Human genes influence the interaction between Streptococcus mutans and host caries susceptibility: a genome-wide association study in children with primary dentition / 国际口腔科学杂志·英文版

Streptococcus mutans is a well-known cause of dental caries, due to its acidogenicity, aciduricity, and ability to synthesize exopolysaccharides in dental plaques. Intriguingly, not all children who carry S. mutans manifest caries, even with similar characteristics in oral hygiene, diet, and other environmental factors. This phenomenon suggests that host susceptibility potentially plays a role in the development of dental caries; however, the association between host genetics, S. mutans, and dental caries remains unclear. Therefore, this study examined the influence of host gene-by-S. mutans interaction on dental caries. Genome-wide association analyses were conducted in 709 US children (<13 years old), using the dbGap database acquired from the center for oral health research in appalachia (COHRA) and the Iowa Head Start programmes (GEIRS). A generalized estimating equation was used to examine the gene-by-S. mutans interaction effects on the outcomes (decayed and missing/filled primary teeth due to caries). Sequentially, the COHRA and GEIRS data were used to identify potential interactions and replicate the findings. Three loci at the genes interleukin 32 (IL32), galactokinase 2 (GALK2), and CUGBP, Elav-like family member 4 (CELF4) were linked to S. mutans carriage, and there was a severity of caries at a suggestive significance level among COHRA children (P < 9 × 10), and at a nominal significance level among GEIRS children (P = 0.047-0.001). The genetic risk score that combined the three loci also significantly interacted with S. mutans (P < 0.000 1). Functional analyses indicated that the identified genes are involved in the host immune response, galactose carbohydrate metabolism, and food-rewarding system, which could potentially be used to identify children at high risk for caries and to develop personalized caries prevention strategies.

A Population-Based Genomic Study of Inherited Metabolic Diseases Detected Through Newborn Screening

BACKGROUND: A newborn screening (NBS) program has been utilized to detect asymptomatic newborns with inherited metabolic diseases (IMDs). There have been some bottlenecks such as false-positives and imprecision in the current NBS tests. To overcome these issues, we developed a multigene panel for IMD testing and investigated the utility of our integrated screening model in a routine NBS environment. We also evaluated the genetic epidemiologic characteristics of IMDs in a Korean population. METHODS: In total, 269 dried blood spots with positive results from current NBS tests were collected from 120,700 consecutive newborns. We screened 97 genes related to NBS in Korea and detected IMDs, using an integrated screening model based on biochemical tests and next-generation sequencing (NGS) called NewbornSeq. Haplotype analysis was conducted to detect founder effects. RESULTS: The overall positive rate of IMDs was 20%. We identified 10 additional newborns with preventable IMDs that would not have been detected prior to the implementation of our NGS-based platform NewbornSeq. The incidence of IMDs was approximately 1 in 2,235 births. Haplotype analysis demonstrated founder effects in p.Y138X in DUOXA2, p.R885Q in DUOX2, p.Y439C in PCCB, p.R285Pfs*2 in SLC25A13, and p.R224Q in GALT. CONCLUSIONS: Through a population-based study in the NBS environment, we highlight the screening and epidemiological implications of NGS. The integrated screening model will effectively contribute to public health by enabling faster and more accurate IMD detection through NBS. This study suggested founder mutations as an explanation for recurrent IMD-causing mutations in the Korean population.

A Case of Infantile Hepatic Hemangioendothelioma Incidentally Detected during the Evaluation of Galactosemia

Galactosemia is a group of inherited enzyme deficiencies characterized by increase in the blood galactose levels. This condition may be associated with deficiencies of galactose-1-phosphate uridyl transferase, galactokinase, or uridine diphosphate galactose-4-epimerase. However, the elevated galactose identified by neonatal screening tests has several other possible etiologies, including hepatic hemangioendothelioma, hepatic hemangioma, and patent ductus venosus with hypoplasia of the portal vein. We report a 13-day-old Korean male with hepatic hemangioendothelioma, which was incidentally detected during the evaluation for suspected galactosemia. Laboratory studies revealed that mildly elevated levels of galactose, galactose-1-phosphate and alpha-fetoprotein, at the time of admission, were gradually decreased to the normal range over the 6 months of observation. Ultrasonography showed a well-defined heterogeneous hypoechoic mass in the liver, and magnetic resonance imaging study showed multiple enhanced mass lesions, which was compatible with the diagnosis of a hepatic hemangioendothelioma. Thus, hepatic imaging, especially ultrasonography, should be performed if neonatal screening suggests galactosemia.

Galactosemia / 한양의대학술지

Galactosemia, a term that denotes the presence of galactose in the blood, is the name of rare inborn error of galactose metabolism due to a deficiency of the enzyme galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT) and uridine diphosphate-galactose 4-epimerase (GALE). GALT deficiency is the most common and shows the most severe clinical manifestation, including hepatomegaly, cataracts, and mental retardation. The main symptom of GALT deficiency is juvenile cataracts. GALE deficiency has two different forms; benign and severe forms. The benign form has no clinical significance, however, the severe form shows the same clinical manifestations as those of GALT deficiency.

Intrahepatic Arterio-Venous Shunts in a Patient with Hypergalactosemia Detected by Neonatal Screening

We report a case of 15 days old newborn presenting with hypergalactosemia detected by newborn screening who had intrahepatic arterio-venous shunts with multiple pin-head sized cutaneous hemangiomas. Plasma level of galactose was elevated to 11.3 mg/dL at age of 7 days, but the activity of galactose-metabolizing enzymes including galactose-1- phosphate uridyltransferase, galactokinase, and uridine diphosphate galactose-4-epimerase were all normal. Intrahepatic arterio-venous shunts were diagnosed by abdominal ultrasonography with color doppler ultrasonography and abdominal computed tomography. At age of 3 months, the plasma level of galactose further elevated to 14.73 mg/dL, at which time lactose-free cows milk formula was started. At age of 6 months, the plasma level of galactose decreased to within normal range with disappearance of previously noted multiple cutaneous hemangiomas. In hypergalactosemia of the newborn, the intrahepatic shunts should be considered as a possible cause, once hereditary enzyme deficiencies have been ruled out.

Galactosemia: a treatable metabolic disorder

Case Reports: A term male baby was delivered normally in hospital with Apgar score 10/10 at 5 minutes, weighting 3200 grams and no congenital anomaly was apparent. Baby was sent home same day. He was brought on 5th day with complaint of jaundice. Total Serum bilirubin was 21.0-mg% with predominant indirect hyperbilirubinemia. No evidence of ABO, Rh incompatibility, glucose-6-phosphate dehydrogenase[G6PD] deficiency or any other cause of jaundice detected at this stage. He was admitted in hospital and phototherapy was started. Baby remained active, aferbile, feeding well during hospital stay. Serum bilirubin dropped to 13.0-mg% on 10th day and was discharged in satisfactory condition. But he was readmitted after one day with complaint of poor feeding, drowsiness, hypothermia and lethargy. With clinical impression of neonatal sepsis, injection ceftriaxone and amikacin were started empirically. Mild jaundice was still present. Investigations revealed hemoglobin [Hb] 13.0 gm%, total leukocyte count[TLC] 2800/mm3, platelets 40,000/mm3, blood glucose 60mg% and serum bilirubin 8.0mg%. Condition of baby improved after 24 hours. He became active and started taking feeds. Blood culture revealed growth of E. coli, sensitive to above antibiotics. Antibiotics were continued for 12 days and baby was discharged. On follow up after 10 days at 01-month of age, baby was quite pale looking, deeply jaundiced and not gaining weight. He weighed only 3.3 kg at 35 days of age. Investigations revealed Hb: 8.0 gm%, serum bilirubin 18.0 mg%, Alanine transferase[ALT] 190iu/l, Alkaline phosphatase 1056 u/l with predominant indirect hyperbilirubinemia. Urine examination revealed no abnormality. Ultrasonography[USG] of abdomen revealed mild hepatomegaly with diffuse increased echogenecity. New clinical finding was bilateral lenticular haze [oil droplet type], confirmed by ophthalmologist. Urine for reducing substances was repeated which was strongly positive with Benedict's solution but negative with glucostix. Keeping in mind the possibility of glactosemia, breast-feeding was stopped and replaced with Soy based milk. Red cell concentrate was also transfused and further investigations were done to rule out other causes of persistent indirect hyperbilirubinemia. On induction of lactose free milk, jaundice remarkably regressed in about one week time. Lenticular opacities almost completely disappeared and LFTS became normal in about one month time. Baby is on regular follow up. He is now one year old weighing 9.5 kg and achieving developmental milestones normal for age

Galactosemia Detected by Neonatal Screening Test

PURPOSE: The genetic disturbance of galactosemia is expressed as a cellular deficiency of either galactose-1-phosphate uridyltransferase(GALT) or galactokinase(GALK) or UDP galactose 4-epimerase(GALE). To find-out the pattern of galactosemia in Korea, we retrospectively analyzed cases of galactosemia detected by neonatal screening program. METHODS: We analyzed medical records of patients who visited Soonchunhyang University Hospital at age of 1 month after showing abnormalities in neonatal screening of galactosemia. For accurate diagnosis, galactose was measured by enzyme immunoassay(EIA) and fluorophotometer, also galactose-1-phosphate by fluorophotometer. Enzyme activities of GALK, GALT and GALE in RBC and galactose-1-phosphate were measured by radioisotope assay(RIA). Beutler test were done. Patients went on a lactose-free diet and follow-up tests for galactose, galactose-1-phosphate level and enzyme activity were performed. RESULTS: 10 patients(male : 6, female : 4) were diagnosed as galactosemia. Two patients had GALK deficiency and two had GALT deficiency. Six were GALE deficient showing the largest number. In two patients with GALK deficiency, GALT and GALE activities were normal but GALK activities showed respectively reduced activity. For GALT deficiency, two patients had low GALT activity in RBC and showed genotype of Duarte 2/G(galactosemia) in DNA analysis. In one patient, GALT activity was normal. Three patients seemed to be heterozygote state of GALE deficiency according to GALE activity levels. Four patients showed GALK hyperactivity. CONCLUSION: GALE deficiency provided the highest number. After lactose-free diet, galactose and galactose-1-phosphate were normaly maintained. Neonatal screening on galactosemia is essential for preventing life-threatening symptoms and an accurate diagnosis is needed for finding out the type of galactosemia which is important for prognosis.

Comunicação entre mitocôndria e núcleo controla a transcrição do gene GAL1 de Saccharomyces cerevisae / Communication between mitochondrial and nuclear controls Saccharomyces cerevisiae GAL1 gene transcription

O gene nuclear GAL1 de Saccharomyces cerevisiae codifica uma galactoquinase induzida por galactose e reprimida por glicose. Três evidências indicam que a transcrição de GAL1 é dependente da atividade mitocondrial. Linhagens petite, com deleção no DNA da organela (pî) ou rompimento em gene nuclear, que codifica a farnesil transferase mitocondrial, são incapazes de induzir GAL1. Os inibidores de respiração antimicina-A e azoteto de sódio (NaN3), que atuam, respectivamente, nos complexos III e IV da cadeia de transporte de elétrons, impedem a indução de GAL1. Em células crescidas em glicose ou glicerol, o oligômero formado pela proteína URF13, na presença de metomil, produz um poro na membrana mitocondrial...

Screening for galactosemia: Philippines experience. Newborn Screening Study Group.

Galactosemia is an inborn error of galactose metabolism due to a deficiency of any of the galactokinase, galactose-1-phosphate uridyl transferase (GALT), or epimerase enzymes. The Philippines, with its pilot newborn screening project, has been screening for this disorder for 2 years now. A total of 62,841 babies have been screened using the galactose and galactose-1-phosphate spot test. Confirmatory testing is done by the newborn screening laboratory of the The New Children's Hospital in Westmead, Australia. Two cases of galactosemia: 1 classical galactosemia and 1 galactokinase deficiency have so far been confirmed. Clinical review, problems encountered, and management are described. Long-term outcome of these patients, however, is yet to be determined.