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Zhonghua Gan Zang Bing Za Zhi =... Feb 2023To investigate the family gene features in Crigler-Najjar syndrome (CNS) type II. The gene and related bilirubin metabolism genes were comprehensively analysed in a...
To investigate the family gene features in Crigler-Najjar syndrome (CNS) type II. The gene and related bilirubin metabolism genes were comprehensively analysed in a CNS-II family (3 CNS-II, 1 Gilbert syndrome, and 8 normal subjects). The genetics basis of CNS-II were investigated from the perspective of family analysis. In three cases, compound heterozygous mutations at three sites of the gene (c.-3279T > G, c.211G > A and c.1456T > G) caused CNS-II. Gilbert syndrome and CNS-II were not significantly associated with distribution or diversity loci. The compound heterozygous pathogenic mutations (c.-3279T > G, c.211G > A, and c.1456T > G) at three loci of the gene may be the feature of the newly discovered CNS-II family genes based on the CNS-II family study.
Topics: Humans; Crigler-Najjar Syndrome; Gilbert Disease; Glucuronosyltransferase; Mutation
PubMed: 37137832
DOI: 10.3760/cma.j.cn501113-20211124-00580 -
Journal of the Formosan Medical... Jul 2023Rotor syndrome is a rare, benign, inherited disorder that is commonly associated with mild hyperbilirubinemia. It is caused by bi-allelic pathological variants in both...
Rotor syndrome is a rare, benign, inherited disorder that is commonly associated with mild hyperbilirubinemia. It is caused by bi-allelic pathological variants in both SLCO1B1 and SLCO1B3 genes, causing defective OATP1B1 and OATP1B3 in the sinusoidal membrane and interrupted bilirubin uptake of the hepatocytes. We report five Taiwanese pediatric and adult patients aged 5-32 years presenting with conjugated hyperbilirubinemia, and were found to have genetic variants of SLCO1B1 and SLCO1B3. Two also had history of prolonged neonatal jaundice. Genetic analysis using panel-based next generation sequencing revealed three patients with homozygous mutations c.1738C>T (p.R580∗) in SLCO1B1 and a transposon LINE-1 insertion in SLCO1B3, one patient with homozygous mutations for another haplotype, c.757C>T (p.R253∗) in SLCO1B1 and c.1747+1G>A in SLCO1B3. Another patient had heterozygous c.1738C>T (p.R580∗) in SLCO1B1 linked with a LINE-1 insertion in SLCO1B3, and heterozygous c.757C>T (p.R253∗) in SLCO1B1 linked with c.1747+1G>A in SLCO1B3. In conclusion, we present the first time of genetic diagnosis of Rotor syndrome in Taiwan. Advanced genetic testing has enhanced the diagnosis of rare diseases with mild symptoms.
Topics: Adult; Infant, Newborn; Humans; Child; Organic Anion Transporters, Sodium-Independent; Organic Anion Transporters; Liver-Specific Organic Anion Transporter 1; Solute Carrier Organic Anion Transporter Family Member 1B3; Hyperbilirubinemia, Hereditary; Hyperbilirubinemia; Mutation
PubMed: 36964102
DOI: 10.1016/j.jfma.2023.03.003 -
Asian Journal of Surgery Aug 2023
Topics: Humans; Gilbert Disease; Liver Transplantation; Syndrome
PubMed: 36933959
DOI: 10.1016/j.asjsur.2023.02.091 -
European Journal of Haematology Jun 2023Hereditary hemolytic anemias (HHA) comprise a heterogeneous group of disorders resulting from defective red blood cell (RBC) cytoskeleton, RBC enzyme deficiencies, and...
INTRODUCTION
Hereditary hemolytic anemias (HHA) comprise a heterogeneous group of disorders resulting from defective red blood cell (RBC) cytoskeleton, RBC enzyme deficiencies, and hemoglobin (Hb) synthesis disorders such as thalassemia or sideroblastic anemia.
MATERIALS AND METHODS
Our hemolytic anemia diagnostic next-generation sequencing (NGS) panel includes 28 genes encoding RBC cytoskeletal proteins, membrane transporter, RBC enzymes, and certain bilirubin metabolism genes. The panel covers the complete coding region of these genes, splice junctions, and, wherever appropriate, deep intronic or regulatory regions are also included. Four hundred fifty-six patients with unexplained hemolytic anemia were evaluated using our NGS panel between 2015 and 2019.
RESULTS
We identified pathogenic/likely pathogenic variants in 111/456 (24%) patients that were responsible for the disease phenotype (e.g., moderate to severe hemolytic anemia and hyperbilirubinemia). Approximately 40% of the mutations were novel. As expected, 45/456 (10%) patients were homozygous for the promoter polymorphism in the UGT1A1 gene, A(TA) TAA (UGT1A1*28). 8/45 homozygous UGT1A1*28 cases were associated with additional pathogenic mutations causing hemolytic anemia, likely exacerbating hyperbilirubinemia. The most common mutated genes were membrane cytoskeleton genes SPTA1, and SPTB, followed by PKLR. Complex interactions between SPTA1 low expression alleles, alpha-LELY and alpha-LEPRA alleles, and intragenic SPTA1 variants were associated with hereditary pyropoikilocytosis and autosomal recessive hereditary spherocytosis in 23/111 patients.
CONCLUSIONS
Our results demonstrate that hemolytic anemia is underscored by complex molecular interactions of previously known and novel mutations in RBC cytoskeleton/enzyme genes, and therefore, NGS should be considered in all patients with clinically unexplained hemolytic anemia and in neonates with hyperbilirubinemia. Moreover, low expression alleles alpha-LELY and alpha-LEPRA should be included in all targeted HHA panels.
Topics: Humans; Anemia, Hemolytic, Congenital; Elliptocytosis, Hereditary; Spherocytosis, Hereditary; Cytoskeletal Proteins; Hyperbilirubinemia; High-Throughput Nucleotide Sequencing
PubMed: 36825813
DOI: 10.1111/ejh.13951 -
The British Journal of Radiology Mar 2023The aim of this study is to demonstrate the role of proton magnetic resonance spectroscopy (1H-MRS) in the detection of brain microstructural changes in patients with...
OBJECTIVE
The aim of this study is to demonstrate the role of proton magnetic resonance spectroscopy (1H-MRS) in the detection of brain microstructural changes in patients with Crigler-Najjar syndrome type-I (CNs-I), and its correlation with demographic, neurodevelopmental and laboratory findings.
METHODS
Prospective study was conducted on 25 children with CNs-I and 25 age and sex-matched children, who served as control. They underwent multivoxel 1H-MRS of basal ganglion at echo time 135-144 ms. N-acetyl aspartate/Creatine (NAA/Cr) and Choline (Ch)/Cr were calculated and correlated with demographic, clinical, and laboratory findings of patients with CNs-I.
RESULTS
There was a significant difference in NAA/Cr and Ch/Cr between patients and controls. The cut-off value for NAA/Cr and Ch/Cr used to differentiate patients from controls were 1.8 and 1.2 with an area under the curve (AUC) of 0.91 and 0.84 respectively. There was a significant difference in MRS ratios between patients with neurodevelopmental delay (NDD) and patients without NDD. The cut-off values for NAA/Cr and Ch/Cr used to differentiate between patients with NDD and patients without NDD were 1.47 and 0.99, with AUC of 0.87 and 0.8 respectively. The NAA/Cr and Ch/Cr were well correlated with family history ( = 0.006 and < 0.001) respectively, consanguinity ( < 0.001 and = 0.001), neurodevelopmental delay ( = 0.001 and = 0.004), serum bilirubin level ( = -0.77, < 0.001), ( = -0.49, = 0.014), phototherapy ( < 0.001 and = 0.32), blood transfusion ( < 0.001 and = 0.001) respectively.
CONCLUSION
1H-MRS can be a useful tool in the detection of neurological changes in patients with CNs-I; NAA/Cr and Ch/Cr parameters are well correlated with demographic, clinical, and laboratory findings.
ADVANCES IN KNOWLEDGE
Our study is the first report on using MRS in assessing neurological manifestations in CNs. 1H-MRS can be a useful tool in the detection of neurological changes in patients with CNs-I.
Topics: Humans; Child; Magnetic Resonance Spectroscopy; Prospective Studies; Crigler-Najjar Syndrome; Brain; Creatine; Aspartic Acid; Choline; Demography
PubMed: 36809151
DOI: 10.1259/bjr.20220433 -
Expert Opinion on Biological Therapy Feb 2023
Topics: Humans; Crigler-Najjar Syndrome; Genetic Therapy
PubMed: 36579791
DOI: 10.1080/14712598.2022.2160237 -
International Journal of Molecular... Dec 2022We report a case of a patient with Dubin-Johnson syndrome confirmed by a genetic study. A 50-year-old woman who had symptoms of intermittent right upper quadrant...
We report a case of a patient with Dubin-Johnson syndrome confirmed by a genetic study. A 50-year-old woman who had symptoms of intermittent right upper quadrant abdominal pain was diagnosed with calculous cholecystitis at another institute and was presented to our hospital for a cholecystectomy. She had no history of liver disease, and her physical examination was normal. Abdominal computed tomography showed a gallbladder stone with chronic cholecystitis. During a laparoscopic cholecystectomy for cholecystitis, a smooth, black-colored liver was noted, and a liver biopsy was performed. The biopsy specimen showed coarse, dark brown granules in centrilobular hepatocytes via hematoxylin and eosin staining. We performed a genetic study using the blood samples of the patient. In the () mutation study, a missense mutation in exon 18 was noted. Based on the black-colored liver without nodularity, conjugated hyperbilirubinemia, the liver biopsy results of the coarse pigment in centrilobular hepatocytes, and the mutation, Dubin-Johnson syndrome was diagnosed. The patient was managed with conservative care using hepatotonics. One month after follow-up, total bilirubin and direct bilirubin remained in a similar range. Another follow-up was planned a month later, and the patient maintained her use of hepatotonics.
Topics: Female; Humans; Jaundice, Chronic Idiopathic; Multidrug Resistance-Associated Proteins; Mutation, Missense; Multidrug Resistance-Associated Protein 2; Exons; Mutation; Bilirubin; Genetic Association Studies; Cholecystitis
PubMed: 36555809
DOI: 10.3390/ijms232416168 -
Annals of Translational Medicine Nov 2022Hereditary spherocytosis (HS) is not a rare disease in the department of hematology; however, in the late stage of the disease, patients often have very severe...
BACKGROUND
Hereditary spherocytosis (HS) is not a rare disease in the department of hematology; however, in the late stage of the disease, patients often have very severe cholestasis and are referred to the department of hepatology. Hepatologists may have trouble determining the source of cholestasis, causing treatment difficulties.
CASE DESCRIPTION
We report two 20-year-old patients complaining of "skin and eyes turned to yellow". Patient 1 had no previous hematologic disorders, and patient 2 had a history of anemia without treatment. Laboratory tests suggested anemia and elevated bilirubin in both patients. The direct bilirubin levels were more significantly elevated than the indirect bilirubin levels in both patients, and the patients both suffered from abdominal pain and pancreatitis. However, the degree of anemia could not fully explain the jaundice. Magnetic resonance imaging findings suggested the presence of hepatosplenomegaly and gallstones. Genetic testing identified new mutations in the relevant genes, ultimately confirming the diagnosis of HS. The liver biopsy results for both patients showed obvious intrahepatic cholestasis. Patient 1 underwent splenectomy at a bilirubin level of 125.4 µmol/L, and the bilirubin level returned to normal after surgery, with a good prognosis. However, Patient 2 suffered from pancreatitis during hospitalization and was unable to undergo splenectomy. Endoscopic retrograde cholangiopancreatography was implemented, but the bilirubin level continued to rise, and Patient 2 ultimately gave up treatment and passed away.
CONCLUSIONS
For hepatologists, identifying the source of jaundice (hemolysis, hepatocyte destruction, or biliary obstruction) is important for treatment, supplemented by liver biopsy and genetic testing if necessary. In the 2 cases covered in this article, early-stage HS caused hemolytic jaundice with predominantly elevated indirect bilirubin, and as the disease progressed, patients developed severe cholestasis probably related to transient biliary obstruction caused by gallstones and hepatocellular injury due to abnormal bilirubin metabolism. In addition, in patients with HS combined by intrahepatic cholestasis, early consideration of splenectomy may delay disease progression and achieve a better prognosis. Of course, this conclusion needs to be confirmed by more clinical studies.
PubMed: 36544651
DOI: 10.21037/atm-22-5076 -
Angiology Aug 2023
Topics: Humans; Gilbert Disease; Vascular Stiffness; Hypertension; Ventricular Function, Left
PubMed: 36408872
DOI: 10.1177/00033197221139917