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Journal of Pediatric Genetics Jun 2013Bardet-Biedl syndrome (BBS) is a rare multisystem genetic disease, with high phenotypic and genetic heterogeneity. Rod-cone dystrophy, obesity, polydactyly,... (Review)
Review
Bardet-Biedl syndrome (BBS) is a rare multisystem genetic disease, with high phenotypic and genetic heterogeneity. Rod-cone dystrophy, obesity, polydactyly, hypogonadism, cognitive impairment and renal abnormalities have been established as primary features. There are 17 BBS genes (BBS1-BBS17) described to date, which explain 70-80% of the patients clinically diagnosed, therefore more BBS genes remain to be identified. BBS belongs to a group of diseases known as ciliopathies. In general, ciliopathies and BBS in particular share a partial overlapping phenotype that makes them complicated to diagnose. We present an up-to-date review including clinical, epidemiologic and genetic aspects of the syndrome.
PubMed: 27625843
DOI: 10.3233/PGE-13051 -
Expert Opinion on Pharmacotherapy Apr 2023Bardet-Biedl Syndrome (BBS) is a rare, multisystemic ciliopathy with an incidence of obesity of 89%. Mutations in genes encoding BBS proteins are linked to reduced...
INTRODUCTION
Bardet-Biedl Syndrome (BBS) is a rare, multisystemic ciliopathy with an incidence of obesity of 89%. Mutations in genes encoding BBS proteins are linked to reduced leptin sensitivity of hypothalamic POMC neurons and reduced activation of the melanocortin-4 receptor (MC4R) pathway due to deficient α-MSH production by hypothalamic POMC neurons. The MC4R pathway is involved in controlling body weight and energy metabolism, and its disruption is linked to hyperphagia and obesity. Setmelanotide is an MC4R agonist that counteracts deficiencies in the MC4R pathway of individuals with BBS.
AREAS COVERED
Data from clinical trials were reviewed along with information available from setmelanotide's approval for treatment of obesity in people ages ≥6y with a clinical diagnosis of BBS.
EXPERT OPINION
Setmelanotide is available as a daily injectable that can be used for amelioration of obesity in people with Bardet-Biedl syndrome. Its cost is substantial, which may limit its use, but among those who respond, setmelanotide can reduce body mass dramatically and potentially improve comorbid conditions associated with obesity. Setmelanotide treatment has generally tolerable side effects, primarily injection site reactions and nausea/vomiting that generally improve with continued use; almost all people using setmelanotide experience marked skin darkening due to off-target activation of cutaneous MC1R.
Topics: Humans; Adult; Child; alpha-MSH; Bardet-Biedl Syndrome; Pro-Opiomelanocortin; Obesity
PubMed: 37013719
DOI: 10.1080/14656566.2023.2199152 -
Molecular Syndromology Feb 2014Bardet-Biedl syndrome (BBS) is an autosomal recessive disease characterized by retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, renal... (Review)
Review
Bardet-Biedl syndrome (BBS) is an autosomal recessive disease characterized by retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, renal involvement, and male hypogenitalism. BBS is genetically heterogeneous, and to date 18 genes (BBS1-18) have been described. Mutations in known BBS genes account for approximately 70-80% of cases, and triallelic inheritance has been suggested in about 5%. Many minor features can be helpful in making the clinical diagnosis. Recently, the use of next-generation sequencing technologies has accelerated the identification of novel genes and causative disease mutations in known genes. This report presents a concise overview of the current knowledge on clinical data in BBS and the progress in molecular genetics research. A future objective will be the development of BBS diagnosis kits in order to offer genetic counseling for families at risk.
PubMed: 24715851
DOI: 10.1159/000357054 -
Clinical Ophthalmology (Auckland, N.Z.) 2021Bardet-Biedl syndrome is a complex heterogeneous ciliopathy caused by genetic mutations. Although establishing genotype-phenotype correlations has been challenging, some...
BACKGROUND
Bardet-Biedl syndrome is a complex heterogeneous ciliopathy caused by genetic mutations. Although establishing genotype-phenotype correlations has been challenging, some regional variations have been previously reported. Due to its relative geographic isolation, Puerto Rico has a greater prevalence of Bardet-Biedl syndrome than do other regions. We sought to characterize the most frequent genotypic variations in a local cohort of Bardet-Biedl syndrome patients and report any genotypic-phenotypic trends.
METHODS
Twenty-seven patients from an ophthalmology clinic in Puerto Rico with genetically confirmed Bardet-Biedl syndrome took a questionnaire inquiring about their most common symptoms. Ophthalmological information was obtained from patient records. The frequencies of the genotypic variations and symptoms were calculated.
RESULTS
In the study population, was the most prevalent mutated gene, followed by . In the BBS1 group, we found homozygotes for c.1169T>G (p.Met390Arg) and c.1645G>T (p.Glu549*), and compound heterozygotes for c.1169T>G (p.Met390Arg) and c.1645G>T (p.Glu549*), with one patient having c.1645G>T (p.Glu549*) and c.432+1G>A (splice donor). All the BBS7 patients were homozygous for c.632C>T (p.Thr211Ile). Compared to BBS7, we found that BBS1 patients generally had a milder ocular and systemic phenotype. However, when analyzing different BBS1 variants, patients with mutations in c.1645G>T (p.Glu549*), both compound heterozygous and homozygous, had more severe systemic phenotypes, overall.
CONCLUSION
Our study was the first detailed genotype-phenotype analysis of the Bardet-Biedl syndrome in Puerto Rico. Genetic mutations in and seem to be the most common culprits behind Bardet-Biedl syndrome in this population. Although patients diagnosed with BBS1 are likely to display milder systemic features, this was not the case with our BBS1 patients having the c.1645G>T (p.Glu549*) mutation. Further studies should focus on the c.1645G>T (p.Glu549*) mutation's impact on the BBS1 gene and protein product.
PubMed: 34526762
DOI: 10.2147/OPTH.S328493 -
Indian Journal of Nephrology 2023Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia.... (Review)
Review
Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia. Cilia are essential to the signaling cascades, and their dysfunction has been tied to a range of renal cystic diseases initiating with studies on the oak ridge polycystic kidney (ORPK) mouse model. Here, we delve into renal cystic pathologies that have been tied with ciliary proteosome and highlight the genetics associated with each. The pathologies are grouped based on the mode of inheritance, where inherited causes that result in cystic kidney disease phenotypes include autosomal dominant and autosomal recessive polycystic kidney disease, nephronophthisis (Bardet-Biedl syndrome and Joubert Syndrome), and autosomal dominant tubulointerstitial kidney disease. Alternatively, phakomatoses-, also known as neurocutaneous syndromes, associated cystic kidney diseases include tuberous sclerosis (TS) and Von Hippel-Lindau (VHL) disease. Additionally, we group the pathologies by the mode of inheritance to discuss variations in recommendations for genetic testing for biological relatives of a diagnosed individual.
PubMed: 37234435
DOI: 10.4103/ijn.ijn_318_21 -
Pediatric Nephrology (Berlin, Germany) Jul 2007The Bardet-Biedl syndrome (BBS) is a significant genetic cause of chronic and end-stage renal failure in children. Despite being a relatively rare recessive condition,... (Review)
Review
The Bardet-Biedl syndrome (BBS) is a significant genetic cause of chronic and end-stage renal failure in children. Despite being a relatively rare recessive condition, BBS has come to prominence during the past few years owing to revelations of primary cilia dysfunction underlying pathogenesis. The study of this multi-system disorder, which includes obesity, cognitive impairment, genito-urinary tract malformations and limb deformities, is beginning to reveal insights into several aspects of mammalian development and organogenesis. Involvement of BBS proteins in disparate pathways such as the non-canonical Wnt and Sonic Hedgehog pathways is highlighting their interplay in disease pathogenesis. Here we review the recent developments in this emerging field, with the emphasis on the renal component of the syndrome and potential future directions.
Topics: Bardet-Biedl Syndrome; Child; Cilia; Hedgehog Proteins; Humans; Kidney Diseases, Cystic; Models, Biological; Signal Transduction; Wnt Proteins
PubMed: 17357787
DOI: 10.1007/s00467-007-0435-0 -
International Journal of Molecular... Aug 2022Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent...
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the 'ciliopathy' field, there is still little information on the mechanisms underlying renal disease. To elucidate these pathomechanisms, we conducted a translational study, including (i) the characterization of the urine metabolomic pattern of BBS patients and controls in a pilot and confirmation study and (ii) the proteomic analysis of the BBS10 interactome, one of the major mutated BBS genes in patients, in a renal-epithelial-derived cell culture model. The urine metabolomic fingerprinting of BBS patients differed from controls in both pilot and confirmation studies, demonstrating an increased urinary excretion of several monocarboxylates, including lactic acid (LA), at both early and late CKD stages. Increased urine LA was detected in the absence of both increased plasmatic LA levels and generalized proximal tubular dysfunction, suggesting a possible renal-specific defective handling. The inner medulla renal epithelial (IMCD3) cell line, where was stably invalidated, displayed an increased proliferative rate, increased ATP production, and an up-regulation of aerobic glycolysis. A mass spectrometry-based analysis detected several putative BBS10 interactors in vitro, indicating a potential role of BBS10 in several biological processes, including renal metabolism, RNA processing, and cell proliferation. The present study suggests that the urine metabolomic pattern of BBS patients may reflect intra-renal metabolic aberrations. The analysis of BBS10 interactors unveils possible novel functions, including cell metabolism.
Topics: Bardet-Biedl Syndrome; Chaperonins; Humans; Mutation; Proteomics; Renal Insufficiency, Chronic
PubMed: 36012682
DOI: 10.3390/ijms23169420 -
ELife Jul 2023The BBSome is an octameric protein complex that regulates ciliary transport and signaling. Mutations in BBSome subunits are closely associated with ciliary defects and... (Review)
Review
The BBSome is an octameric protein complex that regulates ciliary transport and signaling. Mutations in BBSome subunits are closely associated with ciliary defects and lead to ciliopathies, notably Bardet-Biedl syndrome. Over the past few years, there has been significant progress in elucidating the molecular organization and functions of the BBSome complex. An improved understanding of BBSome-mediated biological events and molecular mechanisms is expected to help advance the development of diagnostic and therapeutic approaches for BBSome-related diseases. Here, we review the current literature on the structural assembly, transport regulation, and molecular functions of the BBSome, emphasizing its roles in cilium-related processes. We also provide perspectives on the pathological role of the BBSome in ciliopathies as well as how these can be exploited for therapeutic benefit.
Topics: Humans; Cilia; Ciliopathies; Bardet-Biedl Syndrome
PubMed: 37466224
DOI: 10.7554/eLife.87623 -
Cureus Oct 2022Bardet-Biedl syndrome (BBS) is a rare multisystem disease, with autosomal recessive inheritance and genetic heterogeneity characterized by post-axial polydactyl,...
Bardet-Biedl syndrome (BBS) is a rare multisystem disease, with autosomal recessive inheritance and genetic heterogeneity characterized by post-axial polydactyl, cone-rods dystrophy, and central obesity. BBS involves many organs in the body with variable complications and the life span of affected individuals. Clinical confirmation of the disorder can be done using a revised criterion that consists of primary or major features and secondary or minor features. Primary features of BBS include hypogonadism, polydactyly, obesity, retinitis pigmentosa, and learning disability. While ataxia, poor coordination, brachydactyly, diabetes mellitus, speech abnormalities, liver fibrosis, hearing loss, spasticity, and cardiovascular anomaly constitute the secondary features. In this study, we report a case of a five-year-old Saudi girl who presented with language delay, delay in milestones, progressive weight gain, excised polydactyly, and retinitis pigmentosa. An integrated medicine approach would substantially improve the quality of life of the affected individuals and their families by enhancing both physical and mental health.
PubMed: 36348931
DOI: 10.7759/cureus.29912 -
Orphanet Journal of Rare Diseases Jul 2023Bardet-Biedl syndrome (BBS) is a rare, genetically heterogeneous obesity syndrome associated with hyperphagia. Given the early onset of BBS symptoms in childhood and...
BACKGROUND
Bardet-Biedl syndrome (BBS) is a rare, genetically heterogeneous obesity syndrome associated with hyperphagia. Given the early onset of BBS symptoms in childhood and multifaceted complications, this study aimed to quantify the caregiver burden associated with BBS.
METHODS
A cross-sectional, multi-country survey of caregivers from the United States (US), United Kingdom (UK), Canada, and Germany was designed to quantify the extent of caregiver burden associated with obesity and hyperphagia symptoms (i.e., uncontrollable hunger) among patients with BBS.
RESULTS
A total of 242 caregivers across the four countries met the inclusion criteria and completed the survey. The mean (standard deviation [SD]) age of the caregivers was 41.9 (6.7) years, and the mean (SD) age of individuals with BBS in their care was 12.0 (3.7) years. Hyperphagia contributed to a BBS diagnosis in 230 of 242 individuals (95.0%). On average, caregivers used eight different weight management approaches for those in their care and expressed a strong desire for more effective weight management methods. Based on the Impacts of Hyperphagia: Caregiver version, patients' hyperphagia had a moderate-to-severe impact on caregiver mood (56.6%), sleep (46.6%), and relationships (48.0%). Caregivers reported experiencing a high level of personal strain (mean [SD], 17.1 [2.9]) and family impact (mean [SD] score, 26.0 [3.8]) due to BBS, as measured by the Revised Impact on Family Scale. Among caregivers in the workforce, there also was high impairment in total work productivity (mean [SD], 60.9% [21.4%]) due to caring for patients with BBS according to the Work Productivity and Activity Impairment. More than half (53%) of the caregivers reported spending over 5,000 out-of-pocket in local currency for medical expenses for the patient with BBS in their care.
CONCLUSIONS
Obesity and hyperphagia have negative impacts on the lives of caregivers of patients with BBS. The burden is demonstrated to be multifaceted, with various components that may interact with and confound each other, including intensive weight management efforts, productivity loses, impaired family dynamics and out-of-pocket medical expenses.
Topics: Humans; Adult; Child; Bardet-Biedl Syndrome; Caregiver Burden; Cross-Sectional Studies; Obesity; Hyperphagia; Surveys and Questionnaires
PubMed: 37415214
DOI: 10.1186/s13023-023-02692-8