserve brown adipocyte function and tissue homeostasis, it is crucial to maintain a pool of adipocyte progenitor cells (APCs), which differentiate into mature brown adipocytes. Two distinct APC subpopulations in BAT are platelet-derived growth factor receptor α (PDGFRA)-expressing cells and highly thermogenic transient-receptor potential (TRP) vanilloid 1 (TRPV1) APCs derived from vascular smooth muscle (VSM) cells. One subcellular compartment, enriched with a unique receptor repertoire that has been proposed to play a key role during APC differentiation is the primary cilium. Increasing ciliary cAMP levels, has been shown to promote APC differentiation. Notably, AC3 is predominantly localized in primary cilia of APCs. However, how AC3 regulates ciliary cAMP signaling in brown APCs to control proliferation and differentiation is not known. I demonstrated that loss of AC3 in brown APCs reduces ciliary cAMP synthesis and in turn subpopulation expansion and differentiation. Furthermore, loss of AC3 in highly thermogenic APCs reduced BAT activity during an acute cold stimulus. In contrast increased ciliary AC3 abundance promoted expansion of brown APCs in BAT after cold exposure. My results reveal that AC3-mediated ciliary cAMP signaling is controlling brown APC differentiation and function and, therefore, a crucial regulator of BAT homeostasis. The ciliary dysfunction Bardet-Biedl syndrome (BBS) caused by mutations in one of the BBS genes leads to severe obesity and altered ciliary GPCR composition. Loss of BBS proteins has been associated with impaired thermogenesis and lipid metabolism, and on a cellular level a fate switch to a more fibrogenic phenotype in white APCs. However, whether BBS affects the function of brown APCs is not known. I demonstrated that loss of BBS8 reduces ciliary AC3 abundance in brown APCs and in turn subpopulation expansion and differentiation in BAT. These results reveal that BBS affects ciliary cAMP signaling in brown APCs and thereby alters subpopulation abundance and adipogenesis, and potentially BAT function.
2026-05-20 | Primary Cilia-Mediated GPCR Signaling in Neuroendocrine Physiology
Primary cilia are important signaling organelles found on most cell types in the human body, including neurons and endocrine cells where they are responsible for coordinating diverse signaling pathways for cell-cell communication. Yet, despite their ubiquitous nature, how cilia composition and signaling are regulated across development, physiological inputs, and disease is not fully understood; an overview of cilia function in signaling and disease is provided in Chapter 1. I propose that the primary cilium serves as a dynamic signaling hub whose molecular composition and function are actively remodeled throughout development and under different physiological constraints and that their dysfunction leads to neuroendocrine disease features observed in syndromic ciliopathies.In Chapter 2, I provide results that specifically demonstrate that primary cilia and the BBSome component BBS4 are required for postnatal pituitary development, with loss of ciliary signaling resulting in pituitary hypoplasia, altered gonadotroph fate, and impaired Hedgehog (Hh) signaling.Chapter 3 results focus on cilia within the hypothalamus, where I show that neuronal cilia undergo postnatal remodeling of specific ciliary proteins in an age, sex, and physiological state-dependent manner. This is assessed via changes in ciliary length and frequency and protein composition, including a development associated transition f of proteins enriched in hypothalamic cilia from one (Arl13b) to another (Adcy3). Moreover, I identify physiological condition and receptor specific changes in the localization and morphology of neuronal cilia suggesting that they dynamically adapt to metabolic state.Studies investigating the cellular origins of the ciliopathy Bardet–Biedl syndrome (BBS)–associated hyperphagia are the focus of Chapter 4. Specifically, we uncover a surprising mechanism between receptor cilia localization and signaling efficacy in brain feeding centers of the mouse. BBSome disruption selectively reduces ciliary localization of the downstream effector Adcy3 in MC4R-expressing neurons, despite preserved receptor localization. We next identify PKA-mediated negative feedback as a key regulator of ciliary Adcy3 levels, linking GPCR activity to dynamic control of signaling capacity. Notably, loss of ciliary Adcy3 is age dependent and temporally coincides with the onset of hyperphagia and obesity in BBS models.Inhibition of PKA activity in the hypothalamus also leads to obesity and altered ciliary Adcy3 levels. Thus, across different genetic and physiological obesity paradigms, reduced PKA activity, specifically in MC4R-expressing neurons, emerges as a common theme, suggesting ciliary PKA signaling as a central mediator of anorexigenic control.Together, these studies redefine neuronal primary cilia as adaptive signaling compartments whose function depends on coordinated regulation of receptors, effectors, and feedback mechanisms and their implications and future directions are discussed in Chapter 5. They reveal how disruption of ciliary signaling, not simply GPCR mislocalization, drives neuroendocrine disease and obesity, providing new insight into the pathogenesis of ciliopathies and energy balance disorders. A comprehensive understanding of these processes and mechanisms will reveal additional roles for cilia in other behaviors and how their disruption potentially contributes to other neuroendocrine disorders.
2026-04-21 | A systematic literature review of economic evaluations of setmelanotide.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
2026-04-17 | Setmelanotide in Bardet-Biedl Syndrome: A Case Report.
Setmelanotide is a melanocortin-4-receptor agonist used for the treatment of hyperphagia in the genetic obesity syndrome Bardet-Biedl. Presented is a case of diffuse hyperpigmentation in a patient treated with setmelanotide, which represents the most common side effect of this medication. Herein is a review of the literature for other potential side effects that warrant regular dermatologic screening, including alteration of existing melanocytic lesions. Exact screening guidelines have not been completely defined, though it is recommended that patients receive baseline and annual examinations while undergoing treatment with this agent.
gene therapies
2026-08-14 | Clinical, Genetic, and Endocrine Features of Bardet-Biedl Syndrome in a Pediatric and Adult Cohort.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by clinical and genetic heterogeneity. Data on the prevalence of clinical manifestations and comorbidities in BBS, particularly in pediatric patients, are limited. This study aimed to assess the prevalence and various manifestations of endocrine and other clinical comorbidities among pediatric and adult patients with BBS. This retrospective chart review included pediatric and adult patients with BBS evaluated at an academic tertiary care center in the United States between 2000 and 2024. The study included 31 patients (7 children and 24 adults) with seven identified pathogenic variants associated with BBS. The most common genetic etiology was biallelic variants in BBS1 (36%). Obesity was diagnosed in 86% of children and 100% of adults. No children had diabetes or prediabetes, whereas 46% of adults were affected. Dyslipidemia was identified in 29% of children and 46% of adults. No thyroid abnormalities were identified in children, whereas 25% of adults were affected. Retinal dystrophy was present in 71% of children and 96% of adults. Polydactyly was observed in 100% of children and 75% of adults. Chronic kidney disease was present in 29% of children and 63% of adults. This study highlights the clinical heterogeneity and substantial multisystem burden of BBS across pediatric and adult patients. The greater prevalence of diabetes/prediabetes, dyslipidemia, thyroid abnormalities, chronic kidney disease, and visual impairment among adults suggests that these complications may emerge or progress over time. Early recognition, proactive longitudinal surveillance, and comprehensive multidisciplinary care are essential to optimize management across the lifespan.
2026-01-19 | Retinal Degeneration and Visual Outcomes in Patients With Bardet-Biedl Syndrome: Genotypic Influences From a Caribbean Cohort.
Background The Bardet-Biedl syndrome (BBS) is a rare multisystem ciliopathy characterized by retinal degeneration, polydactyly, truncal obesity, hypogonadism, and hypogonadotropism. Progressive rod-cone dystrophy leads to early-onset vision loss. Despite increased genetic screening, BBS remains underdiagnosed in Caribbean populations. This study aims to describe the genetic and ocular phenotype of patients with BBS in Puerto Rico and explore genotype-phenotype correlations. Methods We conducted a retrospective chart review of 36 genetically confirmed BBS patients from a hereditary retinal disease clinic in Puerto Rico. Data collected included best-corrected visual acuity (BCVA), refractive error, visual field mean deviation (MD), and macular optical coherence tomography (OCT) measurements (volume and thickness). Genetic testing identified the BBS subtype and zygosity. Descriptive and statistical analyses were performed. The study was approved by a certified institutional review board (IRB). Results Age ranged from three to 69 years old. Mutations in the BBS1 gene were most frequent (86%), followed by BBS7 (8%), BBS10 (3%), and BBS19 (3%). Most patients had homozygous mutations in the BBS1 (%). The mean BCVA was 2.0 logMAR OD and 2.1 logMAR OS. Patients with homozygotic mutations in the BBS1 had worse vision than compound heterozygotes (p=0.025). Upon visual field examination, the MD was -27.6 dB OD and -28.3 dB OS. Near-absent visual fields occurred in patients with advanced disease. Macular volume and thickness averaged 8.2 mm³/227 µm (OD) and 7.7 mm³/216 µm (OS). Structural damage was associated with inner/outer segment disruption on OCT. Conclusions Mutations in the BBS1 are the most frequent in Puerto Rico, often associated with profound visual impairment and retinal thinning. These findings underscore the importance of early ophthalmic evaluation and genetic testing in patients with syndromic retinitis pigmentosa. Genotype-specific differences in visual decline support personalized surveillance and future therapeutic planning.
2025-11-02 | Bardet-Biedl Syndrome: Ocular Genetic Trials
Bardet-Biedl Syndrome is a rare genetic disorder with autosomal recessive inheritance that affects multiple organ systems. It is characterized by retinal dystrophy, obesity, polydactyly, renal anomalies, and cognitive impairment, this syndrome prominently involves ocular manifestations, which constitute one of the major sources of morbidity. In the majority of cases, progressive retinal degeneration begins in childhood or early adulthood, leading to significant vision loss. The molecular pathogenesis of BBS is associated with genetic mutations that disrupt the function of primary cilia. These mutations occur in genes encoding structural or regulatory components of the BBSome complex, which plays a crucial role in fundamental cellular processes such as cytoskeletal organization, protein trafficking, and intracellular signaling. In recent years, ocular genetic studies have expanded the spectrum of known mutations through functional analyses, while animal models have provided deeper insights into the molecular mechanisms underlying retinal pathology. From a therapeutic standpoint, gene replacement strategies have shown promising results at the preclinical level; however, the considerable genetic heterogeneity and the multisystemic nature of the syndrome pose challenges for the clinical translation of these approaches.
2025-10-29 | Clinical spectrum of Bardet-Biedl Syndrome: A case series
Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by a wide spectrum of clinical manifestations, including retinal dystrophy, obesity, post-axial polydactyly, learning disabilities, hypogonadism, and renal abnormalities. Early recognition is often challenging due to its gradual progression and overlapping features with other conditions, particularly in resource-limited settings where genetic testing is not readily available. We report a series of four Bangladeshi cases with variable phenotypic expressions of BBS. All patients presented with progressive visual impairment, obesity, and polydactyly, accompanied by additional features such as diabetes mellitus, dyslipidemia, hypogonadism, renal impairment, developmental delay, and behavioral disturbances. Diagnosis was established based on Beales’ clinical criteria, with patients meeting multiple primary and secondary features. Renal involvement was observed in two cases, including diabetic nephropathy and focal segmental glomerulosclerosis, underscoring its role as a major determinant of morbidity and mortality. Management required a multidisciplinary approach involving endocrinology, ophthalmology, nephrology, and mental health services, alongside lifestyle modification, pharmacotherapy, and family counseling. This case series highlights the clinical heterogeneity of BBS, the importance of heightened clinical suspicion for early detection, and the need for comprehensive multidisciplinary care to improve long-term outcomes in affected individuals. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S49]
2025-09-02 | Atypical Retinitis Pigmentosa with Systemic Features in Bardet--Biedl Syndrome
Title:Atypical Retinitis Pigmentosa with Systemic Features in Bardet–Biedl SyndromeAuthor1-Muhammad Umar Ahsan, MBBS E-mail:umarahsan219@gmail.com Affiliation: D.G.Khan medical college, Dera Ghazi Khan, Pakistan ORCID: 0009-0008-0627-2521 2- Dr Saba S
cell therapies
2025-10-22 | Renal Transplant in a Bardet-Biedl Syndrome Patient: A First Case From Azerbaijan.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by multisystem involvement, with renal pathology, including end-stage renal disease, being a major cause of morbidity and mortality. This case report presents a 14-year-old boy with BBS and end-stage renal disease who underwent a successful living donor kidney transplantation, marking the first reported case in Azerbaijan. Despite multiple comorbidities, including obesity, hypertension, and high panel reactive antibody levels, the patient achieved stable graft function with a rapid postoperative creatinine decline. Postoperative management focused on immunosuppression and lifestyle adjustments. This case contributes to the limited literature on BBS, highlighting both the challenges and favorable outcomes of renal transplantation in patients with this rare genetic disorder.
2013-04-01 | Proteomic Analysis of Human Blastocoel Fluid and Blastocyst Cells
Human embryonic stem cells (hESCs) are derived from the inner cell mass (ICM) of the blastocyst and can differentiate into any cell type in the human body. These cells hold a great potential for regenerative medicine, but to obtain enough cells needed for medical treatment, culture is required on a large scale. In the undifferentiated state, hESCs appear to possess an unlimited potential for proliferation, but optimal, defined, and safe culture conditions remain a challenge. The aim of the present study was to identify proteins in the natural environment of undifferentiated hESCs, namely, the blastocoel fluid, which is in contact with all the cells in the blastocyst, including hESCs. Fifty-three surplus human blastocysts were donated after informed consent, and blastocoel fluid was isolated by micromanipulation. Using highly sensitive nano-high-pressure liquid chromatography–tandem mass spectrometry, 286 proteins were identified in the blastocoel fluid and 1,307 proteins in the corresponding cells of the blastocyst. Forty-two were previously uncharacterized proteins—8 of these originated from the blastocoel fluid. Furthermore, several heat shock proteins (Hsp27, Hsp60, Hsc70, and Hsp90) were identified in blastocoel fluid together with zona pellucida proteins (ZP2–4), Vitamin D-binding protein, and Retinol-binding protein 4. Proteins that regulate ciliary assembly and function were also identified, including Bardet-Biedl syndrome protein 7. This study has identified numerous proteins that cells from the ICM of the human blastocyst are exposed to via the blastocoel fluid. These results can be an inspiration for the development of improved culture conditions for hESCs.
other
2025-11-24 | Splice-switching antisense oligonucleotides correct cryptic exon inclusion and restore SDCCAG8 protein in Bardet-Biedl Syndrome.
Bardet-Biedl Syndrome (BBS) is a ciliopathy often associated with progressive blindness and obesity. A patient presenting with BBS was discovered to have two mutations within 55bp of each other in intron 7 of SDCCAG8 (BBS16). One of the biallelic mutations, c.740+356C>T, causes inclusion of cryptic exon(s) containing premature termination codons, while c.740+301G>A has not been characterized. We hypothesized that antisense oligonucleotides (ASOs) complementary to the patient's mutations or to the cryptic exon splice sites would correct the splicing of SDCCAG8 between exons 7 and 8 to prevent cryptic exon inclusion and restore SDCCAG8 expression. We systematically screened 20nt-long ASOs tiled across each mutation and ASOs targeting the 3' splice sites of the cryptic exons in patient-derived fibroblasts, using RT-PCR assays to assess exon 7 and 8 splicing. We identified one ASO for each mutation and a cryptic exon-targeting ASO that restored the splicing pattern to that observed in an unaffected cell line. Lead ASOs were further investigated through RT-PCR, RNA sequencing, and western blotting to confirm ASO-mediated restoration of wild-type transcript and protein. Notably, ASO 20, which targets the cryptic exon 7a/7a' splice site rather than patient-specific mutations, achieved the greatest rescue effect, increasing exon 7-8 splicing from 0% to an average of 26% and restoring SDCCAG8 protein from undetectable levels to approximately 40% of wild-type expression. This mutation-agnostic approach could benefit multiple patients with cryptic exon inclusion in this region of SDCCAG8, expanding therapeutic impact beyond traditional N-of-1 ASO strategies. These findings establish a molecular foundation for clinical development of ASO therapy for BBS caused by SDCCAG8 splicing defects.
2025-07-28 | Analysis of the Body Mass Index of Latino Patients With Bardet-Biedl Syndrome.
Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disorder characterized by multi-systemic manifestations, including truncal obesity, rod-cone dystrophy, polydactyly, and learning disabilities. The syndrome is associated with mutations in at least 28 genes, with BBS1 being the most common. This study investigates the correlation between body mass index (BMI) and specific genetic mutations in a cohort of 27 Latino patients with BBS. A chart review of 27 patients with BBS was conducted. Comprehensive ophthalmic evaluations, including best corrected visual acuity (BCVA), optical coherence tomography, and electroretinography, were performed. Genetic screening was conducted using next-generation sequencing with a focus on BBS1, BBS7, and BBS19 mutations. BMI was classified into normal, overweight, and obese categories. Statistical analyses (chi-square and Kruskal-Wallis test) were used to evaluate the data. The cohort had a mean age of 39 years, with 21 patients (77.8%) carrying mutations in the BBS1 gene. Among the cohort, a total of 14 patients (51.9%) were classified as obese, 10 (37.0%) as overweight, and three (11.1%) as normal weight. Obesity was most common in patients with BBS1 mutations, with 11 obese patients (78.6%) carrying BBS1 mutations, while patients with BBS7 and BBS19 mutations exhibited lower rates of obesity. Among obese patients, 10 (71.4%) were homozygous for mutations in the associated genes, and three (21.4%) were compound heterozygotes. Gender did not show statistically significant differences in obesity prevalence; however, male patients were more frequently overweight. This study confirms a strong association between BBS1 mutations and obesity in BBS patients, with homozygous and compound heterozygous mutations contributing to more severe clinical manifestations. Further research is required to better understand the genotype-phenotype relationship and to explore the role of environmental factors, such as physical activity, in modifying obesity outcomes. Larger, more diverse studies are needed to validate these findings and to develop targeted therapeutic strategies for BBS-related obesity.
proteins
2025-10-17 | Effect of Tirzepatide in an Adolescent With Early-Onset Obesity, Hyperphagia, and Type 2 Diabetes
Early-onset severe obesity is rare and largely treatment-resistant to standard measures. Etiologies include syndromic disorders (Prader-Willi, Bardet-Biedl and Alström syndromes), monogenic defects of appetite-regulating pathways - most significantly melanocortin-4-receptor (MC4R) deficiency, but also leptin receptor (LEPR), pro-opiomelanocortin (POMC), and secondary hypothalamic injury, most commonly craniopharyngiomas. Most childhood obesity, however, is polygenic, arising from interactions of environmental and genetic factors. In many patients, no clear etiology is identified. Treatment remains challenging, particularly if hyperphagia and reduced satiety are predominant presenting features. We describe the case of a 19-year-old male with a history of autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), type 2 diabetes mellitus (T2DM) and morbid obesity, who showed a clinically significant response to tirzepatide therapy following failed conventional interventions. This case highlights the potential role of dual incretin therapy in adolescents with severe early-onset obesity and hyperphagia, even in the absence (based on present knowledge) of identifiable hypothalamic or genetic pathology.
2025-10-15 | Efficacy of Semaglutide in Pediatric Patients With Bardet-Biedl Syndrome and Alström Syndrome
Abstract Bardet-Biedl syndrome (BBS) and Alström syndrome (AS) are rare autosomal recessive ciliopathies characterized by severe multisystemic involvement, including metabolic, sensory, and developmental impairments. Both conditions result from primary cilia dysfunction, disrupting pathways such as leptin and insulin signaling, which leads to obesity and insulin resistance. While setmelanotide, a melanocortin-4 receptor agonist, may be an effective therapy for obesity in these conditions (especially BBS), its cost limits accessibility for many patients. We describe two pediatric cases (one with BBS and another with AS) demonstrating significant metabolic improvements with semaglutide, a glucagon-like peptide-1 receptor agonist. These observations suggest that some cases of BBS and AS may be treated with semaglutide.
2025-09-01 | OC29 - Genotype over phenotype: the road less travelled in diagnosing Bardet- Biedl syndrome
Abstract Introduction Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder classified under ciliopathies. It typically presents with a combination of features such as retinal dystrophy, polydactyly, renal abnormalities, hypogonadism, intellectual disability, and obesity. While obesity is a hallmark feature, its occurrence in isolation—without other classical manifestations—is uncommon. With advancements in molecular diagnostics, atypical presentations of BBS are being increasingly identified. Purpose This case report highlights a rare phenotype of BBS, where metabolic abnormalities appeared in the absence of traditional clinical signs. Case Summary A 19-year-old male presented with progressive weight gain beginning at age 5. At the time of evaluation, he weighed 135 kg and had a blood pressure of 158/108 mmHg. Clinical examination revealed acanthosis nigricans and multiple skin tags. Notably, he lacked typical BBS features such as polydactyly, retinal dystrophy, genital anomalies, or cognitive impairment. He had normal neurodevelopment and reported no visual issues. Given the early-onset severe obesity and metabolic features, genetic testing was pursued, which identified a pathogenic mutation in the IFT172 gene—associated with BBS20. This confirmed the diagnosis despite the absence of classical clinical features. Treatment and Follow-up Following genetic confirmation and absence of retinal involvement, the patient was initiated on lifestyle modification and oral semaglutide, starting at 3 mg daily with uptitration to 7 mg over six months. Follow-up at 3 months showed a weight reduction of 10 kg, and by 6 months, a total weight loss of 20 kg was achieved. The treatment was well tolerated with a favorable safety profile. Conclusion This case underscores a mild, atypical presentation of Bardet-Biedl Syndrome, manifesting solely with obesity and features of metabolic syndrome. It emphasizes the critical role of genetic testing in evaluating individuals with early- onset obesity, especially when phenotypic hallmarks are absent. Early diagnosis facilitates timely intervention, genetic counselling, and longitudinal monitoring, as additional features of BBS may develop over time.The positive metabolic response to semaglutide underscores its therapeutic potential in syndromic obesity, even in the absence of classical phenotypic markers.
2025-06-24 | Sudden acquired retinal degeneration syndrome may be an acquired primary ciliopathy, phenotypically similar to human Alström and Bardet-Biedl syndromes.
Sudden acquired retinal degeneration syndrome (SARDS) is an acquired canine disease that presents as rapidly progressive retinal degeneration, often accompanied by polyphagia, weight gain, polydipsia, polyuria, and hyposmia. Alström syndrome (AS) and Bardet-Biedl syndrome (BBS) are rare human autosomal recessive genetic disorders marked by progressive retinopathy, polyphagia, obesity, polydipsia, polyuria, and hyposmia, with varying degrees of phenotypic severity. While the etiology of AS and BBS is partially understood, the cause of acquired SARDS remains elusive. Historically, scientific inquiry has focused on an immunologic insult and/or endocrinopathy as the cause of SARDS. Clinicians have often pointed to these Cushingoid symptoms mentioned above in SARDS patients as evidence of a contributing endocrinopathy. However, systemic cortisol concentrations, both pre- and post-ACTH stimulation, typically do not differ appreciably between normal patients and those with SARDS. Blindness due to photoreceptor degeneration, along with the observed Cushingoid symptoms, may result from dysfunctional or absent primary cilia, as documented in human AS and BBS cases. Recognizing SARDS as a possible acquired ciliopathy may be the first step toward seeking effective treatments.
2025-06-16 | Should GLP-1 receptor agonist therapy be used to treat obesity in Bardet-Biedl syndrome?
Bardet-Biedl syndrome (BBS) is a complex genetic condition that can affect multiple organ systems, frequently causing pigmentary retinopathy, renal abnormalities, polydactyly, and obesity. Metabolic disturbances including obesity, unsuppressed appetite, and an increased risk of type 2 diabetes (T2D) present clinical management challenges. In this issue of the JCI, Singh et al. present a mouse model of a specific BBS subtype with genetic deletion of the Bbs5 gene. The model recapitulates many of the clinical features observed in patients living with BBS5 and sheds light on adipocyte biology, as well as the hypothalamic mechanisms driving hunger- and food-seeking behaviors that fuel the adverse metabolic phenotype. Importantly, exogenous GLP-1 receptor agonist treatment suppressed both appetite and weight, opening opportunities for direct translation into the clinical setting.
small molecules
2026-08-01 | Melanocortin-4 Receptor Regulation of Endocrine Axes and Clinical Effects of Setmelanotide.
Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood. In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time. After 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter. Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects. German Federal Ministry of Research and Education and Rhythm Pharmaceuticals.
2026-07-22 | Regulation and adaption of adenylyl cyclases and cAMP signaling networks in brown and beige adipose tissue
β-adrenergic stimulation of brown adipose tissue (BAT) via G-protein coupled receptors (GPCRs) promotes BAT activity by increasing cellular cAMP levels through activating adenylyl cyclase 3 (AC3). We recently demonstrated that upon cold exposure, BAT expresses a truncated AC3 isoform (AC3-AT). Loss of Adcy3-at increases energy expenditure and protects from obesity and ensuing metabolic imbalances. I revealed that AC3-AT is retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and in turn interacts and sequesters AC3, thereby limiting cAMP synthesis. Thus, these findings reveal that AC3-AT acts as a cold-induced rheostat in BAT, limiting cAMP synthesis during chronic BAT activation. To preserve brown adipocyte function and tissue homeostasis, it is crucial to maintain a pool of adipocyte progenitor cells (APCs), which differentiate into mature brown adipocytes. Two distinct APC subpopulations in BAT are platelet-derived growth factor receptor α (PDGFRA)-expressing cells and highly thermogenic transient-receptor potential (TRP) vanilloid 1 (TRPV1) APCs derived from vascular smooth muscle (VSM) cells. One subcellular compartment, enriched with a unique receptor repertoire that has been proposed to play a key role during APC differentiation is the primary cilium. Increasing ciliary cAMP levels, has been shown to promote APC differentiation. Notably, AC3 is predominantly localized in primary cilia of APCs. However, how AC3 regulates ciliary cAMP signaling in brown APCs to control proliferation and differentiation is not known. I demonstrated that loss of AC3 in brown APCs reduces ciliary cAMP synthesis and in turn subpopulation expansion and differentiation. Furthermore, loss of AC3 in highly thermogenic APCs reduced BAT activity during an acute cold stimulus. In contrast increased ciliary AC3 abundance promoted expansion of brown APCs in BAT after cold exposure. My results reveal that AC3-mediated ciliary cAMP signaling is controlling brown APC differentiation and function and, therefore, a crucial regulator of BAT homeostasis. The ciliary dysfunction Bardet-Biedl syndrome (BBS) caused by mutations in one of the BBS genes leads to severe obesity and altered ciliary GPCR composition. Loss of BBS proteins has been associated with impaired thermogenesis and lipid metabolism, and on a cellular level a fate switch to a more fibrogenic phenotype in white APCs. However, whether BBS affects the function of brown APCs is not known. I demonstrated that loss of BBS8 reduces ciliary AC3 abundance in brown APCs and in turn subpopulation expansion and differentiation in BAT. These results reveal that BBS affects ciliary cAMP signaling in brown APCs and thereby alters subpopulation abundance and adipogenesis, and potentially BAT function.
2026-05-20 | Primary Cilia-Mediated GPCR Signaling in Neuroendocrine Physiology
Primary cilia are important signaling organelles found on most cell types in the human body, including neurons and endocrine cells where they are responsible for coordinating diverse signaling pathways for cell-cell communication. Yet, despite their ubiquitous nature, how cilia composition and signaling are regulated across development, physiological inputs, and disease is not fully understood; an overview of cilia function in signaling and disease is provided in Chapter 1. I propose that the primary cilium serves as a dynamic signaling hub whose molecular composition and function are actively remodeled throughout development and under different physiological constraints and that their dysfunction leads to neuroendocrine disease features observed in syndromic ciliopathies.In Chapter 2, I provide results that specifically demonstrate that primary cilia and the BBSome component BBS4 are required for postnatal pituitary development, with loss of ciliary signaling resulting in pituitary hypoplasia, altered gonadotroph fate, and impaired Hedgehog (Hh) signaling.Chapter 3 results focus on cilia within the hypothalamus, where I show that neuronal cilia undergo postnatal remodeling of specific ciliary proteins in an age, sex, and physiological state-dependent manner. This is assessed via changes in ciliary length and frequency and protein composition, including a development associated transition f of proteins enriched in hypothalamic cilia from one (Arl13b) to another (Adcy3). Moreover, I identify physiological condition and receptor specific changes in the localization and morphology of neuronal cilia suggesting that they dynamically adapt to metabolic state.Studies investigating the cellular origins of the ciliopathy Bardet–Biedl syndrome (BBS)–associated hyperphagia are the focus of Chapter 4. Specifically, we uncover a surprising mechanism between receptor cilia localization and signaling efficacy in brain feeding centers of the mouse. BBSome disruption selectively reduces ciliary localization of the downstream effector Adcy3 in MC4R-expressing neurons, despite preserved receptor localization. We next identify PKA-mediated negative feedback as a key regulator of ciliary Adcy3 levels, linking GPCR activity to dynamic control of signaling capacity. Notably, loss of ciliary Adcy3 is age dependent and temporally coincides with the onset of hyperphagia and obesity in BBS models.Inhibition of PKA activity in the hypothalamus also leads to obesity and altered ciliary Adcy3 levels. Thus, across different genetic and physiological obesity paradigms, reduced PKA activity, specifically in MC4R-expressing neurons, emerges as a common theme, suggesting ciliary PKA signaling as a central mediator of anorexigenic control.Together, these studies redefine neuronal primary cilia as adaptive signaling compartments whose function depends on coordinated regulation of receptors, effectors, and feedback mechanisms and their implications and future directions are discussed in Chapter 5. They reveal how disruption of ciliary signaling, not simply GPCR mislocalization, drives neuroendocrine disease and obesity, providing new insight into the pathogenesis of ciliopathies and energy balance disorders. A comprehensive understanding of these processes and mechanisms will reveal additional roles for cilia in other behaviors and how their disruption potentially contributes to other neuroendocrine disorders.
2026-04-21 | A systematic literature review of economic evaluations of setmelanotide.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
2026-04-17 | Setmelanotide in Bardet-Biedl Syndrome: A Case Report.
Setmelanotide is a melanocortin-4-receptor agonist used for the treatment of hyperphagia in the genetic obesity syndrome Bardet-Biedl. Presented is a case of diffuse hyperpigmentation in a patient treated with setmelanotide, which represents the most common side effect of this medication. Herein is a review of the literature for other potential side effects that warrant regular dermatologic screening, including alteration of existing melanocytic lesions. Exact screening guidelines have not been completely defined, though it is recommended that patients receive baseline and annual examinations while undergoing treatment with this agent.
gene therapies
2026-08-14 | Clinical, Genetic, and Endocrine Features of Bardet-Biedl Syndrome in a Pediatric and Adult Cohort.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by clinical and genetic heterogeneity. Data on the prevalence of clinical manifestations and comorbidities in BBS, particularly in pediatric patients, are limited. This study aimed to assess the prevalence and various manifestations of endocrine and other clinical comorbidities among pediatric and adult patients with BBS. This retrospective chart review included pediatric and adult patients with BBS evaluated at an academic tertiary care center in the United States between 2000 and 2024. The study included 31 patients (7 children and 24 adults) with seven identified pathogenic variants associated with BBS. The most common genetic etiology was biallelic variants in BBS1 (36%). Obesity was diagnosed in 86% of children and 100% of adults. No children had diabetes or prediabetes, whereas 46% of adults were affected. Dyslipidemia was identified in 29% of children and 46% of adults. No thyroid abnormalities were identified in children, whereas 25% of adults were affected. Retinal dystrophy was present in 71% of children and 96% of adults. Polydactyly was observed in 100% of children and 75% of adults. Chronic kidney disease was present in 29% of children and 63% of adults. This study highlights the clinical heterogeneity and substantial multisystem burden of BBS across pediatric and adult patients. The greater prevalence of diabetes/prediabetes, dyslipidemia, thyroid abnormalities, chronic kidney disease, and visual impairment among adults suggests that these complications may emerge or progress over time. Early recognition, proactive longitudinal surveillance, and comprehensive multidisciplinary care are essential to optimize management across the lifespan.
2026-01-19 | Retinal Degeneration and Visual Outcomes in Patients With Bardet-Biedl Syndrome: Genotypic Influences From a Caribbean Cohort.
Background The Bardet-Biedl syndrome (BBS) is a rare multisystem ciliopathy characterized by retinal degeneration, polydactyly, truncal obesity, hypogonadism, and hypogonadotropism. Progressive rod-cone dystrophy leads to early-onset vision loss. Despite increased genetic screening, BBS remains underdiagnosed in Caribbean populations. This study aims to describe the genetic and ocular phenotype of patients with BBS in Puerto Rico and explore genotype-phenotype correlations. Methods We conducted a retrospective chart review of 36 genetically confirmed BBS patients from a hereditary retinal disease clinic in Puerto Rico. Data collected included best-corrected visual acuity (BCVA), refractive error, visual field mean deviation (MD), and macular optical coherence tomography (OCT) measurements (volume and thickness). Genetic testing identified the BBS subtype and zygosity. Descriptive and statistical analyses were performed. The study was approved by a certified institutional review board (IRB). Results Age ranged from three to 69 years old. Mutations in the BBS1 gene were most frequent (86%), followed by BBS7 (8%), BBS10 (3%), and BBS19 (3%). Most patients had homozygous mutations in the BBS1 (%). The mean BCVA was 2.0 logMAR OD and 2.1 logMAR OS. Patients with homozygotic mutations in the BBS1 had worse vision than compound heterozygotes (p=0.025). Upon visual field examination, the MD was -27.6 dB OD and -28.3 dB OS. Near-absent visual fields occurred in patients with advanced disease. Macular volume and thickness averaged 8.2 mm³/227 µm (OD) and 7.7 mm³/216 µm (OS). Structural damage was associated with inner/outer segment disruption on OCT. Conclusions Mutations in the BBS1 are the most frequent in Puerto Rico, often associated with profound visual impairment and retinal thinning. These findings underscore the importance of early ophthalmic evaluation and genetic testing in patients with syndromic retinitis pigmentosa. Genotype-specific differences in visual decline support personalized surveillance and future therapeutic planning.
2025-11-02 | Bardet-Biedl Syndrome: Ocular Genetic Trials
Bardet-Biedl Syndrome is a rare genetic disorder with autosomal recessive inheritance that affects multiple organ systems. It is characterized by retinal dystrophy, obesity, polydactyly, renal anomalies, and cognitive impairment, this syndrome prominently involves ocular manifestations, which constitute one of the major sources of morbidity. In the majority of cases, progressive retinal degeneration begins in childhood or early adulthood, leading to significant vision loss. The molecular pathogenesis of BBS is associated with genetic mutations that disrupt the function of primary cilia. These mutations occur in genes encoding structural or regulatory components of the BBSome complex, which plays a crucial role in fundamental cellular processes such as cytoskeletal organization, protein trafficking, and intracellular signaling. In recent years, ocular genetic studies have expanded the spectrum of known mutations through functional analyses, while animal models have provided deeper insights into the molecular mechanisms underlying retinal pathology. From a therapeutic standpoint, gene replacement strategies have shown promising results at the preclinical level; however, the considerable genetic heterogeneity and the multisystemic nature of the syndrome pose challenges for the clinical translation of these approaches.
2025-10-29 | Clinical spectrum of Bardet-Biedl Syndrome: A case series
Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by a wide spectrum of clinical manifestations, including retinal dystrophy, obesity, post-axial polydactyly, learning disabilities, hypogonadism, and renal abnormalities. Early recognition is often challenging due to its gradual progression and overlapping features with other conditions, particularly in resource-limited settings where genetic testing is not readily available. We report a series of four Bangladeshi cases with variable phenotypic expressions of BBS. All patients presented with progressive visual impairment, obesity, and polydactyly, accompanied by additional features such as diabetes mellitus, dyslipidemia, hypogonadism, renal impairment, developmental delay, and behavioral disturbances. Diagnosis was established based on Beales’ clinical criteria, with patients meeting multiple primary and secondary features. Renal involvement was observed in two cases, including diabetic nephropathy and focal segmental glomerulosclerosis, underscoring its role as a major determinant of morbidity and mortality. Management required a multidisciplinary approach involving endocrinology, ophthalmology, nephrology, and mental health services, alongside lifestyle modification, pharmacotherapy, and family counseling. This case series highlights the clinical heterogeneity of BBS, the importance of heightened clinical suspicion for early detection, and the need for comprehensive multidisciplinary care to improve long-term outcomes in affected individuals. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S49]
2025-09-02 | Atypical Retinitis Pigmentosa with Systemic Features in Bardet--Biedl Syndrome
Title:Atypical Retinitis Pigmentosa with Systemic Features in Bardet–Biedl SyndromeAuthor1-Muhammad Umar Ahsan, MBBS E-mail:umarahsan219@gmail.com Affiliation: D.G.Khan medical college, Dera Ghazi Khan, Pakistan ORCID: 0009-0008-0627-2521 2- Dr Saba S
cell therapies
2025-10-22 | Renal Transplant in a Bardet-Biedl Syndrome Patient: A First Case From Azerbaijan.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by multisystem involvement, with renal pathology, including end-stage renal disease, being a major cause of morbidity and mortality. This case report presents a 14-year-old boy with BBS and end-stage renal disease who underwent a successful living donor kidney transplantation, marking the first reported case in Azerbaijan. Despite multiple comorbidities, including obesity, hypertension, and high panel reactive antibody levels, the patient achieved stable graft function with a rapid postoperative creatinine decline. Postoperative management focused on immunosuppression and lifestyle adjustments. This case contributes to the limited literature on BBS, highlighting both the challenges and favorable outcomes of renal transplantation in patients with this rare genetic disorder.
2013-04-01 | Proteomic Analysis of Human Blastocoel Fluid and Blastocyst Cells
Human embryonic stem cells (hESCs) are derived from the inner cell mass (ICM) of the blastocyst and can differentiate into any cell type in the human body. These cells hold a great potential for regenerative medicine, but to obtain enough cells needed for medical treatment, culture is required on a large scale. In the undifferentiated state, hESCs appear to possess an unlimited potential for proliferation, but optimal, defined, and safe culture conditions remain a challenge. The aim of the present study was to identify proteins in the natural environment of undifferentiated hESCs, namely, the blastocoel fluid, which is in contact with all the cells in the blastocyst, including hESCs. Fifty-three surplus human blastocysts were donated after informed consent, and blastocoel fluid was isolated by micromanipulation. Using highly sensitive nano-high-pressure liquid chromatography–tandem mass spectrometry, 286 proteins were identified in the blastocoel fluid and 1,307 proteins in the corresponding cells of the blastocyst. Forty-two were previously uncharacterized proteins—8 of these originated from the blastocoel fluid. Furthermore, several heat shock proteins (Hsp27, Hsp60, Hsc70, and Hsp90) were identified in blastocoel fluid together with zona pellucida proteins (ZP2–4), Vitamin D-binding protein, and Retinol-binding protein 4. Proteins that regulate ciliary assembly and function were also identified, including Bardet-Biedl syndrome protein 7. This study has identified numerous proteins that cells from the ICM of the human blastocyst are exposed to via the blastocoel fluid. These results can be an inspiration for the development of improved culture conditions for hESCs.
other
2025-11-24 | Splice-switching antisense oligonucleotides correct cryptic exon inclusion and restore SDCCAG8 protein in Bardet-Biedl Syndrome.
Bardet-Biedl Syndrome (BBS) is a ciliopathy often associated with progressive blindness and obesity. A patient presenting with BBS was discovered to have two mutations within 55bp of each other in intron 7 of SDCCAG8 (BBS16). One of the biallelic mutations, c.740+356C>T, causes inclusion of cryptic exon(s) containing premature termination codons, while c.740+301G>A has not been characterized. We hypothesized that antisense oligonucleotides (ASOs) complementary to the patient's mutations or to the cryptic exon splice sites would correct the splicing of SDCCAG8 between exons 7 and 8 to prevent cryptic exon inclusion and restore SDCCAG8 expression. We systematically screened 20nt-long ASOs tiled across each mutation and ASOs targeting the 3' splice sites of the cryptic exons in patient-derived fibroblasts, using RT-PCR assays to assess exon 7 and 8 splicing. We identified one ASO for each mutation and a cryptic exon-targeting ASO that restored the splicing pattern to that observed in an unaffected cell line. Lead ASOs were further investigated through RT-PCR, RNA sequencing, and western blotting to confirm ASO-mediated restoration of wild-type transcript and protein. Notably, ASO 20, which targets the cryptic exon 7a/7a' splice site rather than patient-specific mutations, achieved the greatest rescue effect, increasing exon 7-8 splicing from 0% to an average of 26% and restoring SDCCAG8 protein from undetectable levels to approximately 40% of wild-type expression. This mutation-agnostic approach could benefit multiple patients with cryptic exon inclusion in this region of SDCCAG8, expanding therapeutic impact beyond traditional N-of-1 ASO strategies. These findings establish a molecular foundation for clinical development of ASO therapy for BBS caused by SDCCAG8 splicing defects.
2025-07-28 | Analysis of the Body Mass Index of Latino Patients With Bardet-Biedl Syndrome.
Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disorder characterized by multi-systemic manifestations, including truncal obesity, rod-cone dystrophy, polydactyly, and learning disabilities. The syndrome is associated with mutations in at least 28 genes, with BBS1 being the most common. This study investigates the correlation between body mass index (BMI) and specific genetic mutations in a cohort of 27 Latino patients with BBS. A chart review of 27 patients with BBS was conducted. Comprehensive ophthalmic evaluations, including best corrected visual acuity (BCVA), optical coherence tomography, and electroretinography, were performed. Genetic screening was conducted using next-generation sequencing with a focus on BBS1, BBS7, and BBS19 mutations. BMI was classified into normal, overweight, and obese categories. Statistical analyses (chi-square and Kruskal-Wallis test) were used to evaluate the data. The cohort had a mean age of 39 years, with 21 patients (77.8%) carrying mutations in the BBS1 gene. Among the cohort, a total of 14 patients (51.9%) were classified as obese, 10 (37.0%) as overweight, and three (11.1%) as normal weight. Obesity was most common in patients with BBS1 mutations, with 11 obese patients (78.6%) carrying BBS1 mutations, while patients with BBS7 and BBS19 mutations exhibited lower rates of obesity. Among obese patients, 10 (71.4%) were homozygous for mutations in the associated genes, and three (21.4%) were compound heterozygotes. Gender did not show statistically significant differences in obesity prevalence; however, male patients were more frequently overweight. This study confirms a strong association between BBS1 mutations and obesity in BBS patients, with homozygous and compound heterozygous mutations contributing to more severe clinical manifestations. Further research is required to better understand the genotype-phenotype relationship and to explore the role of environmental factors, such as physical activity, in modifying obesity outcomes. Larger, more diverse studies are needed to validate these findings and to develop targeted therapeutic strategies for BBS-related obesity.
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Drug Discovery Landscape
5 orphan drug designations for Bardet-Biedl syndrome, including 2 approved therapies.
5 orphan drug designations for Bardet-Biedl syndrome, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant, replication incompetent adeno-associated virus viral vector platform with a serotype 8 capsid and a cDNA encoding the human BBS10 gene (AAV8-RK-BBS10) | gene therapies | FDA | 2024-10-11 | — | MeiraGTx UK II Ltd |
adeno-associated virus 2/8 expressing human BBS1 gene | gene therapies | FDA | 2020-10-16 | — | Axovia Therapeutics |
adeno-associated virus 2/9 expressing human BBS1 gene | gene therapies | FDA | 2020-10-16 | — | Axovia Therapeutics |
setmelanotide [Imcivree] | small molecules | FDA | 2019-09-19 | 2022-06-16 | Rhythm Pharmaceuticals, Inc |
Setmelanotide [Imcivree] | small molecules | EMA | 2019-08-21 | 2022-09-05 | Rhythm Pharmaceuticals Netherlands B.V. |
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