Bardet-Biedl Syndrome ciliopathy is linked to altered hematopoiesis and dysregulated self-tolerance.

Bardet-Biedl Syndrome (BBS) is a pleiotropic genetic disease caused by the dysfunction of primary cilia. The immune system of patients with ciliopathies has not been investigated. However, there are multiple indications that the impairment of the processes typically associated with cilia may have influence on the hematopoietic compartment and immunity. In this study, we analyze clinical data of BBS patients and corresponding mouse models carrying mutations in Bbs4 or Bbs18. We find that BBS patients have a higher prevalence of certain autoimmune diseases. Both BBS patients and animal models have altered red blood cell and platelet compartments, as well as elevated white blood cell levels. Some of the hematopoietic system alterations are associated with BBS-induced obesity. Moreover, we observe that the development and homeostasis of B cells in mice is regulated by the transport complex BBSome, whose dysfunction is a common cause of BBS. The BBSome limits canonical WNT signaling and increases CXCL12 levels in bone marrow stromal cells. Taken together, our study reveals a connection between a ciliopathy and dysregulated immune and hematopoietic systems.

Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons.

Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding of BBS aetiology, the molecular and cellular mechanisms underlying cognitive impairment in BBS remain elusive. Here, we report that the loss of BBS proteins causes synaptic dysfunction in principal neurons, providing a possible explanation for the cognitive impairment phenotype observed in BBS patients. Using synaptosomal proteomics and immunocytochemistry, we demonstrate the presence of Bbs proteins in the postsynaptic density (PSD) of hippocampal neurons. Loss of Bbs results in a significant reduction of dendritic spines in principal neurons of Bbs mouse models. Furthermore, we show that spine deficiency correlates with events that destabilise spine architecture, such as impaired spine membrane receptor signalling, known to be involved in the maintenance of dendritic spines. Our findings suggest a role for BBS proteins in dendritic spine homeostasis that may be linked to the cognitive phenotype observed in BBS.

Correction: Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons.

[This corrects the article DOI: 10.1371/journal.pbio.3000414.].

Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome.

Bardet-Biedl syndrome is a rare autosomal recessive, multisystem disease characterized by retinal dystrophy, renal malformation, obesity, intellectual disability, polydactyly, and hypogonadism. Nineteen disease-causing genes (BBS1-19) have been identified, of which mutations in BBS1 are most common in North America and Europe. A hallmark of the disease, renal malformation is heterogeneous and is a cause of morbidity and mortality through the development of CKD. We studied the prevalence and severity of CKD in 350 patients with Bardet-Biedl syndrome-related renal disease attending the United Kingdom national Bardet-Biedl syndrome clinics to further elucidate the phenotype and identify risk indicators of CKD. Overall, 31% of children and 42% of adults had CKD; 6% of children and 8% of adults had stage 4-5 CKD. In children, renal disease was often detected within the first year of life. Analysis of the most commonly mutated disease-associated genes revealed that, compared with two truncating mutations, two missense mutations associated with less severe CKD in adults. Moreover, compared with mutations in BBS10, mutations in BBS1 associated with less severe CKD or lack of CKD in adults. Finally, 51% of patients with available ultrasounds had structural renal abnormalities, and 35% of adults were hypertensive. The presence of structural abnormalities or antihypertensive medication also correlated statistically with stage 3b-5 CKD. This study describes the largest reported cohort of patients with renal disease in Bardet-Biedl syndrome and identifies risk factors to be considered in genetic counseling.

Burden of hyperphagia and obesity in Bardet-Biedl syndrome: a multicountry survey.

BACKGROUND: Signs and symptoms of Bardet-Biedl syndrome (BBS) occur during early childhood, progress over time, and place substantial, multifaceted burden on patients and their caregivers. Hyperphagia may be a contributing factor to early-onset obesity in BBS; however, there are limited insights into its impacts on patients and caregivers. We quantified disease burden as it relates to the physical and emotional impacts of hyperphagia in BBS. METHODS: The CAREgiver Burden in BBS (CARE-BBS) study was a multicountry, cross-sectional survey of adult caregivers of patients with BBS who have had hyperphagia and obesity. The survey consisted of questionnaires including Symptoms of Hyperphagia, Impacts of Hyperphagia, Impact of Weight on Quality of Life (IWQOL)-Kids Parent Proxy, and Patient-Reported Outcome Measurement Information System (PROMIS) v1.0-Global Health 7. In addition, clinical characteristics, medical history, and weight management questions were included. Outcomes were scored and summarized descriptively in aggregate and by country, age, and obesity severity according to weight class. RESULTS: There were 242 caregivers of patients with BBS who completed the survey. Caregivers observed hyperphagic behaviors throughout the day, with negotiating for food (90%) and waking up and asking or looking for food during the night (88%) being the most frequent. Hyperphagia had at least a moderate negative impact on most patients' mood/emotions (56%), sleep (54%), school (57%), leisure (62%), and familial relationships (51%). Hyperphagia affected concentration at school (78%), and symptoms of BBS contributed to patients missing ≥ 1 day of school a week (82%). Responses from the IWQOL-Kids Parent Proxy suggested obesity most greatly negatively affected physical comfort (mean [standard deviation (SD)], 41.7 [17.2]), body esteem (41.0 [17.8]), and social life (41.7 [18.0]). On the PROMIS questionnaire, mean (SD) global health score for pediatric patients with BBS and overweight or obesity (36.8 [10.6]) was lower than the general population (mean, 50). CONCLUSIONS: Evidence from this study suggests that hyperphagia and obesity may have broad negative impacts on the lives of patients with BBS, including physical health, emotional well-being, school performance, and personal relationships. Therapies that target hyperphagia may alleviate the extensive clinical and nonclinical impacts experienced by patients with BBS and their caregivers.

Caregiver burden in Bardet-Biedl syndrome: findings from the CARE-BBS study.

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.

Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results.

BACKGROUND: Bardet-Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity. There is limited evidence on how hyperphagia and obesity affect health-related quality of life in patients with Bardet-Biedl syndrome, and on how management of these symptoms may influence disease burden. This analysis evaluated changes in health-related quality of life in adults and children with Bardet-Biedl syndrome in a Phase 3 trial following 1 year of setmelanotide treatment (ClinicalTrials.gov identifier: NCT03746522). METHODS: Patients with Bardet-Biedl syndrome and obesity received 52 weeks of treatment with setmelanotide and completed various self-reported health-related quality of life measures. Patients aged < 18 years or their caregiver completed the Pediatric Quality of Life Inventory (PedsQL; meaningful improvement, 4.4-point change); adults aged ≥ 18 years completed the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-Lite; meaningful improvement range, 7.7-12-point change). Descriptive outcomes were reported in patients with data both at active treatment baseline and after 52 weeks of treatment. RESULTS: Twenty patients (< 18 years, n = 9; ≥ 18 years, n = 11) reported health-related quality of life at baseline and 52 weeks. For children and adolescents, PedsQL score mean change from baseline after 52 weeks was + 11.2; all patients with PedsQL impairment at baseline (n = 4) experienced clinically meaningful improvement. In adults, IWQOL-Lite score mean change from baseline was + 12.0. Of adults with IWQOL-Lite impairment at baseline (n = 8), 62.5% experienced clinically meaningful improvement. In adults, IWQOL-Lite score was significantly correlated with changes in percent body weight (P = 0.0037) and body mass index (P = 0.0098). CONCLUSIONS: After 1 year of setmelanotide, patients reported clinically meaningful improvements across multiple health-related quality of life measures. This study highlights the need to address the impaired health-related quality of life in Bardet-Biedl syndrome, and supports utility of setmelanotide for reducing this burden. Trial Registration NCT03746522. Registered November 19, 2018, https://clinicaltrials.gov/ct2/show/NCT03746522 .

Implications of Antimuscarinic Autoantibodies in Postural Tachycardia Syndrome.

Functional autoantibodies directed to the M2 muscarinic acetylcholine receptor (M2R) could affect the heart rate directly by altering cardiac M2R activity and/or indirectly by changing vagal-mediated cardiac M2R activity. We measured M2R autoantibody activity in sera from 10 subjects with postural tachycardia syndrome (POTS) and 5 healthy control subjects using a cell-based bioassay. Half of the POTS subjects demonstrated presence of elevated M2R autoantibody activity, while no significant M2R autoantibody activity was found in the healthy subjects. Serum-derived immunoglobulin G (IgG) from antibody-positive POTS patients induced a dose-dependent activation of M2R, which was blocked by the muscarinic antagonist atropine. Moreover, antibody-positive POTS IgG decreased the responsiveness to oxotremorine, an orthosteric muscarinic agonist, indicating an indirect inhibitory effect. These data suggest that M2R autoantibodies may contribute to the pathophysiology of POTS by increasing the normal vagal withdrawal during upright posture through its negative allosteric modulation of M2R activity. M2 muscarinic receptor-activating autoantibodies are present in a subgroup of patients with POTS and act as a negative allosteric modulator of the orthosteric ligand response.

Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period.

BACKGROUND: Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients. METHODS: This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m2 for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522. FINDINGS: Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment. INTERPRETATION: Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome. FUNDING: Rhythm Pharmaceuticals.

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts.

BACKGROUND: Ciliary dysfunction underlies a range of genetic disorders collectively termed ciliopathies, for which there are no treatments available. Bardet-Biedl syndrome (BBS) is characterised by multisystemic involvement, including rod-cone dystrophy and renal abnormalities. Together with Alström syndrome (AS), they are known as the 'obesity ciliopathies' due to their common phenotype. Nonsense mutations are responsible for approximately 11% and 40% of BBS and AS cases, respectively. Translational readthrough inducing drugs (TRIDs) can restore full-length protein bypassing in-frame premature termination codons, and are a potential therapeutic approach for nonsense-mediated ciliopathies. METHODS: Patient fibroblasts harbouring nonsense mutations from two different ciliopathies (Bardet-Biedl Syndrome and Alström Syndrome) were treated with PTC124 (ataluren) or amlexanox. Following treatment, gene expression, protein levels and ciliogenesis were evaluated. The expression of intraflagellar transport protein IFT88 and G-protein coupled receptor SSTR3 was investigated as a readout of ciliary function. FINDINGS: mRNA expression was significantly increased in amlexanox-treated patient fibroblasts, and full-length BBS2 or ALMS1 protein expression was restored in PTC124- and amlexanox-treated fibroblasts. Treatment with TRIDs significantly improved ciliogenesis defects in BBS2Y24*/R275* fibroblasts. Treatment recovered IFT88 expression and corrected SSTR3 mislocalisation in BBS2Y24*/R275* and ALMS1S1645*/S1645* fibroblasts, suggesting rescue of ciliary function. INTERPRETATION: The recovery of full-length BBS2 and ALMS1 expression and correction of anatomical and functional ciliary defects in BBS2Y24*/R275* and ALMS1S1645*/S1645* fibroblasts suggest TRIDs are a potential therapeutic option for the treatment of nonsense-mediated ciliopathies. FUNDING: Wellcome Trust 205174/Z/16/Z, National Centre for the Replacement, Refinement & Reduction of Animals in Research. Deutsche Forschungsgemeinschaft SPP2127 (DFG Grant MA 6139/3-1).

The Role of GnRH Receptor Autoantibodies in Polycystic Ovary Syndrome.

OBJECTIVE: Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? DESIGN AND METHODS: We retrospectively screened sera from 40 patients with PCOS and 14 normal controls (NCs) with regular menses using enzyme-linked immunosorbent assay (ELISA) for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified immunoglobulin (Ig)G using a cell-based GnRHR bioassay. RESULTS: The mean ELISA value in the PCOS group was markedly higher than the NC (P = .000036) and the OIC (P = .0028) groups. IgG from a sample of 5 PCOS subjects, in contrast to a sample of 5 OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. The GnRHR antagonist cetrorelix significantly suppressed (P < .01) the elevated GnRHR activity induced by IgG from 7 PCOS patients while the IgG activity level from 7 OIC subjects was unchanged. Five other OIC subjects had relatively high ELISA values at or above the 95% confidence limits. On further study, 3 had normal or low activity while 2 had elevated IgG-induced GnRHR activity. One suppressed with cetrorelix while the other did not. The copresence of PCOS IgG increased the responsiveness to GnRH and shifted the dosage response curve to the left (P < .01). CONCLUSIONS: GnRHR-ECL2-AAb are significantly elevated in patients with PCOS compared with NCs. Their presence raises important etiological, diagnostic, and therapeutic implications.

A novel DNA repair disorder with thrombocytopenia, nephrosis and features overlapping Cockayne syndrome.

We report on four siblings with Cockayne-like syndrome with thrombocytopenia and nephrotic syndrome. The parents were healthy and consanguineous, consistent with an autosomal recessive mode of disease inheritance. UV irradiation of fibroblasts revealed an intermediate sensitivity between normal and standard Cockayne syndrome (CS) control cells. A genome-wide linkage scan conducted using Affymetrix 10K arrays provided exclusion of the known CS genes in the family, and evidence that the disease gene maps to 1p33-p31.1. Thrombocytopenia has not previously been linked with CS, but two patients with CS in association with nephrotic syndrome have previously been documented and the phenotypes are compared with the patients described here. We suggest that this Cockayne-like phenotype with thrombocytopenia and nephrotic syndrome may be a novel DNA repair disorder, and propose that further investigation of other affected families may help identify the causative genetic defect.

A functional cell-based bioassay for assessing adrenergic autoantibody activity in postural tachycardia syndrome.

BACKGROUND: Activating autoantibodies (AAb) to adrenergic receptors (AR) have previously been reported in patients with postural tachycardia syndrome (POTS). These AAb may contribute to a final common pathway for overlapping disease processes, reflecting a possible autoimmune contribution to POTS pathophysiology. In prior studies, measurement of AAb activity was inferred from costly, low-throughput, and laborious physiological assays. In the present study, we developed and validated an alternative cell-based bioassay for measuring AAb activity in serum by means of pre-treatment with monoamine oxidase (MAO). METHODS: A total of 37 POTS patients and 61 sex-matched healthy control participants were included. Serum was pre-treated with MAO to remove endogenous catecholamines that could falsely inflate AR activation by AAb. A receptor-transfected cell-based bioassay was used to detect presence of α1AR-AAb and ß1AR-AAb in serum. RESULTS: MAO effectively degraded catecholamines as demonstrated by suppression of norepinephrine-induced α1AR activation in POTS (6.4 â€‹± â€‹0.7 vs. 5.5 â€‹± â€‹0.9; P â€‹= â€‹0.044) and in controls (4.1 â€‹± â€‹0.5 vs. 3.9 â€‹± â€‹0.6; P â€‹= â€‹0.001). Mean activity values were greater in the POTS vs. Controls for α1AR-AAb (6.2 â€‹± â€‹1.2 vs. 5.3 â€‹± â€‹1.0; P â€‹< â€‹0.001) and ß1AR-AAb (5.7 â€‹± â€‹1.8 vs. 4.1 â€‹± â€‹0.9; P â€‹< â€‹0.001). Compared to controls, more POTS patients were positive for α1AR-AAb activity (22% vs 4%; P â€‹= â€‹0.007) and ß1AR-AAb activity (52% vs. 2%; P â€‹< â€‹0.001). CONCLUSIONS: The co-presence of norepinephrine in serum samples can artifactually elevate α1AR and ß1AR activity, which can be avoided by serum pre-treatment with MAO. Using this novel bioassay, we show that POTS patients have increased α1AR-AAb and ß1AR-AAb activity compared to healthy controls in the largest POTS cohort reported to-date.

Fluorescence approaches to growing macromolecule crystals.

Trace fluorescent labeling, typically less than 1%, can be a powerful aid in macromolecule crystallization. Precipitation concentrates a solute, and crystals are the most densely packed solid form. The more densely packed the fluorescing material, the brighter the emission from it; thus, fluorescence intensity of a solid phase is a good indication of whether or not one has crystals. The more brightly fluorescing crystalline phase is easily distinguishable, even when embedded in an amorphous precipitate. This approach conveys several distinct advantages: one can see what the protein is doing in response to the imposed conditions, and distinguishing between amorphous and microcrystalline precipitated phases is considerably simpler. The higher fluorescence intensity of the crystalline phase led the authors to test if they could derive crystallization conditions from screen outcomes that had no obvious crystalline material, but simply "bright spots" in the precipitated phase. Preliminary results show that the presence of these bright spots, not observable under white light, is indeed a good indicator of potential crystallization conditions.

Managing Bardet-Biedl Syndrome-Now and in the Future.

Bardet-Biedl syndrome is a rare autosomal recessive multisystem disorder caused by defects in genes encoding for proteins that localize to the primary cilium/basal body complex. Twenty-one disease-causing genes have been identified to date. It is one of the most well-studied conditions in the family of diseases caused by defective cilia collectively known as ciliopathies. In this review, we provide an update on diagnostic developments, clinical features, and progress in the management of Bardet-Biedl syndrome. Advances in diagnostic technologies including exome and whole genome sequencing are expanding the spectrum of patients who are diagnosed with Bardet-Biedl syndrome and increasing the number of cases with diagnostic uncertainty. As a result of the diagnostic developments, a small number of patients with only one or two clinical features of Bardet-Biedl syndrome are being diagnosed. Our understanding of the syndrome-associated renal disease has evolved and is reviewed here. Novel interventions are developing at a rapid pace and are explored in this review including genetic therapeutics such as gene therapy, exon skipping therapy, nonsense suppression therapy, and gene editing. Other non-genetic therapies such as gene repurposing, targeted therapies, and non-pharmacological interventions are also discussed.

The Endocrine and Metabolic Characteristics of a Large Bardet-Biedl Syndrome Clinic Population.

Context: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder in which previous reports have described obesity and a metabolic syndrome. Objective: We describe the endocrine and metabolic characteristics of a large BBS population compared with matched control subjects. Design: We performed a case-control study. Setting: This study was performed at a hospital clinic. Patients: Study patients had a clinical or genetic diagnosis of BBS. Main Outcome Measurements: Our study determined the prevalence of a metabolic syndrome in our cohort. Results: A total of 152 subjects were studied. Eighty-four (55.3%) were male. Mean (± standard deviation) age was 33.2 ± 1.0 years. Compared with age-, sex-, and body mass index-matched control subjects, fasting glucose and insulin levels were significantly higher in subjects with BBS (glucose: BBS, 5.2 ± 1.2 mmol/L vs control, 4.9 ± 0.9 mmol/L, P = 0.04; insulin: BBS, 24.2 ± 17.0 pmol/L vs control, 14.2 ± 14.8 pmol/L, P < 0.001). Serum triglycerides were significantly higher in subjects with BBS (2.0 ± 1.2 mmol/L) compared with control subjects (1.3 ± 0.8 mmol/L; P < 0.001), but total cholesterol, high-density lipoprotein, and low-density lipoprotein were similar in both groups. Systolic blood pressure was higher in the BBS group (BBS, 135 ± 18 mm Hg vs control subjects, 129 ± 16 mm Hg; P = 0.02). Alanine transaminase was raised in 34 (26.8%) subjects with BBS, compared with five (8.9%) control subjects (P = 0.01). The rate of metabolic syndrome, determined using International Diabetes Federation criteria, was significantly higher in the BBS group (54.3%) compared with control subjects (26% P < 0.001). Twenty-six (19.5%) of male subjects with BBS were hypogonadal (serum testosterone, 9.9 ± 5.3 mmol/L), but significant pituitary abnormalities were uncommon. Subclinical hypothyroidism was present in 24 of 125 (19.4%) patients with BBS, compared with 3 of 65 (4.6%) control subjects (P = 0.01). Conclusions: Insulin resistance and the metabolic syndrome are increased in adult patients with BBS compared with matched control subjects. Increased subclinical hypothyroidism in the BBS cohort needs further investigation.

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.

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.

Longevity and Patau syndrome: what determines survival?

The authors report of an 8-year-old girl with non-mosaic Patau syndrome. The median life expectancy of Patau syndrome is 7-10 days, and 90% die in the first year of life. Survival is often attributed to mosaicism and the severity of associated malformations. We delineate the developing phenotype and review the literature discussing potential contributory factors to longevity.