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Molecular Genetics & Genomic Medicine Apr 2022Beckwith-Wiedemann syndrome (BWS) is an inherited disorder affecting 1 in 10,500 to 13,700 newborns worldwide. The disease is caused in a vast majority of patients by a...
BACKGROUND
Beckwith-Wiedemann syndrome (BWS) is an inherited disorder affecting 1 in 10,500 to 13,700 newborns worldwide. The disease is caused in a vast majority of patients by a molecular defect in the imprinted chromosome 11p15.5. Hereditary spherocytosis (HS) is a form of hemolytic anemia associated with a variety of mutations leading to congenital red blood cell (RBC) membrane defects. The prevalence of HS varies by geographic regions around the world, ranging from 1.2 in 100,000 in Asia to 1 in 2000 in Northern Europe.
METHODS AND RESULTS
Herein, we report for the first time a rare case diagnosed with co-existing BWS and HS. Based on the classical presentations, including macroglossia, hepatosplenomegaly, and macrosomia, the patient was first suspected with BWS. MS-MLPA confirmed the BWS diagnosis based on hypomethylation of maternal 11p15.5 (KCNQ1OT1), but no copy number variations in chromosome 11 was detected by CNV-seq. Nevertheless, to scrutinize molecular causes of other symptoms of the patient, including anemia, hyperbilirubinemia, and jaundice, a whole exome sequencing (WES) was performed. We identified a novel and de novo mutation in ANK1 gene (c.520delC). This frameshift mutation of ANK1 gene results in a truncated protein without important functional domains and impaired membrane stability and structure of the resultant red blood cells (RBCs), leading to a definitive diagnosis of HS.
CONCLUSION
The present case demonstrated that multiple genetic and epigenetic aberrations might co-exist in the complex genetic diseases. For such kind of complicated cases, the different types of molecular tests, such as WES and MS-MLPA, should be utilized in combination to reveal independent causal molecular events. The identifications from this study added new insights into the understanding of molecular mechanisms underlying the co-existing HS and BWS.
Topics: Ankyrins; Beckwith-Wiedemann Syndrome; DNA Methylation; Humans; Infant, Newborn; Mutation; Spherocytosis, Hereditary; Exome Sequencing
PubMed: 35218326
DOI: 10.1002/mgg3.1903 -
The Journal of Physiology Apr 2022Circulating bilirubin is associated with reduced serum cholesterol concentrations in humans and in hyperbilirubinaemic Gunn rats. However, mechanisms contributing to...
Circulating bilirubin is associated with reduced serum cholesterol concentrations in humans and in hyperbilirubinaemic Gunn rats. However, mechanisms contributing to hypocholesterolaemia remain unknown. Therefore, this study aimed to investigate cholesterol synthesis, transport and excretion in mutant Gunn rats. Adult Gunn and control rats were assessed for daily faecal sterol excretion using metabolic cages, and water was supplemented with [1- C]-acetate to determine cholesterol synthesis. Bile was collected to measure biliary lipid secretion. Serum and liver were collected for biochemical analysis and for gene/protein expression using RT-qPCR and western blot, respectively. Additionally, serum was collected and analysed from juvenile rats. A significant interaction of sex, age and phenotype on circulating lipids was found with adult female Gunn rats reporting significantly lower cholesterol and phospholipids. Female Gunn rats also demonstrated elevated cholesterol synthesis, greater biliary lipid secretion and increased total faecal cholesterol and bile acid excretion. Furthermore, they possessed increased hepatic low-density lipoprotein (LDL) receptor and SREBP2 expression. In contrast, there were no changes to sterol metabolism in adult male Gunn rats. This is the first study to demonstrate elevated faecal sterol excretion in female hyperbilirubinaemic Gunn rats. Increased sterol excretion creates a negative intestinal sterol balance that is compensated for by increased cholesterol synthesis and LDL receptor expression. Therefore, reduced circulating cholesterol is potentially caused by increased hepatic uptake via the LDL receptor. Future studies are required to further evaluate the sexual dimorphism of this response and whether similar findings occur in females with benign unconjugated hyperbilirubinaemia (Gilbert's syndrome). KEY POINTS: Female adult hyperbilirubinaemic (Gunn) rats demonstrated lower circulating cholesterol, corroborating human studies that report a negative association between bilirubin and cholesterol concentrations. Furthermore, female Gunn rats had elevated sterol excretion creating a negative intestinal sterol balance that was compensated for by elevated cholesterol synthesis and increased hepatic low-density lipoprotein (LDL) receptor expression. Therefore, elevated LDL receptor expression potentially leads to reduced circulating cholesterol levels in female Gunn rats providing an explanation for the hypocholesterolaemia observed in humans with elevated bilirubin levels. This study also reports a novel interaction of sex with the hyperbilirubinaemic phenotype on sterol metabolism because changes were only reported in females and not in male Gunn rats. Future studies are required to further evaluate the sexual dimorphism of this response and whether similar findings occur in females with benign unconjugated hyperbilirubinaemia (Gilbert's syndrome).
Topics: Animals; Bilirubin; Cholesterol; Female; Gilbert Disease; Hyperbilirubinemia; Hypercholesterolemia; Lipoproteins, LDL; Liver; Male; Rats; Rats, Gunn; Receptors, LDL; Sex Characteristics; Sterols
PubMed: 35156712
DOI: 10.1113/JP282395 -
Journal of Clinical and Experimental... 2021Gilbert's syndrome (GS) is a hereditary pathology that affects approximately 10% of the world's population. In most cases, GS is associated with the polymorphism of...
BACKGROUND/OBJECTIVES
Gilbert's syndrome (GS) is a hereditary pathology that affects approximately 10% of the world's population. In most cases, GS is associated with the polymorphism of gene coding the enzyme bilirubin uridine diphosphate glucuronosyltransferase (UGT-1A) which plays a key role in the bilirubin metabolism. The presence of an additional TA repeat in the TATA box of the gene promoter (the allelic variant of 7TA, abbreviated as ) leads to a significant decrease in the enzymatic activity of UGT-1A in the liver and to decrease in glucuronidation process as a consequence. The aim of the study is to estimate the prevalence of the 6TA/6TA, 6TA/7TA, and 7TA/7TA genotypes of promoter and to analyze the effect of these variants on bilirubin levels in healthy men in North-West Russia and patients with a clinical diagnosis of GS.
METHODS
Genotyping of the ∗28 (rs8175347) polymorphism was carried out by real-time PCR.
RESULTS
The results obtained indicate an increased probability of GS developing in residents of the North-West region of Russia compared with other representatives of the Caucasians.
CONCLUSIONS
Despite the fact that the level of serum bilirubin increases with the rise in the number of additional TA dinucleotides in the gene promoter tests of clinical manifestations only (jaundice, fatigue, sleep disturbances, nausea, belching, and so on) and increased bilirubin levels in patients with normal liver function do not allow unequivocally diagnose GS. genotyping should be used as a prognostic risk factor for such pathology development.
PubMed: 34866848
DOI: 10.1016/j.jceh.2021.01.006 -
Metabolism: Clinical and Experimental Dec 2021The protective role of mildly elevated bilirubin against CVD and diabetes mellitus type 2 (DMT2) is associated with a favorable lipid phenotype. As the mechanistic...
BACKGROUND
The protective role of mildly elevated bilirubin against CVD and diabetes mellitus type 2 (DMT2) is associated with a favorable lipid phenotype. As the mechanistic understanding of this protection in humans remains elusive, we aimed to assess the metabolomics profile of mildly hyperbilirubinemic (Gilbert's syndrome; GS) individuals especially targeting lipid catabolism.
METHODS AND RESULTS
Using NMR serum metabolomics of 56 GS individuals and 56 age and gender-matched healthy controls, GS individuals demonstrated significantly greater concentrations of acetylcarnitine (+20%, p < 0.001) and the ketone bodies, 3-hydroxybutyric acid (+132%, p < 0.001), acetoacetic acid (+95%, p < 0.001) and acetone (+46%, p < 0.001). Metabolites associated with an increased mitochondrial lipid metabolism such as citrate (+15%, p < 0.001), anaplerotic amino acid intermediates and creatinine were significantly greater and creatine significantly reduced in GS individuals. Stimulators of lipid catabolism including AMPK (+59%, p < 0.001), pPPARα (+24%, p < 0.001) and T3 (+9%, p = 0.009) supported the metabolomics data while concomitantly blood glucose and insulin (-33%, p = 0.002) levels were significantly reduced. We further showed that the increased lipid catabolism partially mediates the favorable lipid phenotype (lower triglycerides) of GS individuals. Increased trimethylamine (+35%, p < 0.001) indicated changes in trimethylamine metabolism, an emerging predictor of metabolic health.
CONCLUSION
We showed an enhanced lipid catabolism in mildly hyperbilirubinemic individuals, novel evidence as to why these individuals are leaner and protected against chronic metabolic diseases emphasizing bilirubin to be a promising future target in obese and dyslipidemia patients.
Topics: Adult; Bilirubin; Female; Gilbert Disease; Humans; Lipid Metabolism; Male; Metabolome; Metabolomics; Middle Aged; Young Adult
PubMed: 34653509
DOI: 10.1016/j.metabol.2021.154913 -
Frontiers in Cellular and Infection... 2021The heme catabolite bilirubin has anti-inflammatory, anti-oxidative and anti-mutagenic effects and its relation to colorectal cancer (CRC) risk is currently under...
The heme catabolite bilirubin has anti-inflammatory, anti-oxidative and anti-mutagenic effects and its relation to colorectal cancer (CRC) risk is currently under evaluation. Although the main metabolic steps of bilirubin metabolism, including the formation of stercobilin and urobilin, take place in the human gastrointestinal tract, potential interactions with the human gut microbiota are unexplored. This study investigated, whether gut microbiota composition is altered in Gilbert's Syndrome (GS), a mild form of chronically elevated serum unconjugated bilirubin (UCB) compared to matched controls. Potential differences in the incidence of CRC-associated bacterial species in GS were also assessed. To this end, a secondary investigation of the BILIHEALTH study was performed, assessing 45 adults with elevated UCB levels (GS) against 45 age- and sex-matched controls (C). Fecal microbiota analysis was performed using 16S rRNA gene sequencing. No association between mildly increased UCB and the composition of the gut microbiota in this healthy cohort was found. The alpha and beta diversity did not differ between C and GS and both groups showed a typical representation of the known dominant phyla. Furthermore, no difference in abundance of and , which have been associated with the mucosa of CRC patients were observed between the groups. A sequence related to the strain YIT 12065 was identified with a weak association value of 0.521 as an indicator species in the GS group. This strain has been previously associated with a lower body mass index, which is typical for the GS phenotype. Overall, sex was the only driver for an identifiable difference in the study groups, as demonstrated by a greater bacterial diversity in women. After adjusting for confounding factors and multiple testing, we can conclude that the GS phenotype does not affect the composition of the human gut microbiota in this generally healthy study group.
Topics: Case-Control Studies; Clostridiales; Female; Gastrointestinal Microbiome; Gilbert Disease; Humans; RNA, Ribosomal, 16S
PubMed: 34604105
DOI: 10.3389/fcimb.2021.701109 -
Diagnostics (Basel, Switzerland) Aug 2021Congenital hemolytic anemias (CHAs) are a group of diseases characterized by premature destruction of erythrocytes as a consequence of intrinsic red blood cells... (Review)
Review
Congenital hemolytic anemias (CHAs) are a group of diseases characterized by premature destruction of erythrocytes as a consequence of intrinsic red blood cells abnormalities. Suggestive features of CHAs are anemia and hemolysis, with high reticulocyte count, unconjugated hyperbilirubinemia, increased lactate dehydrogenase (LDH), and reduced haptoglobin. The peripheral blood smear can help the differential diagnosis. In this review, we discuss the clinical management of severe CHAs presenting early on in the neonatal period. Appropriate knowledge and a high index of suspicion are crucial for a timely differential diagnosis and management. Here, we provide an overview of the most common conditions, such as glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and hereditary spherocytosis. Although rare, congenital dyserythropoietic anemias are included as they may be suspected in early life, while hemoglobinopathies will not be discussed, as they usually manifest at a later age, when fetal hemoglobin (HbF) is replaced by the adult form (HbA).
PubMed: 34573891
DOI: 10.3390/diagnostics11091549 -
Molecular Genetics & Genomic Medicine Nov 2021
Topics: Crigler-Najjar Syndrome; Glucuronosyltransferase; Humans; Infant; Male; Mutation, Missense; Phenotype
PubMed: 34545702
DOI: 10.1002/mgg3.1805 -
World Journal of Clinical Cases Jul 2021Hereditary spherocytosis (HS) is a common type of hemolytic anemia caused by a red cell membrane disorder. HS type 1 (HS1) is mostly caused by mutations in ankyrin ()....
BACKGROUND
Hereditary spherocytosis (HS) is a common type of hemolytic anemia caused by a red cell membrane disorder. HS type 1 (HS1) is mostly caused by mutations in ankyrin (). Newborns with HS1 usually only exhibit anemia and mild jaundice. We herein report a case of HS1 and discuss its clinical characteristics.
CASE SUMMARY
A 2-d-old male full-term newborn was admitted to our hospital with severe, intractable neonatal jaundice. Laboratory investigations showed hemolytic anemia and hyperbilirubinemia and excluded immune-mediated hemolysis. The patient underwent two exchange transfusions and one plasmapheresis resulting in significantly reduced serum bilirubin. Hematologic analyses and genomic DNA sequencing studies were performed. The trio clinical exome sequencing revealed a null heterozygous mutation in the patient's gene: c.841C > T(p.Arg281Ter). This mutation results in the premature termination of the ANK1 protein.
CONCLUSION
Our case demonstrates that genetic analysis can be an essential method for diagnosing HS when a newborn has severe hyperbilirubinemia.
PubMed: 34307574
DOI: 10.12998/wjcc.v9.i19.5245 -
Ethiopian Journal of Health Sciences Jan 2021Gilbert syndrome is a well-recognized condition causing unconjugated hyperbilirubinemia with otherwise normal transaminases and liver function tests.
BACKGROUND
Gilbert syndrome is a well-recognized condition causing unconjugated hyperbilirubinemia with otherwise normal transaminases and liver function tests.
CASE
A 21 year old male patient presented with recurrent episodes of jaundice over four years. The episodes were preceded by stressful conditions and intercurrent illnesses. All laboratory prameters were normal except an unconjugated hyperbilirubinemia. A diagnosis of Gilbert syndrome was made after careful clinical evaluation.
CONCLUSION
Recognizing Gilbert syndrome has important clinical implicaitions by avoiding uncessary and expensive workup of patients with jaundice. Mangement entails avoiding stressful conditions and prolonged fasting.
Topics: Adult; Fasting; Gilbert Disease; Humans; Hyperbilirubinemia; Male; Young Adult
PubMed: 34158769
DOI: 10.4314/ejhs.v31i1.24