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Pediatric Obesity Feb 2021Bardet-Biedl syndrome (BBS) is a rare genetic disorder that severely inhibits primary cilia function. BBS is typified by obesity in adulthood, but pediatric weight...
BACKGROUND
Bardet-Biedl syndrome (BBS) is a rare genetic disorder that severely inhibits primary cilia function. BBS is typified by obesity in adulthood, but pediatric weight patterns, and thus optimal periods of intervention, are poorly understood.
OBJECTIVES
To examine body mass differences by age, gender, and genotype in children and adolescents with BBS.
METHODS
We utilized the largest international registry of BBS phenotypes. Anthropometric and genetic data were obtained from medical records or participant/family interviews. Participants were stratified by age and sex categories. Genotype and obesity phenotype were investigated in a subset of participants with available data.
RESULTS
Height and weight measurements were available for 552 unique individuals with BBS. The majority of birth weights were in the normal range, but rates of overweight or obesity rapidly increased in early childhood, exceeding 90% after age 5. Weight z-scores in groups >2 years were above 2.0, while height z-scores approached 1.0, but were close to 0.0 in adolescents. Relative to those with the BBS10 genotype, the BBS1 cohort had a lower BMI z-score in the 2-5 and 6-11 age groups, with similar BMI z-scores thereafter. Children with biallelic loss of function (LOF) genetic variants had significantly higher BMI z-scores compared to missense variants.
CONCLUSION
Despite normal birth weight, most individuals with BBS experience rapid weight gain in early childhood, with high rates of overweight/obesity sustained through adolescence. Children with LOF variants are disproportionally affected. Our findings support the need for earlier recognition and initiation of weight management therapies in BBS.
Topics: Adolescent; Age Factors; Bardet-Biedl Syndrome; Body Height; Body Mass Index; Body Weight; Chaperonins; Child; Child, Preschool; Female; Genetic Markers; Genotype; Humans; Infant; Infant, Newborn; Longitudinal Studies; Male; Microtubule-Associated Proteins; Pediatric Obesity; Phenotype; Prevalence; Registries; Risk Factors; Sex Factors
PubMed: 32700463
DOI: 10.1111/ijpo.12703 -
American Journal of Medical Genetics.... Mar 2022Bardet-Biedl syndrome (BBS) is a rare pleiotropic disorder known as a ciliopathy. Despite significant genetic heterogeneity, BBS1 and BBS10 are responsible for major... (Review)
Review
Bardet-Biedl syndrome (BBS) is a rare pleiotropic disorder known as a ciliopathy. Despite significant genetic heterogeneity, BBS1 and BBS10 are responsible for major diagnosis in western countries. It is well established that eight BBS proteins, namely BBS1, 2, 4, 5, 7, 8, 9, and 18, form the BBSome, a multiprotein complex serving as a regulator of ciliary membrane protein composition. Less information is available for BBS6, BBS10, and BBS12, three proteins showing sequence homology with the CCT/TRiC family of group II chaperonins. Even though their chaperonin function is debated, scientific evidence demonstrated that they are required for initial BBSome assembly in vitro. Recent studies suggest that genotype may partially predict clinical outcomes. Indeed, patients carrying truncating mutations in any gene show the most severe phenotype; moreover, mutations in chaperonin-like BBS proteins correlated with severe kidney impairment. This study is a critical review of the literature on genetics, expression level, cellular localization and function of BBS proteins, focusing primarily on the chaperonin-like BBS proteins, and aiming to provide some clues to understand the pathomechanisms of disease in this setting.
Topics: Bardet-Biedl Syndrome; Chaperonins; Group II Chaperonins; Humans; Mutation
PubMed: 35373910
DOI: 10.1002/ajmg.c.31970 -
The Journal of Clinical Investigation Apr 2021Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by...
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.
Topics: Amino Acid Substitution; Animals; Bardet-Biedl Syndrome; Chaperonins; Cyclic AMP; Female; HEK293 Cells; Humans; Hypothalamus; Induced Pluripotent Stem Cells; Male; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Mutation, Missense; Neurons; Second Messenger Systems
PubMed: 33630762
DOI: 10.1172/JCI146287 -
Genes Jul 2022The aim of this study was to characterize the ophthalmic and genetic features of Bardet Biedl (BBS) syndrome in a cohort of patients from a German specialized ophthalmic...
The aim of this study was to characterize the ophthalmic and genetic features of Bardet Biedl (BBS) syndrome in a cohort of patients from a German specialized ophthalmic care center. Sixty-one patients, aged 5−56 years, underwent a detailed ophthalmic examination including visual acuity and color vision testing, electroretinography (ERG), visually evoked potential recording (VEP), fundus examination, and spectral domain optical coherence tomography (SD-OCT). Adaptive optics flood illumination ophthalmoscopy was performed in five patients. All patients had received diagnostic genetic testing and were selected upon the presence of apparent biallelic variants in known BBS-associated genes. All patients had retinal dystrophy with morphologic changes of the retina. Visual acuity decreased from ~0.2 (decimal) at age 5 to blindness 0 at 50 years. Visual field examination could be performed in only half of the patients and showed a concentric constriction with remaining islands of function in the periphery. ERG recordings were mostly extinguished whereas VEP recordings were reduced in about half of the patients. The cohort of patients showed 51 different likely biallelic mutations—of which 11 are novel—in 12 different BBS-associated genes. The most common associated genes were BBS10 (32.8%) and BBS1 (24.6%), and by far the most commonly observed variants were BBS10 c.271dup;p.C91Lfs*5 (21 alleles) and BBS1 c.1169T>G;p.M390R (18 alleles). The phenotype associated with the different BBS-associated genes and genotypes in our cohort is heterogeneous, with diverse features without genotype−phenotype correlation. The results confirm and expand our knowledge of this rare disease.
Topics: Aging; Bardet-Biedl Syndrome; DNA Mutational Analysis; Electroretinography; Eye Diseases; Humans; Microtubule-Associated Proteins; Mutation; Retina
PubMed: 35886001
DOI: 10.3390/genes13071218 -
Cold Spring Harbor Perspectives in... Jul 2017The ciliopathies Bardet-Biedl syndrome and Alström syndrome cause obesity. How ciliary dysfunction leads to obesity has remained mysterious, partly because of a lack of... (Review)
Review
The ciliopathies Bardet-Biedl syndrome and Alström syndrome cause obesity. How ciliary dysfunction leads to obesity has remained mysterious, partly because of a lack of understanding of the physiological roles of primary cilia in the organs and pathways involved in the regulation of metabolism and energy homeostasis. Historically, the study of rare monogenetic disorders that present with obesity has informed our molecular understanding of the mechanisms involved in nonsyndromic forms of obesity. Here, we present a framework, based on genetic studies in mice and humans, of the molecular and cellular pathways underlying long-term regulation of energy homeostasis. We focus on recent progress linking these pathways to the function of the primary cilia with a particular emphasis on the roles of neuronal primary cilia in the regulation of satiety.
Topics: Alstrom Syndrome; Animals; Bardet-Biedl Syndrome; Cilia; Energy Metabolism; Humans; Mice; Obesity; Satiety Response
PubMed: 28096262
DOI: 10.1101/cshperspect.a028217 -
International Medical Case Reports... 2021Bardet-Biedl syndrome (BBS) is a rare familial and multi-system disorder with an autosomal recessive pattern of inheritance and wide range of clinical variability. Its...
Bardet-Biedl syndrome (BBS) is a rare familial and multi-system disorder with an autosomal recessive pattern of inheritance and wide range of clinical variability. Its main manifestations are progressive retinal dystrophy, renal dysfunction, post-axial polydactyly, central obesity, mental retardation, and hypogonadism. Renal failure is known to be the main cause of death in patients with BBS. Retinal dystrophy and other eye diseases seen in patients with BBS can cause severe visual impairment and blindness at an early age. After written consent was obtained from the patient, we report the clinical and laboratory data of the first case from Ethiopia of an 18-year-old boy with multi-system manifestations of the Bardet-Biedl Syndrome. We discuss the main clinical manifestations of the syndrome including its potentially blinding and fatal features. We emphasize the need for diagnosis of this syndrome at an early age as possible so that proper and multidisciplinary medical care can be given for such patients to prevent unnecessary morbidity and early mortality.
PubMed: 33776488
DOI: 10.2147/IMCRJ.S299421 -
Clinical Genetics Apr 2022The aim of this study was to explore kidney failure (KF) in Bardet-Biedl syndrome (BBS), focusing on high-risk gene variants, demographics, and morbidity. We employed...
The aim of this study was to explore kidney failure (KF) in Bardet-Biedl syndrome (BBS), focusing on high-risk gene variants, demographics, and morbidity. We employed the Clinical Registry Investigating BBS (CRIBBS) to identify 44 (7.2%) individuals with KF out of 607 subjects. Molecularly confirmed BBS was identified in 37 KF subjects and 364 CRIBBS registrants. KF was concomitant with recessive causal variants in 12 genes, with BBS10 the most predominant causal gene (26.6%), while disease penetrance was highest in SDCCAG8 (100%). Two truncating variants were present in 67.6% of KF cases. KF incidence was increased in genes not belonging to the BBSome or chaperonin-like genes (p < 0.001), including TTC21B, a new candidate BBS gene. Median age of KF was 12.5 years, with the vast majority of KF occurring by 30 years (86.3%). Females were disproportionately affected (77.3%). Diverse uropathies were identified, but were not more common in the KF group (p = 0.672). Kidney failure was evident in 11 of 15 (73.3%) deaths outside infancy. We conclude that KF poses a significant risk for premature morbidity in BBS. Risk factors for KF include female sex, truncating variants, and genes other than BBSome/chaperonin-like genes highlighting the value of comprehensive genetic investigation.
Topics: Bardet-Biedl Syndrome; Chaperonins; Child; Female; Humans; Male; Mutation; Penetrance; Renal Insufficiency
PubMed: 35112343
DOI: 10.1111/cge.14119 -
Cureus Dec 2021Bardet-Biedl syndrome (BBS), also known as Laurence-Moon-Bardet-Biedl syndrome, is a unique autosomal recessive genetic disorder that involves multiple organ systems...
Bardet-Biedl syndrome (BBS), also known as Laurence-Moon-Bardet-Biedl syndrome, is a unique autosomal recessive genetic disorder that involves multiple organ systems with an incidence under 1/100,000 in Europe and the USA. We present a case of a 27-year-old male with BBS and a past medical history of hypertension. He was diagnosed with BBS when he was a child. His physical examination showed polydactyly in the feet. His renal ultrasound showed the left kidney with a double collecting system and measured 1.9 × 6.1 × 3.6 cm and extended from the left upper quadrant to the left lower quadrant. His CT of the abdomen showed a horseshoe-shaped kidney with right moiety. Renal abnormalities in BBS have been identified recently. BBS is also associated with various cardiac manifestations such as patent ductus arteriosus, cardiomyopathies, and valvular diseases. BBS requires multidisciplinary management and a close follow-up with a nephrologist to decrease morbidity and mortality. Genetic and molecular mapping of this disorder will aid the understanding of congenital renal ciliopathies.
PubMed: 35103156
DOI: 10.7759/cureus.20577 -
Ophthalmic Genetics Jun 2021: To provide a detailed ophthalmic phenotype of two male patients with Bardet-Biedl Syndrome (BBS) due to mutations in the gene: Two brothers ages 26 (Patient 1, P1)...
: To provide a detailed ophthalmic phenotype of two male patients with Bardet-Biedl Syndrome (BBS) due to mutations in the gene: Two brothers ages 26 (Patient 1, P1) and 23 (P2) underwent comprehensive ophthalmic evaluations over three years. Visual function was assessed with full-field electroretinograms (ffERGs), kinetic and chromatic perimetry, multimodal imaging with spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) with short- (SW) and near-infrared (NIR) excitation lights and adaptive optics scanning light ophthalmoscopy (AOSLO).: Both siblings had a history of obesity and postaxial polydactyly; P2 had diagnoses of type 1 Diabetes Mellitus, Addison's disease, high-functioning autism-spectrum disorder and -12D myopia. Visual acuities were better than 20/30. Kinetic fields were moderately constricted. Cone-mediated ffERGs were undetectable, rod ERGs were ~80% of normal mean. Static perimetry showed severe central cone and rod dysfunction. Foveal to parafoveal hypoautofluorescence, most obvious on NIR-FAF, co-localized with outer segment shortening/loss and outer nuclear layer thinning by SD-OCT, and with reduced photoreceptors densities by AOSLO. A structural-functional dissociation was confirmed for cone- and rod-mediated parameters. Worsening of the above abnormalities was documented by SD-OCT and FAF in P2 at 3 years. Gene screening identified compound heterozygous mutations in (p.Val266Glu: c.797 T > A of maternal origin; c.1781_1783delCAT, paternal) in both patients.: -associated retinal degeneration may present as a progressive cone-rod dystrophy pattern, reminiscent of both the murine and non-human primate models of the disease. Predominantly central retinal abnormalities in both cone and rod photoreceptors showed a structural-functional dissociation, an ideal scenario for gene augmentation treatments.
Topics: Adaptor Proteins, Signal Transducing; Adult; Bardet-Biedl Syndrome; Cone-Rod Dystrophies; Cytoskeletal Proteins; Electroretinography; Genetic Therapy; Humans; Male; Models, Animal; Mutation; Ophthalmoscopy; Optical Imaging; Phenotype; Retina; Siblings; Tomography, Optical Coherence; Visual Acuity; Visual Field Tests; Young Adult
PubMed: 33729075
DOI: 10.1080/13816810.2021.1888132 -
Orphanet Journal of Rare Diseases Jun 2021Overweight and obesity are common features of the rare disease Bardet-Biedl syndrome (BBS). Sleep and physical activity are behaviors that might impact overweight and...
BACKGROUND
Overweight and obesity are common features of the rare disease Bardet-Biedl syndrome (BBS). Sleep and physical activity are behaviors that might impact overweight and obesity and thus may play a key role in the health and well-being of people with BBS. Objectively-measured sleep and physical activity patterns in people with BBS are not well known. We evaluated objectively-measured sleep and physical activity patterns in the largest cohort to date of people with BBS.
RESULTS
Short sleep duration, assessed using wrist-worn accelerometers, was common in both children and adults with BBS. Only 7 (10%) of adults and 6 (8%) of children met age-specific sleep duration recommendations. Most adults 64 (90%) achieved recommended sleep efficiency. The majority of children 26 (67%) age 6-12 years achieved recommended sleep efficiency, but among children age 13-18, only 18 (47%). In both adults and children, sleep duration was significantly negatively correlated with duration of prolonged sedentary time. In children age 6-12 sleep duration was also significantly related to total activity score, children with lower sleep duration had lower total activity scores.
CONCLUSIONS
Insufficient sleep duration is very common in people with BBS. Prolonged sedentary time and short sleep duration are both potentially important health-related behaviors to target for intervention in people with BBS.
Topics: Adolescent; Adult; Bardet-Biedl Syndrome; Child; Cohort Studies; Exercise; Humans; Obesity; Sleep
PubMed: 34127036
DOI: 10.1186/s13023-021-01911-4