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Annals of Medicine and Surgery (2012) May 2024Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder impacting multiple organs. Characterized by renal dysfunction, retinal dystrophy, obesity,...
INTRODUCTION AND IMPORTANCE
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder impacting multiple organs. Characterized by renal dysfunction, retinal dystrophy, obesity, polydactyly, intellectual disability, and hypogonadism, it lacks targeted treatment. Diagnosis relies on clinical criteria, and management emphasizes early detection, complication screening, and genetic counselling.
CASE PRESENTATION
A 4-year-old boy, born to first-cousin parents, presented with refractory iron-deficiency anaemia (IDA) and recurrent respiratory infections. Prenatal ultrasound revealed renal and limb anomalies. Physical examination showed dysmorphic features, polydactyly, and a giant-congenital naevus. Genetic testing revealed a homozygous MKKS variant. Despite oral iron, severe IDA persisted. Intravenous iron therapy yielded significant improvement.
CLINICAL DISCUSSION
BBS, an autosomal recessive ciliopathy, involves various genes. In this case, the MKKS gene variant contributed to the syndrome. The incidence of BBS in the Arab population is discussed, emphasizing its rarity and varied clinical presentations. Incidence in the Arab population, including Palestine, is 1 in 13 500. Diagnostic criteria, encompassing major and minor features, highlight BBS complexity. Renal anomalies, visual disturbances, and cutaneous manifestations are common. Multidisciplinary care addresses systemic involvement with emerging treatments like setmelanotide.
CONCLUSION
This case underscores BBS's rarity and complexity, featuring unique aspects like giant nevi and refractory IDA. Comprehensive management addresses renal, visual, cardiac, and neurologic aspects. Genetic counselling, prenatal testing, and preimplantation genetic diagnosis prevent transmission. Limitations include lacking local epidemiological data and prior studies in Palestine. This case contributes insights, stressing multidisciplinary management and prompting further research in underexplored populations.
PubMed: 38694397
DOI: 10.1097/MS9.0000000000001954 -
Genes Apr 2024Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic...
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 ( = 5) and Usher syndrome ( = 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 (c.432_435del, p.Phe144Leufs*14), (c.(7301+1_7302-1)_(9369+1_9370-1)del), and (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.
Topics: Humans; Retinitis Pigmentosa; Male; Female; Adult; Adolescent; Child; Young Adult; Usher Syndromes; Brazil; Middle Aged; High-Throughput Nucleotide Sequencing; Bardet-Biedl Syndrome; Mutation
PubMed: 38674450
DOI: 10.3390/genes15040516 -
Children (Basel, Switzerland) Mar 2024Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or...
INTRODUCTION
Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or other biomarkers to estimate the phenotypic consequences. Therefore, CyKD in children heavily relies on clinical and diagnostic testing to predict the long-term outcomes.
AIM
A retrospective study aimed to provide a concise overview of this condition and analyze real-life data from a single-center pediatric CyKD cohort followed during a 12-year period.
METHODS AND MATERIALS
Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes.
RESULTS
During the study period, 112 patients received a diagnosis of pediatric CyKD. Male patients were more involved than female (1:0.93). Fifty-six patients had a multicystic dysplastic kidney; twenty-one of them had an autosomal dominant disorder; fifteen had an isolated renal cyst; ten had been diagnosed with autosomal recessive polycystic kidney disease; three had the tuberous sclerosis complex; two patients each had Bardet-Biedl, Joubert syndrome, and nephronophthisis; and one had been diagnosed with the trisomy 13 condition. Genetic testing was performed in 17.9% of the patients, revealing disease-causing mutations in three-quarters (75.0%) of the tested patients. The most commonly presenting symptoms were abdominal distension (21.4%), abdominal pain (15.2%), and oligohydramnios (12.5%). Recurrent urinary tract infections (UTI) were documented in one-quarter of the patients, while 20.5% of them developed hypertension during the long-term follow-up. Antibiotic prophylaxis and antihypertensive treatment were the most employed therapeutic modalities. Seventeen patients progressed to chronic kidney disease (CKD), with thirteen of them eventually reaching end-stage renal disease (ESRD). The time from the initial detection of cysts on an ultrasound (US) to the onset of CKD across the entire cohort was 59.0 (7.0-31124.0) months, whereas the duration from the detection of cysts on an US to the onset of ESRD across the whole cohort was 127.0 (33.0-141.0) months. The median follow-up duration in the cohort was 3.0 (1.0-7.0) years. The patients who progressed to ESRD had clinical symptoms at the time of initial clinical presentation.
CONCLUSION
This study is the first large cohort of patients reported from Croatia. The most common CyKD was the multicystic dysplastic kidney disease. The most common clinical presentation was abdominal distention, abdominal pain, and oliguria. The most common long-term complications were recurrent UTIs, hypertension, CKD, and ESRD.
PubMed: 38671609
DOI: 10.3390/children11040392 -
BMC Medical Genomics Apr 2024Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies,...
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.
Topics: Humans; Male; Female; Taiwan; Ciliopathies; Child; Child, Preschool; Mutation; Exome Sequencing; Bardet-Biedl Syndrome; Adolescent; Infant; Abnormalities, Multiple; Retina; Syndrome; Cilia; Eye Abnormalities; Cerebellum; Proteins; Kidney Diseases, Cystic
PubMed: 38671463
DOI: 10.1186/s12920-024-01880-0 -
Frontiers in Pediatrics 2024
PubMed: 38659695
DOI: 10.3389/fped.2024.1401593 -
BMC Medical Genomics Apr 2024This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia,...
A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts.
BACKGROUND
This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts. The presence of renal agenesis and cryptorchidism expands the clinical manifestations due to ARL2BP variants. The detailed, long-term follow-up contributes valuable insights into disease progression, aiding clinical diagnosis and patient management.
CASE PRESENTATION
The male patient complained of photophobia as the first symptom when he was 20 years old followed by nyctalopia, loss of central visual acuity and peripheral visual field ten years later. Genetic analysis identified a likely pathogenic homozygous variant (c.294-1G > C) involving the splicing acceptor site of intron 4. Reported symptoms together with full-field stimulus threshold testing, electroretinogram and advanced multimodal imaging allowed us to recognize the typical characteristics of a mixed retinal dystrophy. Despite the end-stage retinal disease, this patient still retained a useful residual vision at 63 years and had a slow disease progression during the last 5 years of evaluation.
DISCUSSION AND CONCLUSIONS
Our findings underscore the variable clinical presentation of ARL2BP variants, emphasizing the importance of a nuanced approach in diagnosing and managing patients. The presence of renal cysts warrants consideration of a differential diagnosis, particularly with Senior-Loken (SLS), Bardet-Biedl (BBS) and Joubert syndromes (JS) but also with Short Rib Thoracic Dysplasia 9, highlighting the need for careful phenotypic evaluation in these cases.
Topics: Humans; Male; Cone-Rod Dystrophies; Congenital Abnormalities; Homozygote; Kidney; Kidney Diseases; RNA Splice Sites; Situs Inversus; Syndrome; Middle Aged
PubMed: 38649918
DOI: 10.1186/s12920-024-01868-w -
The Journal of Biological Chemistry Apr 2024Mutations in the adiponectin receptor 1 gene (AdipoR1) lead to retinitis pigmentosa and are associated with age-related macular degeneration. This study explores the...
Mutations in the adiponectin receptor 1 gene (AdipoR1) lead to retinitis pigmentosa and are associated with age-related macular degeneration. This study explores the effects of AdipoR1 gene deficiency in mice, revealing a striking decline in ω3 polyunsaturated fatty acids (PUFA), an increase in ω6 fatty acids, and elevated ceramides in the retina. The AdipoR1 deficiency impairs peroxisome proliferator-activated receptor α signaling, which is crucial for FA metabolism, particularly affecting proteins associated with FA transport and oxidation in the retina and retinal pigmented epithelium. Our lipidomic and proteomic analyses indicate changes that could affect membrane composition and viscosity through altered ω3 PUFA transport and synthesis, suggesting a potential influence of AdipoR1 on these properties. Furthermore, we noted a reduction in the Bardet-Biedl syndrome proteins, which are crucial for forming and maintaining photoreceptor outer segments that are PUFA-enriched ciliary structures. Diminution in Bardet-Biedl syndrome-proteins content combined with our electron microscopic observations raises the possibility that AdipoR1 deficiency might impair ciliary function. Treatment with inhibitors of ceramide synthesis led to substantial elevation of ω3 LC-PUFAs, alleviating photoreceptor degeneration and improving retinal function. These results serve as the proof of concept for a ceramide-targeted strategy to treat retinopathies linked to PUFA deficiency, including age-related macular degeneration.
PubMed: 38636661
DOI: 10.1016/j.jbc.2024.107291 -
International Journal of Medical... 2024Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies,...
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. 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. 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. 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.
Topics: Female; Male; Humans; Bardet-Biedl Syndrome; Comorbidity; Heterozygote; Obesity; Renal Insufficiency, Chronic
PubMed: 38617006
DOI: 10.7150/ijms.92766 -
Orphanet Journal of Rare Diseases Apr 2024Bardet-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...
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.
Topics: Humans; Bardet-Biedl Syndrome; Phenotype; Genotype; Chaperonins; Mutation; Ciliopathies
PubMed: 38584252
DOI: 10.1186/s13023-024-03150-9 -
Current Issues in Molecular Biology Mar 2024Bardet-Biedl syndrome (BBS), one of the most common forms of syndromic inherited retinal diseases (IRDs), is characterized by the combination of retinal degeneration...
Bardet-Biedl syndrome (BBS), one of the most common forms of syndromic inherited retinal diseases (IRDs), is characterized by the combination of retinal degeneration with additional extra-ocular manifestations, including obesity, intellectual disability, kidney disease, polydactyly and other skeletal abnormalities. We observed an Israeli patient with autosomal recessive apparently non-syndromic rod-cone dystrophy (RCD). Extra-ocular findings were limited to epilepsy and dental problems. Genetic analysis with a single molecule molecular inversion probes-based panel that targets the exons and splice sites of 113 genes associated with retinitis pigmentosa and Leber congenital amaurosis revealed a homozygous rare missense variant in the gene (c.263C>T;p.(Ser88Leu)). This variant, which affects a highly conserved amino acid, is also located in the last base of Exon 3, and predicted to be splice-altering. An in vitro minigene splice assay demonstrated that this variant leads to the partial aberrant splicing of Exon 3. Therefore, we suggest that this variant is likely hypomorphic. This is in agreement with the relatively mild phenotype observed in the patient. Hence, the findings in our study expand the phenotypic spectrum associated with variants and indicate that variants in this gene should be considered not only in BBS patients but also in individuals with non-syndromic IRD or IRD with very mild extra-ocular manifestations.
PubMed: 38534779
DOI: 10.3390/cimb46030163