Bardet-Biedl syndrome: A clinical overview focusing on diagnosis, outcomes and best-practice management.

Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by early-onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss due to rod-cone dystrophy. BBS is an autosomal recessive disorder with >20 implicated genes. The genotype-phenotype relationship in BBS is not clear, and there may be additional modifying factors. The underlying mechanism is dysfunction of primary cilia. In BBS, receptor trafficking in and out of the cilia is compromised, affecting multiple organ systems. Along with early-onset obesity, hyperphagia is a prominent symptom and contributes significantly to clinical morbidity and caregiver burden. While there is no cure for BBS, setmelanotide is a new pharmacotherapy approved for treatment of obesity in BBS. The differential diagnosis for BBS includes other ciliopathies, such as Alstrom syndrome, and other genetic obesity syndromes, such as Prader-Willi syndrome. Careful clinical history and genetic testing can help determine the diagnosis and a multidisciplinary team is necessary to guide clinical management.

Gene therapy rescues olfactory perception in a clinically relevant ciliopathy model of Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a hereditary genetic disorder that results in numerous clinical manifestations including olfactory dysfunction. Of at least 21 BBS-related genes that can carry multiple mutations, a pathogenic mutation, BBS1M390R, is the single most common mutation of clinically diagnosed BBS outcomes. While the deletion of BBS-related genes in mice can cause variable penetrance in different organ systems, the impact of the Bbs1M390R mutation in the olfactory system remains unclear. Using a clinically relevant knock-in mouse model homozygous for Bbs1M390R, we investigated the impact of the mutation on the olfactory system and tested the potential of viral-mediated, wildtype gene replacement therapy to rescue smell loss. The cilia of olfactory sensory neurons (OSNs) in Bbs1M390R/M390R mice were significantly shorter and fewer than those of wild-type mice. Also, both peripheral cellular odor detection and synaptic-dependent activity in the olfactory bulb were significantly decreased in the mutant mice. Furthermore, to gain insight into the degree to which perceptual features are impaired in the mutant mice, we used whole-body plethysmography to quantitatively measure odor-evoked sniffing. The Bbs1M390R/M390R mice showed significantly higher odor detection thresholds (reduced odor sensitivity) compared to wild-type mice; however, their odor discrimination acuity was still well maintained. Importantly, adenoviral expression of Bbs1 in OSNs restored cilia length and re-established both peripheral odorant detection and odor perception. Together, our findings further expand our understanding for the development of gene therapeutic treatment for congenital ciliopathies in the olfactory system.

Linear porokeratosis associated with Bardet-Biedl syndrome: A case report.

This case report presents a 17-year-old boy with Bardet-Biedl syndrome (BBS) and a long-standing hyperpigmented eruption on the left trunk and upper extremity, clinically and histologically consistent with linear porokeratosis (LP). BBS patients frequently require solid organ transplant, and subsequent immunosuppression places them at especially high risk for malignant transformation of premalignant skin lesions such as LP. Although BBS affects multiple organ systems, there are only a handful of case reports detailing associated cutaneous involvement, and, to our knowledge, this is the first reported case of linear porokeratosis occurring in patient with BBS.

Gene Therapeutic Reversal of Peripheral Olfactory Impairment in Bardet-Biedl Syndrome.

Olfactory dysfunction is a pervasive but underappreciated health concern that affects personal safety and quality of life. Patients with olfactory dysfunctions have limited therapeutic options, particularly those involving congenital diseases. Bardet-Biedl syndrome (BBS) is one such disorder, where olfactory loss and other symptoms manifest from defective cilium morphology and/or function in various cell types/tissues. Olfactory sensory neurons (OSNs) of BBS mutant mice lack the capacity to build/maintain cilia, rendering the cells incapable of odor detection. Here we examined OSN cilium defects in Bbs1 mutant mice and assessed the utility of gene therapy to restore ciliation and function in young and adult mice. Bbs1 mutant mice possessed short residual OSN cilia in which BBSome protein trafficking and odorant detection were defective. Gene therapy with an adenovirus-delivered wild-type Bbs1 gene restored OSN ciliation, corrected BBSome cilium trafficking defects, and returned acute odor responses. Finally, using clinically approved AAV serotypes, we demonstrate, for the first time, the capacity of AAVs to restore ciliation and odor detection in OSNs of Bbs1 mutants. Together, our data demonstrate that OSN ciliogenesis can be promoted in differentiated cells of young and adult Bbs1 mutants and highlight the potential of gene therapy as a viable restorative treatment for congenital olfactory disorders.

Toward personalized medicine in Bardet-Biedl syndrome.

Personalized medicine is becoming routine in the treatment of common diseases such as cancer, but has lagged behind in the field of rare diseases. It is currently in the early stages for the treatment of Bardet-Biedl syndrome. Advances in the understanding of ciliary biology and diagnostic techniques have opened up the prospect of treating BBS in a patient-specific manner. Owing to their structure and function, cilia provide an attractive therapeutic target and genetic therapies are being explored in ciliopathy treatment. Promising avenues include gene therapy, gene editing techniques and splice-correcting and read-through therapies. Targeted drug design has been successful in the treatment of genetic disease and research is underway in the discovery of known and novel drugs to treat Bardet-Biedl syndrome.

Bardet-Biedl syndrome: Genetics, molecular pathophysiology, and disease management.

Primary cilia play a key role in sensory perception and various signaling pathways. Any defect in them leads to group of disorders called ciliopathies, and Bardet-Biedl syndrome (BBS, OMIM 209900) is one among them. The disorder is clinically and genetically heterogeneous, with various primary and secondary clinical manifestations, and shows autosomal recessive inheritance and highly prevalent in inbred/consanguineous populations. The disease mapped to at least twenty different genes (BBS1-BBS20), follow oligogenic inheritance pattern. BBS proteins localizes to the centerosome and regulates the biogenesis and functions of the cilia. In BBS, the functioning of various systemic organs (with ciliated cells) gets deranged and results in systemic manifestations. Certain components of the disease (such as obesity, diabetes, and renal problems) when noticed earlier offer a disease management benefit to the patients. However, the awareness of the disease is comparatively low and most often noticed only after severe vision loss in patients, which is usually in the first decade of the patient's age. In the current review, we have provided the recent updates retrieved from various types of scientific literature through journals, on the genetics, its molecular relevance, and the clinical outcome in BBS. The review in nutshell would provide the basic awareness of the disease that will have an impact in disease management and counseling benefits to the patients and their families.

Bardet-Biedl syndrome: multiple fingers with multiple defects!

Bardet-Biedl syndrome (BBS) is a rare congenital ciliopathy characterised by rod-cone dystrophy, postaxial polydactyly, central obesity, mental retardation, hypogonadism and renal dysfunction. A 45-year-old Indian man presented with New York Heart Association class 2 dyspnoea of 3 months duration. He was blind since childhood. He was obese, cyanosed, and had clubbing and polydactyly. Systemic examination revealed presence of wide and fixed split second heart sound with systolic murmur in the left parasternal area. Work up unmasked the presence of secondary polycythaemia, atypical retinitis pigmentosa and partial atrioventricular defect. He was diagnosed to have BBS based on clinical and radiological features. This case is interesting for its rarity and also for the peculiarity of its cardiovascular association. Polydactyly with a suspicious clinical background is the clue and by itself warrants the clinician to search for occult anomalies. Clinicians must be aware of this syndrome, for which an early diagnosis and a multidisciplinary approach will significantly improve mortality and morbidity in patients.

Subretinal gene therapy of mice with Bardet-Biedl syndrome type 1.

PURPOSE: To study safety and efficacy of subretinal adeno-associated virus (AAV) vector AAV-Bbs1 injection for treatment of a mouse model of Bardet-Biedl syndrome type 1 (BBS1). METHODS: Constructs containing a wild-type (WT) Bbs1 gene with and without a FLAG tag in AAV2/5 vectors were generated. Viral genomes were delivered by subretinal injection to right eyes and sham injections to left eyes at postnatal day 30 (P30) to P60. Transgene expression and BBSome reconstitution were evaluated by immunohistochemistry and Western blotting following sucrose gradient ultracentrifugation. Retinal function was analyzed by electroretinogram (ERG) and structure by optical coherence tomography (OCT). Histology and immunohistochemistry were performed on selected eyes. RESULTS: Expression of FLAG-tagged Bbs1 was demonstrated in photoreceptor cells using antibody directed against the FLAG tag. Coinjection of AAV-GFP demonstrated transduction of 24% to 32% of the retina. Western blotting demonstrated BBS1 protein expression and reconstitution of the BBSome. ERG dark-adapted bright flash b-wave amplitudes were higher in AAV-Bbs1-injected eyes than in sham-injected fellow eyes in more than 50% of 19 animals. Anti-rhodopsin staining demonstrated improved localization of rhodopsin in AAV-Bbs1-treated eyes. WT retinas injected with AAV-Bbs1 with or without a FLAG tag showed outer retinal degeneration on ERG, OCT, and histology. CONCLUSIONS: In a knock-in model of BBS1, subretinal delivery of AAV-Bbs1 rescues BBSome formation and rhodopsin localization, and shows a trend toward improved ERG. BBS is challenging to treat with gene therapy due to the stoichiometry of the BBSome protein complex and overexpression toxicity.

Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. Many associated minor features can be helpful in making a diagnosis and are important in the clinical management of BBS. The diagnosis is based on clinical findings and can be confirmed by sequencing of known disease-causing genes in 80% of patients. BBS genes encode proteins that localise to the cilia and basal body and are involved in cilia biogenesis and function. Mutations lead to defective cilia accounting in part for the pleiotropic effects observed in BBS. We provide an overview of BBS including the clinical findings, current understanding of cilia biology, and a practical approach to diagnosis, genetic counselling and up-to-date management.

A case series of Bardet-Biedl syndrome in a large Turkish family and review of the literature.

BACKGROUND AND AIM: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder. We aimed to report a case series of Bardet-Biedl syndrome in a Turkish family and review the literature. PATIENTS AND METHODS: This family had 3 females and 4 males, totally 7 alive; 2 children (1 female and 1 male) had died. Parents were consanguineous. The first was a birth of twins and female sibling of these twins had congenital anal atresia and died when she was three-month old. Third (30 yr), 4th (28 yr) and 9th (19 yr) alive siblings were obese, blind and diabetic. We detected truncal obesity, postaxial polydactyly, cognitive impairment and hypogonadism. Rod-cone dystrophy was detected in ophthalmic examination. With these typical clinical findings, BBS was diagnosed. There was also a male member of the family which shared the same features of his affected brothers but he had died while he was eight months old. Marked glycosuria was determined and urine density was 1021 g/cm3. There was not any further endocrinological abnormality. Fasting blood glucose levels were changing between 290 and 452 mg/dl and the last glycated hemoglobine levels (A1c) were 9.3%, 11.2% and 12.8%, respectively. Diabetes mellitus and obesity were treated with diet, exercise, multiple daily insulin injections and metformine at the dose of 2000 mg/d. CONCLUSIONS: Although it is an infrequent condition due to autosomal recessive transmission, consanguineous marriage may increase the risk of emergence of BBS. Genetic counseling is a very important issue in the family of patients with BBS, in order to prevent new cases.

Educational paper: ciliopathies.

Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment. Ciliary dysfunction has been shown to underlie a broad range of overlapping, clinically and genetically heterogeneous phenotypes, collectively termed ciliopathies. Literally, all organs can be affected. Frequent cilia-related manifestations are (poly)cystic kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous system, occurring either isolated or as part of syndromes. Characterization of ciliopathies and the decisive role of primary cilia in signal transduction and cell division provides novel insights into tumorigenesis, mental retardation, and other common causes of morbidity and mortality, including diabetes mellitus and obesity. New technologies ("Next generation sequencing/NGS") have considerably improved genetic research and diagnostics by allowing simultaneous investigation of all disease genes at reduced costs and lower turn-around times. This is undoubtedly a result of the dynamic development in the field of human genetics and deserves increased attention in genetic counselling and the management of affected families.

U1 snRNA-mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation.

Bardet-Biedl syndrome (BBS) is a multisystem disorder caused by ciliary defects. To date, mutations in 15 genes have been associated with the disease and BBS1 is most frequently affected in patients with BBS. The use of homozygosity mapping in a large consanguineous family allowed us to identify the splice donor site (SD) mutation c.479G>A in exon 5 of BBS1. Clinically affected family members show symptoms of retinitis pigmentosa (RP) but lack other primary features that would clearly support the diagnosis of BBS. In agreement with this exceptionally mild BBS1-associated phenotype, we did not detect obvious ciliary defects in patient-derived cells. SDs are bound by the U1 small nuclear RNA (U1), a process that initiates exon recognition during splicing. The mutation described herein interferes with U1 binding and induces aberrant splicing of BBS1. For a gene therapeutic approach, we have adapted the sequence of U1 to increase its complementarity to the mutated SD. Lentiviral treatment of patient-derived fibroblasts with the adapted U1 partially corrected aberrant splicing of endogenously expressed BBS1 transcripts. This therapeutic effect was dose-dependent. Our results show that the adaptation of U1 can correct pathogenic effects of splice donor site mutations and suggest a high potential for gene therapy.

Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model.

Patients with Bardet-Biedl syndrome (BBS) experience severe retinal degeneration as a result of impaired photoreceptor transport processes that are not yet fully understood. To date, there is no effective treatment for BBS-associated retinal degeneration, and blindness is imminent by the second decade of life. Here we report the development of an adeno-associated viral (AAV) vector that rescues rhodopsin mislocalization, maintains nearly normal-appearing rod outer segments, and prevents photoreceptor death in the Bbs4-null mouse model. Analysis of the electroretinogram a-wave indicates that rescued rod cells are functionally indistinguishable from wild-type rods. These results demonstrate that gene therapy can prevent retinal degeneration in a mammalian BBS model.