RESUMEN
Hyperbilirubinemia is the main mechanism that causes neonatal jaundice, and genetics is one of the risk factors of hyperbilirubinemia. Therefore, this study aims to explore the correlation between two genes, UGT1A1 and SLCO1B1, and hyperbilirubinemia in Thai neonates. One hundred thirty seven neonates were recruited from Division of Clinical Chemistry, Ramathibodi Hospital. UGT1A1*28 and *6 were determined by pyrosequencing whereas, SLCO1B1 388A > G and 521 T > C genetic variants were determined by TaqMan® real-time polymerase chain reaction. Neonates carrying with homozygous (AA) and heterozygous (GA) variants in UGT1A1*6 were significantly related to hyperbilirubinemia development compared with wild type (GG; P < 0.001). To the combined of UGT1A1, total bilirubin levels in homozygous variant were higher significantly than heterozygous variant and wild type (P = 0.002, P = 0.003, respectively). Moreover, SLCO1B1 combination was significant differences between the hyperbilirubinemia and the control group (P = 0.041). SLCO1B1 521 T > C variant provide protection for Thai neonatal hyperbilirubinemia (P = 0.041). There are no significant differences in UGT1A1*28 and SLCO1B1 388A > G for the different severity of hyperbilirubinemia. The combined UGT1A1*28 and *6 polymorphism is a strong risk factor for the development of severe hyperbilirubinemia in Thai neonates. Therefore, we suggest neonates with this gene should be closely observed to avoid higher severities of bilirubin.
Asunto(s)
Hiperbilirrubinemia Neonatal , Ictericia Neonatal , Bilirrubina , Glucuronosiltransferasa , Humanos , Hiperbilirrubinemia Neonatal/genética , Recién Nacido , Ictericia Neonatal/complicaciones , Ictericia Neonatal/genética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Polimorfismo Genético , TailandiaRESUMEN
Upshaw-Schulman syndrome is a rare congenital form of thrombotic thrombocytopenic purpura (TTP) characterized by single or recurrent episodes of thrombocytopenia, microangiopathic hemolyticanemia (MAHA), and widespread microvascular thrombosis, leading to the ischemic damage of multiple organs (mainly kidney, heart and brain). A 6-mo-old female infant, second born of a third-degree consanguineous marriage, with a history of severe neonatal jaundice with thrombocytopenia secondary to hemolysis requiring exchange transfusion on day 2 of life, presented with high-grade fever without focus of 2-d duration. Initial workup revealed microangiopathic hemolyticanemia with thrombocytopenia. In view of microangiopathic hemolyticanemia with thrombocytopenia against a background of severe neonatal jaundice, a diagnosis of congenital TTP was considered and was managed with FFP transfusion. The diagnosis was confirmed with her exome sequencing showing autosomal recessive homozygous frameshift deletion c.2063delG (p.Trp688fs) at Exon 17 (NM_139025) of ADAMTS 13 gene.
Asunto(s)
Proteína ADAMTS13 , Ictericia Neonatal , Púrpura Trombocitopénica Trombótica , Proteína ADAMTS13/genética , Exones/genética , Femenino , Homocigoto , Humanos , Lactante , Ictericia Neonatal/genética , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/genética , Púrpura Trombocitopénica Trombótica/terapia , Eliminación de SecuenciaRESUMEN
BACKGROUND: Neonatal jaundice may cause severe neurological damage if poorly evaluated and diagnosed when high bilirubin occurs. The study explored how to effectively integrate high-dimensional genetic features into predicting neonatal jaundice. METHODS: This study recruited 984 neonates from the Suzhou Municipal Central Hospital in China, and applied an ensemble learning approach to enhance the prediction of high-dimensional genetic features and clinical risk factors (CRF) for physiological neonatal jaundice of full-term newborns within 1-week after birth. Further, sigmoid recalibration was applied for validating the reliability of our methods. RESULTS: The maximum accuracy of prediction reached 79.5% Area Under Curve (AUC) by CRF and could be marginally improved by 3.5% by including genetic variant (GV). Feature importance illustrated that 36 GVs contributed 55.5% in predicting neonatal jaundice in terms of gain from splits. Further analysis revealed that the main contribution of GV was to reduce the false-positive rate, i.e., to increase the specificity in the prediction. CONCLUSIONS: Our study shed light on the theoretical and practical value of GV in the prediction of neonatal jaundice.
Asunto(s)
Hiperbilirrubinemia Neonatal , Ictericia Neonatal , Bilirrubina , Humanos , Recién Nacido , Ictericia Neonatal/diagnóstico , Ictericia Neonatal/genética , Aprendizaje Automático , Reproducibilidad de los Resultados , Factores de RiesgoRESUMEN
Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) is an autosomal recessive disease resulting from biallelic SLC25A13 mutations, and its diagnosis relies on genetic analysis. This study aimed to characterize the pathogenicity of 2 novel splice-site variants of SLC25A13 gene. Two patients (C0476 and C0556) suspected to have NICCD, their family members and 9 healthy volunteers were recruited as the research subjects. The SLC25A13 genotypes NG_012247.2(NM_014251.3): c.[852_855del]; [69+5G > A] in patient C0476 and c.[1453-1G > A]; [1751-5_1751-4ins (2684)] in patient C0556 were identified by means of polymerase chain reaction, long and accurate polymerase chain reaction, as well as Sanger sequencing. The 2 splice-site variants were absent in control databases and predicted to be pathogenic by computational analysis. The alternative splice variants in monocyte-derived macrophages from patient C0476 demonstrated exon 2 skipping [r.16_69del; p.(Val6_Lys23del)] in vivo, while minigene analysis revealed both exon 2-skipping and retained products from c.69+5G > A in vitro. In the patient C0556, an aberrant transcript [r.1453del; p.(Gly485Valfs*22)] resulting from c.1453-1G > A was detected on minigene splicing study. Thus, c.69+5G > A and c.1453-1G > A were both proved to be pathogenic. The 2 novel splice-site variants expanded the SLC25A13 mutation spectrum and provided reliable molecular markers for the definite diagnosis and genetic counseling of NICCD in the affected families.
Asunto(s)
Colestasis Intrahepática/genética , Ictericia Neonatal/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Línea Celular , Células Cultivadas , Colestasis Intrahepática/patología , Humanos , Lactante , Ictericia Neonatal/patología , Macrófagos/metabolismo , Masculino , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Mutación , Sitios de Empalme de ARNRESUMEN
AIM: Neonatal jaundice is associated with higher risk of attention deficit hyperactivity disorder (ADHD), but it is unclear if the association is influenced by genetic and other familial factors. In this large population-based study, we investigated the association between neonatal jaundice and ADHD while adjusting for familial factors. METHODS: We linked several Swedish registers to identify all singleton births without congenital malformations between 1992 and 2000 (n = 814 420, including 384 290 full siblings) and followed them up until 2009. We calculated hazard ratios (HRs) for the association between neonatal jaundice and ADHD, adjusting for pregnancy, delivery and neonatal characteristics including prematurity, and parental age and education. We repeated the analyses among siblings to adjust for shared familial factors. RESULTS: At a population level, children treated for neonatal jaundice had an increased risk of ADHD (adjusted HR (aHR): 1.13, 95% CI: 1.05-1.22). In the sibling comparisons, there was no clear association between neonatal jaundice and ADHD (aHR: 1.03, 95% CI: 0.82-1.29). CONCLUSION: We found no evidence of an independent association between neonatal jaundice and ADHD within siblings in this large population-based study, suggesting that the association is probably influenced by shared familial factors, such as parental genetic and/or lifestyle effects.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Ictericia Neonatal , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Niño , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Ictericia Neonatal/epidemiología , Ictericia Neonatal/genética , Embarazo , Factores de Riesgo , Hermanos , Suecia/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVES: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy worldwide associated with hemolysis as well as neonatal jaundice, kernicterus, and even death. The goal of this study is to determinate the prevalence of G6PD deficiency in icteric neonates and to investigate its biochemical, hematological and molecular characteristics. PATIENTS AND METHODS: This cross sectional study was carried out on 154 icteric newborns admitted to the Bechir Hamza Children's Hospital in Tunisia. Laboratory evaluations included complete blood count, total serum bilirubin level (TSB), and erythrocyte G6PD activity. The G6PD activity was determined using a quantitative assay, which allowed us to divide the total population into two groups: normal and deficient population. The common G6PD Tunisian mutations (GdA - and GdMed) were determined using the amplification refractory mutation system (ARMS-PCR) method. RESULTS: The prevalence of G6PD deficiency among total population (154 icteric newborns) was 18.83%. Male neonates showed a higher incidence of G6PD deficiency of 11.03% compared to females (7.79%). There was no statistical difference between the two groups (normal and deficient), in relation to the sex, peak TSB level, age at peak TSB, hemoglobin level, and hematocrit. However, there was a significant difference in gestational age. In the deficient group, 48.28% neonates presented the peak TSB level between 3 to 7 days and 55% of the cases show a peak TSB level greater than 250 µmol/L. The G6PD G202A variant was found in 41.37% of cases. CONCLUSION: This study shows a higher prevalence of G6PD deficiency in icteric newborns of Tunisia (18.83%). This emphasizes the necessity of neonatal screening for G6PD deficiency to prevent the exposure of these newborns to known hemolytic agents and, subsequently, to prevent kernicterus or other serious complications.
Asunto(s)
Deficiencia de Glucosafosfato Deshidrogenasa/epidemiología , Ictericia Neonatal/epidemiología , Análisis Químico de la Sangre , Estudios Transversales , Análisis Mutacional de ADN , Femenino , Edad Gestacional , Glucosafosfato Deshidrogenasa/análisis , Glucosafosfato Deshidrogenasa/sangre , Glucosafosfato Deshidrogenasa/genética , Deficiencia de Glucosafosfato Deshidrogenasa/sangre , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Pruebas Hematológicas , Humanos , Recién Nacido , Ictericia Neonatal/sangre , Ictericia Neonatal/complicaciones , Ictericia Neonatal/genética , Masculino , Prevalencia , Túnez/epidemiologíaRESUMEN
BACKGROUND: Phototherapy is used on the majority of preterm infants with unconjugated hyperbilirubinaemia. The use of fluorescent tube phototherapy is known to induce oxidative DNA damage in infants and has largely been replaced by blue light-emitting diode phototherapy (BLP). To date, it is unknown whether BLP also induces oxidative DNA damage in preterm infants. OBJECTIVE: To determine whether BLP in preterm infants induces oxidative DNA damage as indicated by 8-hydroxy-2'deoxyguanosine (8-OHdG). DESIGN: Observational cohort study. METHODS: Urine samples (n=481) were collected in a cohort of 40 preterm infants (24-32 weeks' gestational age) during the first week after birth. Urine was analysed for the oxidative marker of DNA damage 8-OHdG and for creatinine, and the 8-OHdG/creatinine ratio was calculated. Durations of phototherapy and levels of irradiance were monitored as well as total serum bilirubin concentrations. RESULTS: BLP did not alter urinary 8-OHdG/creatinine ratios (B=0.2, 95% CI -6.2 to 6.6) at either low (10-30 µW/cm2/nm) or high (>30 µW/cm2/nm) irradiance: (B=2.3, 95% CI -5.7 to 10.2 and B=-3.0, 95% CI -11.7 to 5.6, respectively). Also, the 8-OHdG/creatinine ratios were independent on phototherapy duration (B=-0.1, 95% CI -0.3 to 0.1). CONCLUSIONS: BLP at irradiances up to 35 µW/cm2/nm given to preterm infants ≤32 weeks' gestation does not affect 8-OHdG, an oxidative marker of DNA damage.
Asunto(s)
Daño del ADN , Enfermedades del Prematuro/terapia , Ictericia Neonatal/terapia , Estrés Oxidativo , Fototerapia/efectos adversos , 8-Hidroxi-2'-Desoxicoguanosina/orina , Biomarcadores/orina , Creatinina/orina , Edad Gestacional , Humanos , Recien Nacido con Peso al Nacer Extremadamente Bajo , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/genética , Ictericia Neonatal/genética , Estudios Longitudinales , Fototerapia/métodos , Estudios ProspectivosRESUMEN
BACKGROUND: To investigate the relationship between unexplained indirect hyperbilirubinemia of Vietnamese newborns and the polymorphism of the promoter TATA box and exon 1 of bilirubin uridine diphosphate glucuronosyltransferase (UGT1A1) gene. METHODS: A total of 149 neonates were divided into the hyperbilirubinemia group (n = 99) and control group (n = 50). The gene polymorphisms of UGT1A1 gene in the two groups were detected by PCR and direct sequencing, which revealed the relationship between UGT1A1 polymorphism with neonatal hyperbilirubinemia of neonates. The types of UGT1A1 polymorphism in the hyperbilirubinemia group and the peak total serum bilirubin (PSB) levels with different genotypes were observed. RESULTS: (1) (TA)7 insertion mutation, 211G>A, 189C>T, 190G>A, 378C>T and 686C>A were detected. (2) The allele frequency of 211G>A allele mutation was significantly different between the two groups (p < 0.05). (3) Logistic regression analysis showed that homozygosity and heterozygosity of 211G>A were both significantly associated with neonatal hyperbilirubinemia. (4) In the hyperbilirubinemia group, the peak total serum bilirubin level of 211G>A homozygous neonates was higher than that of the wild-type neonates (p < 0.05). CONCLUSIONS: We noted that there was an association between neonates with unexplained indirect hyperbilirubinemia in Vietnam and the polymorphism of UGT1A1c.211G>A. In addition, the homozygous 211G>A polymorphism was related to the degree of hyperbilirubinemia. IMPACT: Our article provided data on UGT1A1 polymorphism distribution in the Vietnamese population, which have not been reported yet. Our findings revealed that mutations in UGT1A1 gene are risk factors for unexplained hyperbilirubinemia in Vietnamese neonates. Our article will strengthen the cognition of neonatal jaundice at the genetic level in the pediatric field in Vietnam.
Asunto(s)
Glucuronosiltransferasa/sangre , Glucuronosiltransferasa/genética , Hiperbilirrubinemia Neonatal/sangre , Hiperbilirrubinemia Neonatal/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Alelos , Bilirrubina/sangre , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Homocigoto , Humanos , Recién Nacido , Ictericia Neonatal/sangre , Ictericia Neonatal/genética , Masculino , Mutación , Reacción en Cadena de la Polimerasa , Análisis de Regresión , Análisis de Secuencia de ADN , VietnamRESUMEN
OBJECTIVE: This study aimed to assess the probable relationship between icter in neonates with ABO incompatibility hemolysis and UGT1A1 gene polymorphism. STUDY DESIGN: There were 65 ABO hemolytic disease of the newborn (HDN) neonates of full term in the study group and 82 non-ABO HDN neonates of full term in the compared group. We tested the UGT1A1 gene mutation of neonates of ABO HDN and non-ABO HDN. We compared the incidence of hyperbilirubinemia between neonates with and without UGT1A1 mutations in the ABO HDN and non-ABO HDN, to determine the relationship between icter in neonates with ABO HDN and UGT1A1 gene polymorphism. SPSS 13.0 were used to analyze those two groups' data. RESULTS: There was statistically significant difference of the serum bilirubin level between the Gly71Arg homozygous and no mutation group in the ABO HDN patients (p < 0.05). When hyperbilirubinemia was defined as serum bilirubin concentration >342 µmol/L, the incidence of hyperbilirubinemia between patients of UGT1A1 and non-UGT1A1 mutations in the ABO HDN group was significantly different (p < 0.05). But in the non-ABO HDN group, no significant difference was found. CONCLUSION: Individuals with Gly71Arg homozygous contributed to their hyperbilirubinemia in ABO HDN patients.
Asunto(s)
Eritroblastosis Fetal/genética , Glucuronosiltransferasa/genética , Ictericia Neonatal/genética , Mutación , Polimorfismo Genético , Sistema del Grupo Sanguíneo ABO , Bilirrubina/sangre , Incompatibilidad de Grupos Sanguíneos/complicaciones , China , Enfermedad de Gilbert/complicaciones , Enfermedad de Gilbert/etnología , Enfermedad de Gilbert/genética , Homocigoto , Humanos , Recién Nacido , Ictericia Neonatal/etnologíaRESUMEN
BACKGROUND: Hemoglobin (Hb) Constant Spring is an alpha-globin gene variant due to a mutation of the stop codon resulting in the elongation of the encoded polypeptide from 141 to 172 amino acid residues. Patients with homozygous Hb Constant Spring are usually mildly anemic. METHODS: We retrospectively describe clinical manifestations, diagnosis, laboratory investigations, treatment, and associated findings in pediatric patients with homozygous Hb Constant Spring followed-up at Srinagarind Hospital. RESULTS: Sixteen pediatric cases (5 males and 11 females) were diagnosed in utero (N=6) or postnatal (n=10). Eleven cases were diagnosed with homozygous Hb Constant Spring, 4 with homozygous Hb Constant Spring with heterozygous Hb E, and 1 with homozygous Hb Constant Spring with homozygous Hb E. Three cases were delivered preterm. Six patients had low birth weights. Clinical manifestations included fetal anemia in 6 cases, hepatomegaly in 1 case, hepatosplenomegaly in 2 cases, splenomegaly in 1 case. Twelve cases exhibited early neonatal jaundice, 9 of which required phototherapy. Six cases received red cell transfusions; 1 (3), >1 (3). After the first few months of life, almost all patients had mild microcytic hypochromic anemia and an increased reticulocyte count with a wide red cell distribution (RDW), but no longer required red cell transfusion. At 1 to 2 years of age, some patients still had mild microcytic hypochromic anemia and some had normocytic hypochromic anemia with Hb around 10 g/dL, increased reticulocyte count and wide RDW. Associated findings included hypothyroidism (2), congenital heart diseases (4), genitourinary abnormalities (3), gastrointestinal abnormalities (2), and developmental delay (1). SUMMARY: Pediatric patients with homozygous Hb Constant Spring developed severe anemia in utero and up to the age of 2 to 3 months postnatal, requiring blood transfusions. Subsequently, their anemia was mild with no evidence of hepatosplenomegaly. Their Hb level was above 9 g/dL with hypochromic microcytic blood pictures as well as wide RDW. Blood transfusions have not been necessary since then.
Asunto(s)
Anemia , Transfusión de Eritrocitos , Hemoglobinas Anormales/genética , Homocigoto , Fototerapia , Anemia/genética , Anemia/patología , Anemia/terapia , Preescolar , Femenino , Humanos , Lactante , Recién Nacido de Bajo Peso , Ictericia Neonatal/genética , Ictericia Neonatal/patología , Ictericia Neonatal/terapia , Masculino , Estudios RetrospectivosRESUMEN
Various mutations in the genes encoding alpha spectrin (SPTA1) or beta spectrin (SPTB) are known to cause erythrocyte membrane disorders, sometimes associated with severe neonatal jaundice and anemia. We used a next-generation sequencing panel to evaluate 3 unrelated neonates who had puzzling cases of nonimmune hemolytic jaundice. In each case, we identified novel mutations in either SPTA1 or SPTB. Correlating erythrocyte morphology, clinical course, and computational analysis, we submit that each of the 3 variants is a probable pathogenic cause of the hereditary hemolytic conditions in these patients. We hope other pediatric practitioners caring for neonates with what appears to be idiopathic severe neonatal hyperbilirubinemia will look for spectrin variants as a possible cause, because additional cases with these specific variants along with this clinical phenotype are needed to confirm our postulate that these 3 cases are indeed pathogenic mutations.
Asunto(s)
Eliptocitosis Hereditaria/genética , Ictericia Neonatal/genética , Mutación/genética , Espectrina/genética , Esferocitosis Hereditaria/complicaciones , Adulto , Eliptocitosis Hereditaria/complicaciones , Femenino , Humanos , Recién Nacido , Ictericia Neonatal/complicaciones , Ictericia Neonatal/terapia , Masculino , FototerapiaRESUMEN
OBJECTIVE: In the present study, we investigated the effects of promoter polymorphism and an exon-1 mutation (G71R) in the UGT1A1 gene in neonates with unexplained hyperbilirubinemia and direct Coombs-negative [DC(-)] ABO incompatibility. METHODS: Two-hundred term neonates in their first week of life and without additional icterogenic factors were included in the study. Neonates with a serum total bilirubin (STB) level ≥17 mg/dL constituted the hyperbilirubinemia group (n = 100), while the control group comprised healthy neonates with a STB level <12.9 mg/dL (n = 100). The cases were further subdivided into unexplained hyperbilirubinemia (n = 50), ABO(+) hyperbilirubinemia (n = 50), ABO(-) control (n = 50), and ABO(+) control (n = 50) groups on the basis of the presence or absence of DC(-) ABO incompatibility. DNA was isolated from peripheral blood and amplified by PCR, and UGT1A1 gene promoter and exon-1 were sequenced to verify sequence alterations. RESULTS: The frequency of TA6/6, TA6/7, TA7/7, and GGA/GGA, GGA/AGA, AGA/AGA genotypes was found to be 63.5%, 21%, 15.5%, and 91.5%, 8%, 0.5%, respectively. While both heterozygous and homozygous TA7 polymorphism increased risk of hyperbilirubinemia in the ABO(+) hyperbilirubinemia group (heterozygous OR 16.76, 95% CI:3.52-79.70, p < 0.0001; homozygous OR 6.81, 95% CI:1.98-23:42, p = 0.002), only heterozygous TA7 polymorphism increased jaundice risk (OR 5.08 95% CI:76-14.65, p = 0.003) in unexplained hyperbilirubinemia. But, the coexistence of G71R mutation and promoter polymorphism or G71R mutation and DC(-) ABO incompatibility did not increase the severity of hyperbilirubinemia (p > 0.05). CONCLUSIONS: UGT1A1 gene promoter polymorphism and G71R mutation are possible risk factors for Turkish neonates with DC(-) ABO incompatibility and unexplained hyperbilirubinemia.
Asunto(s)
Glucuronosiltransferasa/genética , Ictericia Neonatal/genética , Mutación , Sistema del Grupo Sanguíneo ABO/inmunología , Incompatibilidad de Grupos Sanguíneos/sangre , Incompatibilidad de Grupos Sanguíneos/genética , Estudios de Casos y Controles , Exones/genética , Femenino , Predisposición Genética a la Enfermedad , Edad Gestacional , Humanos , Hiperbilirrubinemia Neonatal/genética , Recién Nacido , Masculino , Polimorfismo Genético , Embarazo , Regiones Promotoras Genéticas , TurquíaRESUMEN
This study evaluated the correlation of UGT1A1, OATP2 gene mutations and hyperbilirubinemia in newborns in Northern China. Gene mutations were analyzed at the 211 locus of UGT1A1 (Gly71Arg) and 388 locus of OATP2 (Asn130Asp). The 226 enrolled infants were divided into high, moderate, and low risk subgroups according to American Academy of Pediatrics guideline. Blood samples of the enrolled infants were collected for the analysis of the PCR-restriction fragment length polymorphism. The genotypes and allele frequencies of the polymorphisms were compared in each group. Both UGT1A1 and OATP2 gene mutations occur more often in high risk group and moderate risk group than in low risk group. The results suggested that Gly71Arg and Asn130Asp mutations in UGT1A1 and OATP2 genes might be involved in the development of hyperbilirubinemia in neonates.
Asunto(s)
Glucuronosiltransferasa/genética , Ictericia Neonatal/genética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Mutación , Niño , China , Femenino , Genotipo , Humanos , Hiperbilirrubinemia , Hiperbilirrubinemia Neonatal , Recién Nacido , Masculino , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Newborns commonly develop physiological hyperbilirubinemia (also known as jaundice). With increased bilirubin levels being observed in breast-fed infants, breast-feeding has been recognized as a contributing factor for the development of neonatal hyperbilirubinemia. Bilirubin undergoes selective metabolism by UDP-glucuronosyltransferase (UGT) 1A1 and becomes a water soluble glucuronide. Although several factors such as gestational age, dehydration and weight loss, and increased enterohepatic circulation have been associated with breast milk-induced jaundice (BMJ), deficiency in UGT1A1 expression is a known cause of BMJ. It is currently believed that unconjugated bilirubin is metabolized mainly in the liver. However, recent findings support the concept that extrahepatic tissues, such as small intestine and skin, contribute to bilirubin glucuronidation during the neonatal period. We will review the recent advances made towards understanding biological and molecular events impacting BMJ, especially regarding the role of extrahepatic UGT1A1 expression.
Asunto(s)
Glucuronosiltransferasa/metabolismo , Ictericia Neonatal/patología , Leche Humana/química , Bilirrubina/metabolismo , Glucurónidos/metabolismo , Glucuronosiltransferasa/genética , Humanos , Ictericia Neonatal/genética , Hígado/metabolismo , Polimorfismo GenéticoRESUMEN
Organic anion transporter 2 (OATP2) is an uptake transporter located on the basolateral membrane of human hepatocytes. It mediates the transportation of various organic solutes including bilirubin and impacts bilirubin metabolism. It is encoded by the gene of solute carrier organic anion transporter family member 1B1 and the gene variants that inhibit hepatic bilirubin uptake function may reduce the normal functional level of bilirubin elimination and result in neonatal hyperbilirubinemia. In recent years, some studies have indicated that variants of SLCO1B1 are associated with neonatal jaundice. This article reviews the research advance in SLCO1B1 with respect to the structure and function and the relationship between SLCO1B1 mutations and neonatal jaundice.
Asunto(s)
Ictericia Neonatal/genética , Transportadores de Anión Orgánico/genética , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Humanos , Recién Nacido , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Polimorfismo GenéticoRESUMEN
BACKGROUND: Heme oxygenase (HO) is the initial, rate-limiting enzyme in the conversion of heme to bilirubin. Dinucleotide (GT)n repeat length in the promoter region of the encoding gene modulates transcription: shorter alleles, in contrast with longer allele counterparts, are associated with greater gene expression and should result in increased heme catabolism. OBJECTIVE: We compared the rates of heme catabolism and plasma total bilirubin (TB) between HO-1 promoter genotypes of varying (GT)n repeat lengths in glucose-6-phosphate dehydrogenase (G6PD)-normal and -deficient neonates. METHODS: HO-1 promoter length was determined from genomic DNA from previous studies by size discrimination of fluorescently-labeled PCR products with capillary electrophoresis. Sizing was confirmed by sequencing homozygote samples. Alleles were categorized as: short (≤24 GT repeats), medium (25-33 GT repeats), and long (≥34 GT repeats). Previously determined values for blood carboxyhemoglobin, corrected for inspired carbon monoxide (COHbc), and TB were used to determine the rate of heme catabolism and 3rd day TB values for each HO-1 promoter length genotype, respectively. G6PD Mediterranean was determined by PCR analysis. RESULTS: Neither COHbc nor TB values were significantly different between various HO-1 promoter genotypes for either G6PD-normal or -deficient neonates. CONCLUSIONS: In the steady state, HO-1 promoter genotypes, based on the length of (GT)n repeats, do not modulate heme catabolism or 3rd day TB values in either G6PD-normal or -deficient neonates.
Asunto(s)
Deficiencia de Glucosafosfato Deshidrogenasa/genética , Hemo-Oxigenasa 1/genética , Ictericia Neonatal/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Bilirrubina/sangre , Biomarcadores/sangre , Carboxihemoglobina/metabolismo , Estudios de Casos y Controles , Bases de Datos Factuales , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Deficiencia de Glucosafosfato Deshidrogenasa/sangre , Deficiencia de Glucosafosfato Deshidrogenasa/diagnóstico , Deficiencia de Glucosafosfato Deshidrogenasa/enzimología , Glucuronosiltransferasa/genética , Hemo/metabolismo , Hemólisis , Homocigoto , Humanos , Recién Nacido , Ictericia Neonatal/sangre , Ictericia Neonatal/diagnóstico , Ictericia Neonatal/enzimología , Masculino , FenotipoRESUMEN
We evaluated a neonate with severe jaundice but a negative family history. Spherocytes were present and suspected hereditary spherocytosis was confirmed by osmotic fragility and eosin-5-maleimide erythrocyte staining. We found he was a compound heterozygote for two pathogenic mutations in the gene encoding α-spectrin: a previously reported α(LEPRA) inherited from his asymptomatic mother, and a novel α-spectrin mutation in intron 45 +1 disrupting the consensus splice site, from his asymptomatic father.
Asunto(s)
Anemia Hemolítica Congénita/genética , Ancirinas/deficiencia , Ictericia Neonatal/genética , Ictericia Obstructiva/genética , Mutación , Espectrina/genética , Esferocitosis Hereditaria/genética , Anemia Hemolítica Congénita/sangre , Anemia Hemolítica Congénita/diagnóstico , Ancirinas/sangre , Ancirinas/genética , Análisis Mutacional de ADN , Eosina Amarillenta-(YS)/análogos & derivados , Citometría de Flujo , Predisposición Genética a la Enfermedad , Herencia , Heterocigoto , Humanos , Lactante , Recién Nacido , Ictericia Neonatal/sangre , Ictericia Neonatal/diagnóstico , Ictericia Obstructiva/sangre , Ictericia Obstructiva/diagnóstico , Masculino , Fragilidad Osmótica , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Esferocitosis Hereditaria/sangre , Esferocitosis Hereditaria/diagnósticoRESUMEN
OBJECTIVE: To explore the effects of variants in Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) and Heme Oxygenase-1 (HMOX1) on daily physiological bilirubin levels and bilirubin changes during the first week after birth in Chinese newborns. Both UGT1A1 and HMOX1 code rate-limiting enzymes in the bilirubin metabolism pathway. STUDY DESIGN: We conducted a retrospective quantitative trait study to analyze 4154 daily bilirubin values, 3129 bilirubin changes, and 11 polymorphisms of 988 newborns during the natural course of physiological hyperbilirubinemia. RESULTS: For UGT1A1, we found minor allele A of rs4148323 (G211A, UGT1A1*6) contributed to higher daily bilirubin levels on days 4-6 (with contributions to variations increasing from 4.8% to 12.3%), minor allele T of rs887829 (c-364t) contributed to lower daily bilirubin levels for days 6 and 7 (with contributions to variations increasing from 7.0% to 10.2%) (P < .03 for all). In addition, minor alleles of rs887829 and (TA)n repeat (UGT1A1*28), and haplotype T-long-G at rs887829-(TA)n-rs4148323 were associated with a decrease in bilirubin levels from day 5 to day 6 (P < .01 for all). No contribution from HMOX1 was found. CONCLUSION: Bilirubin levels and changes during the middle and late parts of the first week were attributed to variants and haplotypes in UGT1A1. This quantitative trait study may provide a more robust statistical method for determining the association of genetic factors and bilirubin kinetics to predict the development of neonatal bilirubin in early postnatal life.