Afectación ocular como primera y única manifestación del síndrome de Bardet-Biedl: presentación de un caso / Ocular impairment as the first and only manifestation of Bardet–Biedl syndrome: A case report

El síndrome de Bardet-Biedl (SBB) es una ciliopatía que se asocia principalmente a distrofia retiniana, disfunción renal, polidactilia posaxial, obesidad, déficit cognitivo e hipogonadismo. Los síntomas vinculados a la distrofia retiniana no suelen aparecer hasta la primera década de vida, por lo que la detección tiende a retrasarse. La afectación ocular puede ser la forma inicial de manifestación de este síndrome, incluso puede ser la única, por lo que se debería tener en cuenta en el diagnóstico diferencial de una ambliopía en un niño que no mejora a pesar del correcto cumplimiento del tratamiento. Se presenta un caso de baja agudeza visual (AV) en una paciente pediátrica como manifestación inicial que lleva al diagnóstico del SBB y que es, además, el único síntoma que exhibe hasta la fecha, a pesar de tratarse de una enfermedad multisistémica.(AU)

Bardet–Biedl syndrome is a ciliopathy mainly associated with retinal dystrophy, renal dysfunction, post-axial polydactyly, obesity, cognitive deficit and hypogonadism. The symptoms associated with retinal dystrophy do not usually appear until the first decade of life, so the diagnosis is usually delayed. Ocular involvement may be the initial form of manifestation of this syndrome, it may even be the only one, so it should be taken into account in the differential diagnosis of amblyopia in a child who does not improve despite correct compliance with treatment. A case of low visual acuity in a pediatric patient is presented as an initial manifestation that leads to the diagnosis of Bardet–Biedl syndrome, and which is also the only symptom that the patient presents to date, despite being a multisystem disease.(AU)

Molecular and phenotypic characteristics of Bardet-Biedl syndrome in Chinese patients.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a type of non-motile ciliopathy. To date, 26 genes have been reported to be associated with BBS. However, BBS is genetically heterogeneous, with significant clinical overlap with other ciliopathies, which complicates diagnosis. Disability and mortality rates are high in BBS patients; therefore, it is urgent to improve our understanding of BBS. Thus, our study aimed to describe the genotypic and phenotypic spectra of BBS in China and to elucidate genotype-phenotype correlations. METHODS: Twenty Chinese patients diagnosed with BBS were enrolled in this study. We compared the phenotypes of Chinese BBS patients in this study with those from other countries to analyze the phenotypic differences across patients worldwide. In addition, genotype-phenotype correlations were described for our cohort. We also summarized all previously reported cases of BBS in Chinese patients (71 patients) and identified common and specific genetic variants in the Chinese population. RESULTS: Twenty-eight variants, of which 10 are novel, in 5 different BBS-associated genes were identified in 20 Chinese BBS patients. By comparing the phenotypes of BBSome-coding genes (BBS2,7,9) with those of chaperonin-coding genes (BBS10,12), we found that patients with mutations in BBS10 and 12 had an earlier age of onset (1.10 Vs. 2.20, p < 0.01) and diagnosis (4.64 Vs. 13.17, p < 0.01), whereas patients with mutations in BBS2, 7, and 9 had a higher body mass index (28.35 Vs. 24.21, p < 0.05) and more vision problems (p < 0.05). Furthermore, in 91 Chinese BBS patients, mutations were predominant in BBS2 (28.89%) and BBS7 (15.56%), and the most frequent variants were in BBS2: c.534 + 1G > T (10/182 alleles) and BBS7: c.1002delT (7/182 alleles), marking a difference from the genotypic spectra of BBS reported abroad. CONCLUSIONS: We recruited 20 Chinese patients with BBS for genetic and phenotypic analyses, and identified common clinical manifestations, pathogenic genes, and variants. We also described the phenotypic differences across patients worldwide and among different BBS-associated genes. This study involved the largest cohort of Chinese patients with BBS, and provides new insights into the distinctive clinical features of specific pathogenic variants.

Syndromic ciliopathy: a taiwanese single-center study.

BACKGROUND: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes. METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment. RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation. CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

Syndromic Retinitis Pigmentosa: A 15-Patient Study.

Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic conditions. This study reviewed the clinical data of 15 patients with syndromic retinitis pigmentosa from a Rare Disease Reference Center in Brazil and the results of their next-generation sequencing tests. Five males and ten females participated, with the mean ages for ocular disease onset, fundoscopic diagnosis, and molecular evaluation being 9, 19, and 29 years, respectively. Bardet-Biedl syndrome (n = 5) and Usher syndrome (n = 3) were the most frequent diagnoses, followed by other rare conditions. Among the patients, fourteen completed molecular studies, with three negative results and eleven revealing findings in known genes, including novel variants in MKKS (c.432_435del, p.Phe144Leufs*14), USH2A (c.(7301+1_7302-1)_(9369+1_9370-1)del), and CEP250 (c.5383dup, p.Glu1795Glyfs*13, and c.5050del, p.Asp1684Thrfs*9). Except for Kearn-Sayre, all presented an autosomal recessive inheritance pattern with 64% homozygosity results. The long gap between symptom onset and diagnosis highlights the diagnostic challenges faced by the patients. This study reaffirms the clinical heterogeneity of syndromic retinitis pigmentosa and underscores the pivotal role of molecular analysis in advancing our understanding of these diseases.

The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.

Bardet-Biedl syndrome: A focus on genetics, mechanisms and metabolic dysfunction.

Bardet-Biedl syndrome (BBS) is a rare, monogenic, multisystem disorder characterized by retinal dystrophy, renal abnormalities, polydactyly, learning disabilities, as well as metabolic dysfunction, including obesity and an increased risk of type 2 diabetes. It is a primary ciliopathy, and causative mutations in more than 25 different genes have been described. Multiple cellular mechanisms contribute to the development of the metabolic phenotype associated with BBS, including hyperphagia as a consequence of altered hypothalamic appetite signalling as well as alterations in adipocyte biology promoting adipocyte proliferation and adipogenesis. Within this review, we describe in detail the metabolic phenotype associated with BBS and discuss the mechanisms that drive its evolution. In addition, we review current approaches to the metabolic management of patients with BBS, including the use of weight loss medications and bariatric surgery. Finally, we evaluate the potential of targeting hypothalamic appetite signalling to limit hyperphagia and induce clinically significant weight loss.

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.

Ocular impairment as the first and only manifestation of Bardet-Biedl syndrome: A case report.

Bardet-Biedl syndrome is a ciliopathy mainly associated with retinal dystrophy, renal dysfunction, post-axial polydactyly, obesity, cognitive deficit and hypogonadism. The symptoms associated with retinal dystrophy do not usually appear until the first decade of life, so the diagnosis is usually delayed. Ocular involvement may be the initial form of manifestation of this syndrome, it may even be the only one, so it should be taken into account in the differential diagnosis of amblyopia in a child who does not improve despite correct compliance with treatment. A case of low visual acuity in a pediatric patient is presented as an initial manifestation that leads to the diagnosis of Bardet-Biedl Syndrome, and which is also the only symptom that the patient presents to date, despite being a multisystem disease.

POMC Neuron BBSome Regulation of Body Weight is Independent of its Ciliary Function.

The BBSome, a complex of several Bardet-Biedl syndrome (BBS) proteins including BBS1, has emerged as a critical regulator of energy homeostasis. Although the BBSome is best known for its involvement in cilia trafficking, through a process that involve BBS3, it also regulates the localization of cell membrane receptors underlying metabolic regulation. Here, we show that inducible Bbs1 gene deletion selectively in proopiomelanocortin (POMC) neurons cause a gradual increase in body weight, which was associated with higher fat mass. In contrast, inducible deletion of Bbs3 gene in POMC neurons failed to affect body weight and adiposity. Interestingly, loss of BBS1 in POMC neurons led to glucose intolerance and insulin insensitivity, whereas BBS3 deficiency in these neurons is associated with slight impairment in glucose handling, but normal insulin sensitivity. BBS1 deficiency altered the plasma membrane localization of serotonin 5-HT2C receptor (5-HT2CR) and ciliary trafficking of neuropeptide Y2 receptor (NPY2R).In contrast, BBS3 deficiency, which disrupted the ciliary localization of the BBSome, did not interfere with plasma membrane expression of 5-HT2CR, but reduced the trafficking of NPY2R to cilia. We also show that deficiency in BBS1, but not BBS3, alters mitochondria dynamics and decreased total and phosphorylated levels of dynamin-like protein 1 (DRP1) protein. Importantly, rescuing DRP1 activity restored mitochondria dynamics and localization of 5-HT2CR and NPY2R in BBS1-deficient cells. The contrasting effects on energy and glucose homeostasis evoked by POMC neuron deletion of BBS1 versus BBS3 indicate that BBSome regulation of metabolism is not related to its ciliary function in these neurons.

BBS genes are involved in accelerated proliferation and early differentiation of BBS-related tissues.

Bardet-Biedl syndrome (BBS) is an inherited disorder primarily ciliopathy with pleiotropic multi-systemic phenotypic involvement, including adipose, nerve, retinal, kidney, Etc. Consequently, it is characterized by obesity, cognitive impairment and retinal, kidney and cutaneous abnormalities. Initial studies, including ours have shown that BBS genes play a role in the early developmental stages of adipocytes and ß-cells. However, this role in other BBS-related tissues is unknown. We investigated BBS genes involvement in the proliferation and early differentiation of different BBS cell types. The involvement of BBS genes in cellular proliferation were studied in seven in-vitro and transgenic cell models; keratinocytes (hHaCaT) and Ras-transfected keratinocytes (Ras-hHaCaT), neuronal cell lines (hSH-SY5Y and rPC-12), silenced BBS4 neural cell lines (siBbs4 hSH-SY5Y and siBbs4 rPC-12), adipocytes (m3T3L1), and ex-vivo transformed B-cells obtain from BBS4 patients, using molecular and biochemical methodologies. RashHaCaT cells showed an accelerated proliferation rate in parallel to significant reduction in the transcript levels of BBS1, 2, and 4. BBS1, 2, and 4 transcripts linked with hHaCaT cell cycle arrest (G1 phase) using both chemical (CDK4 inhibitor) and serum deprivation methodologies. Adipocyte (m3T3-L1) Bbs1, 2 and 4 transcript levels corresponded to the cell cycle phase (CDK4 inhibitor and serum deprivation). SiBBS4 hSH-SY5Y cells exhibited early cell proliferation and differentiation (wound healing assay) rates. SiBbs4 rPC-12 models exhibited significant proliferation and differentiation rate corresponding to Nestin expression levels. BBS4 patients-transformed B-cells exhibited an accelerated proliferation rate (LPS-induced methodology). In conclusions, the BBS4 gene plays a significant, similar and global role in the cellular proliferation of various BBS related tissues. These results highlight the universal role of the BBS gene in the cell cycle, and further deepen the knowledge of the mechanisms underlying the development of BBS.

Early development and adaptive functioning in children with Bardet-Biedl syndrome.

This study had two aims. Aim one investigated achievement of 10 developmental milestones in children with Bardet-Biedl syndrome (BBS). Aim one data were derived from retrospective responses by caregivers of individuals with BBS who are enrolled in the Clinical Registry Investigating Bardet-Biedl syndrome (CRIBBS). CRIBBS is a natural history registry acquiring serial observations. Aim two investigated early adaptive skills using the Adaptive Behavior Assessment System (ABAS-II 0-5) completed by caregivers of children with BBS aged from 0 to 5. There were 652 individuals with milestone information (with some variability based on availability of information for specific milestones), and 101 individuals (including 95 among the 652) with ABAS-II information. Results revealed wide-ranging delays in adaptive skills, particularly in the domain of Self-Care. Expressive language appears to be the most frequently delayed developmental milestone. We found a difference by BBS genotype wherein individuals with BBS1 had higher adaptive/developmental scores than individuals with BBS10. Age also carried a significant association with adaptive skills diverging farther from a normative trajectory as children with BBS progress through early childhood.

De-Suppression of Mesenchymal Cell Identities and Variable Phenotypic Outcomes Associated with Knockout of Bbs1.

Bardet-Biedl syndrome (BBS) is an archetypal ciliopathy caused by dysfunction of primary cilia. BBS affects multiple tissues, including the kidney, eye and hypothalamic satiety response. Understanding pan-tissue mechanisms of pathogenesis versus those which are tissue-specific, as well as gauging their associated inter-individual variation owing to genetic background and stochastic processes, is of paramount importance in syndromology. The BBSome is a membrane-trafficking and intraflagellar transport (IFT) adaptor protein complex formed by eight BBS proteins, including BBS1, which is the most commonly mutated gene in BBS. To investigate disease pathogenesis, we generated a series of clonal renal collecting duct IMCD3 cell lines carrying defined biallelic nonsense or frameshift mutations in Bbs1, as well as a panel of matching wild-type CRISPR control clones. Using a phenotypic screen and an unbiased multi-omics approach, we note significant clonal variability for all assays, emphasising the importance of analysing panels of genetically defined clones. Our results suggest that BBS1 is required for the suppression of mesenchymal cell identities as the IMCD3 cell passage number increases. This was associated with a failure to express epithelial cell markers and tight junction formation, which was variable amongst clones. Transcriptomic analysis of hypothalamic preparations from BBS mutant mice, as well as BBS patient fibroblasts, suggested that dysregulation of epithelial-to-mesenchymal transition (EMT) genes is a general predisposing feature of BBS across tissues. Collectively, this work suggests that the dynamic stability of the BBSome is essential for the suppression of mesenchymal cell identities as epithelial cells differentiate.

Retinal nerve fibre layer thinning and corneal nerve loss in patients with Bardet-Biedl syndrome.

BACKGROUND: Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic disorder caused by variants in genes involved in the function of the primary cilium. We have harnessed genomics to identify BBS and ophthalmic technologies to describe novel features of BBS. CASE PRESENTATION: A patient with an unclear diagnosis of syndromic type 2 diabetes mellitus, another affected sibling and unaffected siblings and parents were sequenced using DNA extracted from saliva samples. Corneal confocal microscopy (CCM) and retinal spectral domain optical coherence tomography (SD-OCT) were used to identify novel ophthalmic features in these patients. The two affected individuals had a homozygous variant in C8orf37 (p.Trp185*). SD-OCT and CCM demonstrated a marked and patchy reduction in the retinal nerve fiber layer thickness and loss of corneal nerve fibers, respectively. CONCLUSION: This report highlights the use of ophthalmic imaging to identify novel retinal and corneal abnormalities that extend the phenotype of BBS in a patient with syndromic type 2 diabetes.

Sequence variants in different genes underlying Bardet-Biedl syndrome in four consanguineous families.

BACKGROUND: Bardet-Biedl Syndrome (BBS) is a rare (1:13,500-1-160,000) heterogeneous congenital disorder, characterized by postaxial polydactyly, obesity, hypogonadism, rod-cone dystrophy, cognitive impairment, and renal abnormalities (renal cystic dysplasia, anatomical malformation). To date about twenty-five genes have been identified to cause BBS, which accounts for about 80% of BBS diagnosis. METHODS: In the current study, we have performed mutational screening of four Pakistani consanguineous families (A-D) with clinical manifestation of BBS by microsatellite-based genotyping and whole exome sequencing. RESULTS: Analysis of the data revealed four variants, including a novel/unique inheritance pattern of compound heterozygous variants, p.(Ser40*) and p.(Thr259Leufs*21), in MKKS gene, novel homozygous variant, p.(Gly251Val)] in BBS7 gene and two previously reported p.(Thr259Leufs*21) in MKKS and p.(Met1Lys) in BBS5 gene. The variants were found segregated with the disorder within the families. CONCLUSION: The study not only expanded mutations spectrum in the BBS genes, but this will facilitate diagnosis and genetic counselling of families carrying BBS related phenotypes in Pakistani population.

Searching for Effective Methods of Diagnosing Nervous System Lesions in Patients with Alström and Bardet-Biedl Syndromes.

Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare multisystem diseases with an autosomal recessive mode of inheritance and genetic heterogeneity, characterized by visual impairment, hearing impairment, cardiomyopathy, childhood obesity, and insulin resistance. The purpose of our study was to evaluate the indicators of nervous system changes occurring in patients with ALMS and BBS using optical coherence tomography (OCT) and magnetic resonance spectroscopy (MRS) methods compared to a group of healthy subjects. The OCT results showed significantly lower macular thickness in the patient group compared to the control group (p = 0.002). The MRS study observed differences in metabolite levels between the study and control groups in brain areas such as the cerebellum, thalamus, and white matter. After summing the concentrations from all areas, statistically significant results were obtained for N-acetylaspartate, total N-acetylaspartate, and total creatine. Concentrations of these metabolites were reduced in ALMS/BBS patients by 38% (p = 0.0004), 35% (p = 0.0008), and 28% (p = 0.0005), respectively. Our results may help to understand the pathophysiology of these rare diseases and identify strategies for new therapies.

Síndrome de Bardet-Biedl: A propósito de un caso / Bardet-Biedl syndrome: About a case

El síndrome de Bardet-Biedl (SBB) es una entidad poco frecuente, con gran heterogeneidad clínica y genética. Pertenece a las ciliopatías y tiene un modo de herencia autosómico recesivo. Hasta la fecha se han identificado más de 26 genes asociados. Afecta múltiples sistemas con compromiso oftalmológico, renal, cognitivo, esquelético, gonadal y ponderal. Su diagnóstico se basa en criterios clínicos y se confirma mediante estudios genéticos específicos. Presentamos el caso de un paciente de 2 años y 7 meses de edad, con polidactilia, obesidad, retraso del neurodesarrollo y afección renal en quien se arribó al diagnóstico clínico de SBB con posterior confirmación mediante estudio molecular. Se detectó una variante patogénica en homocigosis en el gen BBS2. La sospecha y confirmación diagnóstica permitieron el manejo adecuado del paciente, planificar el seguimiento apropiado y completar el asesoramiento genético familiar

Bardet-Biedl syndrome (BBS) is a rare entity that holds a great clinical and genetic heterogeneity. It is a ciliopathy and has an autosomal recessive inheritance. To this day more than 26 associated genes have been identified. It affects multiple aspects predominantly ophthalmological, renal, cognitive, skeletal, gonadal and weight. The diagnosis is based on clinical criteria and confirmed by specific genetic studies. We describe a case of a 2-year-and 7 month old patient with polydactyly, obe39 sity, neurodevelopmental delay and kidney dysplasia in which clinical diagnosis was suspected by criteria and subsequently has confirmation by molecular study. An homozygous pathogenic variant was detected in the BBS2 gene. The diagnostic suspicion and later confirmation allowed the proper management of this patient as well as an appropriate follow-up and complete genetic family counseling