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PubMedDate not supplied

The effect of galactose metabolic disorders on rat brain Na+,K+-ATPase activity.

To evaluate the effect of galactose metabolic disorders on the brain Na+,K+-ATPase in suckling rats. Separate preincubations of various concentrations (1-16 mM) of the compounds galactose-1-phosphate (Gal-1-P) and galactitol (galtol) with whole brain homogenates at 37 degrees C for 1 h resulted in a dose dependent inhibition of the enzyme whereas the pure enzyme (from porcine cerebral cortex) was stimulated. Glucose-1-phosphate (Glu-1-P) or galactose (Gal) stimulated both rat brain Na+,K+-ATPase and pure enzyme. A mixture of Gal-1-P (2 mM), galtol (2 mM) and Gal (4 mM), concentrations commonly found in untreated patients with classical galactosemia, caused a 35% (p < 0.001) rat brain enzyme inhibition. Additionally, incubation of a mixture of galtol (2 mM) and Gal (1 mM), which is usually observed in galactokinase deficient patients, resulted in a 25% (p < 0.001) brain enzyme inactivation. It is suggested that: a) The indirect inhibition of the brain Na+,K+-ATPase by Gal-1-P should be due to the presence of the epimer Gal and phosphate and that the pure enzyme direct activation by Gal-1-P and Glu-1-P to the presence of phosphate only. b) The observed brain Na+,K+-ATPase inhibitions in the presence of toxic concentrations of Gal-1-P and/or galtol could modulate the neural excitability, the metabolic energy production and the catecholaminergic and serotoninergic system.

Animals↗
PubMed1998

Inborn errors of metabolism in infancy: a guide to diagnosis.

Recent advances in the diagnosis and treatment of inborn errors of metabolism have improved substantially the prognosis for many of these conditions. This makes it essential that the practicing pediatrician be familiar with the clinical presentation of these disorders. A practical clinical approach to the recognition of inborn errors of metabolism in the young infant is presented in this review. Indications for specific laboratory studies are discussed. Guidelines are provided for the stabilization and emergency treatment of critically ill infants. This approach will identify those infants who will benefit from additional evaluation and specific treatment. Many of the inborn errors of metabolism, including urea cycle defects, organic acidemias, and certain disorders of amino acid metabolism, present in the young infant with symptoms of an acute or chronic metabolic encephalopathy. Typical symptoms include lethargy, poor feeding, apnea or tachypnea, and recurrent vomiting. Metabolic acidosis and/or hyperammonemia are observed in many of these conditions, but there are notable exceptions, including nonketotic hyperglycinemia and molybdenum co-factor deficiency. Therefore, appropriate laboratory testing for metabolic disorders should be performed in any infant who exhibits these findings. Although sepsis may be the initial consideration in a neonate with these symptoms, inborn errors of metabolism should always be in the differential diagnosis, particularly in a full-term infant with no specific risk factors. Hypoglycemia may be the predominant finding in a number of inborn errors of metabolism, including glycogen storage disorders, defects in gluconeogenesis, and fatty acid oxidation defects. The latter disorders, among the most common encountered, exhibit marked clinical variability and also may present as a sudden death, a Reye's-like episode, or a cardiomyopathy. Jaundice or other evidence of hepatic dysfunction is the mode of presentation of another important group of inborn errors of metabolism including galactosemia, hereditary tyrosinemia, neonatal hemochromatosis, and a number of other conditions. A subset of lysosomal storage disorders may present very early with coarse facial features, organomegaly, or even hydrops fetalis. Specific patterns of dysmorphic features and congenital anomalies characterize yet another group of inherited metabolic disorders, such as Zellweger syndrome and the Smith-Lemli-Opitz syndrome. Each of these symptom complexes, and the appropriate evaluation of the affected infants, is discussed in more detail in this review.

Acidosis↗
PubMed2006

Introduction to the newborn screening fact sheets.

Newborn screening fact sheets were last revised in 1996 by the Committee on Genetics of the American Academy of Pediatrics. These fact sheets have been revised again because of advances in the field, including technologic innovations such as tandem mass spectrometry, as well as greater appreciation of ethical issues such as informed consent. The fact sheets provide information to assist pediatricians and other professionals who care for children in performing their essential role within the newborn screening public health system. The newborn screening system consists of 5 parts: (1) newborn testing; (2) follow-up of abnormal screening results to facilitate timely diagnostic testing and management; (3) diagnostic testing; (4) disease management, which requires coordination with the medical home and genetic counseling; and (5) continuous evaluation and improvement of the newborn screening system. The following disorders are reviewed in the newborn screening fact sheets (which are available at www.pediatrics.org/cgi/content/full/118/3/e934): biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia,homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies,and tyrosinemia.

DNA↗
PubMed2006

Newborn screening fact sheets.

Newborn screening fact sheets were last revised in 1996 by the American Academy of Pediatrics Committee on Genetics. This revision was prompted by advances in the field since 1996, including technologic innovations, as well as greater appreciation of ethical issues such as those surrounding informed consent. The following disorders are discussed in this revision of the newborn screening fact sheets: biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia, homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies, and tyrosinemia. A series of topics related to newborn screening is discussed in a companion publication to this electronic publication of the fact sheets (available at: www.pediatrics.org/cgi/content/full/118/3/1304). These topics are newborn screening as a public health system; factors contributing to the need for review of the newborn screening system; informed consent; tandem mass spectrometry; DNA analysis in newborn screening; status of newborn screening in the United States; and the effect of sample timing, preterm birth, diet, transfusion, and total parenteral nutrition on newborn screening results.

Blood Transfusion↗
PubMed2000

[Neonatal cholestasis]

OBJECTIVE: To warn pediatricians about the early recognition of cholestasis in newborns and infants. METHODS: A bibliographic research about cholestasis was performed using Medline, and emphasizing the most relevant publications of the last 30 years. RESULTS: The concept of cholestasis and the causes of cholestatic tendency in newborns and infants are described. Several causes of intra and extrahepatic cholestasis are reported as well. In this review, only the diseases with diagnostic, therapeutic or prognostic peculiarities are commented, including extrahepatic biliary atresia, idiopathic neonatal hepatitis, galactosemia, and Alagille s syndrome. Furthermore, several resources are discussed for the diagnosis of cholestasis. CONCLUSIONS: The establishment of the diagnosis of cholestasis through the detection of hyperbilirubinemia in newborns who present jaundice after 14 days of life is a goal that could change the prognosis of several diseases responsible for neonatal cholestasis.

Journal Article↗
PubMedDate not supplied

[Application of a clinical and laboratory protocol for the investigation of inborn errors of metabolism among critically ill children]

OBJECTIVE: The aim of this work was to evaluate a protocol for investigation of Inborn Errors of Metabolism (IEM) in children who are acutely ill.METHODS: Forty six children with clinical suspicion of a metabolic disorder were studied during 2 years. They were selected through request for investigation of IEM from Pediatrics or Neonatal Intensive Care Units located in the metropolitan area of Porto Alegre. Criteria for inclusion were presence of one or more of the following clinical alterations, without defined etiology: Metabolic acidosis, electrolyte disturbances, hypoglycemia, seizures, lethargy, liver disfunction, family history suggestive of IEM. The protocol included clinical evaluation, compulsory tests (performed in all patients) and optional tests (performed selectively according to the results from the first tests or through specific clinical hypothesis).RESULTS: Six cases of IEM were identified: galactosemia, non-ketotic hyperglycinaemia, propionic acidemia, isovaleric acidemia, 3-hydroxy-3-methylglutaric acidemia and deficiency of 3-ketothiolase deficiency.CONCLUSIONS: The frequency of organic acidurias in this group was 4/46 (8.7%), which justifies the inclusion of organic acids analysis among the first line exams in acutely and severely ill children with undefined etiology. The relatively high frequency of IEM (6/46 or 13%), which is comparable to the ones observed in other studies within high risk groups, indicates that the protocol suggested is efficient and justifies the systematic investigation of IEM in not explained critically ill children.

Journal Article↗
PubMed1989

Pathogenesis of diabetic retinopathy.

Diabetic retinopathy involves anatomic changes in retinal vessels and neuroglia. The pathogenetic mechanism responsible for retinopathy is imperfectly understood, but much of the mechanism is apparently reproduced by experimental diabetes in animals and by chronic elevation of blood galactose in nondiabetic animals. The evidence that retinopathy is a consequence of excessive blood sugars and their sequelae is consistent with a demonstrated inhibition of retinopathy by strict glycemic control in diabetic dogs. However, retinopathy in the dog model has shown a tendency to resist intervention by strict control. Biochemical and pathophysiological sequelae of hyperglycemia possibly critical to the development of retinopathy in humans and animal models are being studied in many laboratories. Retinopathy occurs in experimental galactosemia in the absence of the renal hypertrophy, mesangial expansion, and glomerular obliteration typical of diabetes in humans and dogs, implying that retinopathy and nephropathy differ appreciably in pathogenesis.

Animals↗
PubMed1990

Coexistence of nerve conduction deficit with increased Na(+)-K(+)-ATPase activity in galactose-fed mice. Implications for polyol pathway and diabetic neuropathy.

We measured motor nerve conduction velocity (MNCV), Na(+)-K(+)-ATPase activity, polyol-pathway metabolites, and myo-inositol in sciatic nerves from control mice, galactose-fed (20% wt/wt diet) mice, and galactose-fed mice given the aldose reductase inhibitor ponalrestat (300-mg/kg diet). Treatments were maintained for 4 wk. Galactose feeding was associated with a 21.5% reduction in MNCV (P less than 0.001), which was almost completely prevented by ponalrestat. Galactose-fed mice showed an 81% increase in Na(+)-K(+)-ATPase (P less than 0.01), an effect completely prevented by aldose reductase inhibition. Treatment of a separate galactose-fed group with sorbinil (300 mg/kg diet) also attenuated the MNCV deficit and prevented the increased Na(+)-K(+)-ATPase activity associated with galactosemia. Accumulation of galactitol in the nerves of galactose-fed mice was prevented by aldose reductase inhibition, but there were no alterations in myo-inositol levels in the sciatic nerves of any group. These data show that exaggerated flux through the polyol pathway can cause an MNCV deficit that is unrelated to either myo-inositol levels or NA(+)-K(+)-ATPase activity.

Aldehyde Reductase↗
PubMed1992

Glycation of albumin, not glomerular basement membrane, alters permeability in an in vitro model.

The effects of glycation of either albumin, a plasma protein, or GBM were examined in an in vitro model of GBM permeability. Albumin was incubated with glucose in vitro, and nonglycated and glycated albumin were separated by affinity chromatography. Rat GBM was glycated either in vivo after the induction of diabetes or in vitro after incubation with 25 mM glucose. 150 micrograms of GBM was consolidated in an ultrafiltration cell, and albumin permeability across the GBM filter was assessed at an applied pressure (50 mmHg) selected to approximate glomerular capillary pressure in vivo. The sieving coefficient of glycated albumin was greater than the sieving coefficient of nonglycated albumin (0.25 +/- 0.03 vs. 0.10 +/- 0.02; P < 0.05). GBM glycated in vivo in diabetic rats exhibited native albumin and water permeability that was indistinguishable from that for GBM from control rats. Similarly, GBM glycated in vitro by incubation with 25 mM glucose exhibited water and albumin permeability identical to that for GBM incubated in buffer. Thus, the glycation of albumin, but not of GBM, leads to enhanced permeability in an in vitro GBM filtration system. Increased permeability of glycated albumin may contribute to albuminuria and/or renal injury in states of increased circulating glycated albumin such as diabetes and experimental galactosemia.

Animals↗
PubMed1993

Rat galactose-1-phosphate uridyltransferase coding sequence, transcription start site and genomic organization.

Galactosemia is an inborn error of metabolism in humans due to deficient activity of the enzyme galactose-1-phosphate uridyl-transferase (GALT). Using a 1.3 kb Bam HI restriction fragment of the human GALT cDNA as a probe, three cDNAs, 786 bp, 265 bp and 1.4 kb were isolated from a rat liver cDNA library. The total rat GALT coding sequence obtained from these three clones was 1051 nt. Repeat cDNA library screening failed to isolate cDNA clones with additional 5'-coding sequence. Using the 786 bp cDNA as a probe, three genomic clones, RGG1, RGG2, and RGG3 were isolated from a rat genomic library. RGG2 and RGG3 contained additional 5'-coding sequence, missing from the cDNA clones, which was identified by comparison with the human cDNA sequence. The rat GALT sequence, from transcription start site to the polyadenylation tail, is 1254 nt and is divided into 11 exons which span over 3.5 kb of genomic sequence. Primer extension identified the transcription start site as 17 nt 5' to the translation start site. Rat GALT is 379 amino acids long, identical to human GALT, with a derived molecular weight of 43,312 Da similar to the 43,360 Da weight for human GALT. The derived rat amino acid sequence is 90% identical to the human sequence. The isolation of rat GALT genomic sequence will facilitate future investigations of the regulation of expression of the rat GALT gene.

Amino Acid Sequence↗
PubMed1997

Inherited disorders of glycoprotein synthesis: cell biological insights.

Disorders of glycoprotein synthesis have been described only recently, and few have been studied extensively at both the clinical and biochemical level. The identification and characterization of these rare diseases are important, not only for the patients and their families, but because they offer enormous insight into biological processes. For example, the targeting of acid hydrolases to lysosomes by mannose-6-phosphate was discovered as a direct result of the elucidation of the defect in I-cell disease. The notion of carbohydrates as targeting agents continues to have ramifications today, with the success of macrophage-targeted enzyme replacement therapy for Gaucher disease. Likewise, confirmation of the in vivo role of fucose-containing glycans and selectins in neutrophil function came from studies using specimens from patients with leucocyte adhesion deficiency type II due to reduced availability of GDP-fucose. Identification of the in vivo ligands of selectins also has implications for anti-inflammatory therapies. Macular corneal dystrophy and spondyloepiphyseal dysplasia tarda offer an opportunity to investigate the number of different sulfotransferases in cells, their substrates, and their tissue expression. The Ehlers-Danlos progeroid variant offers insight into the function and regulation of the proteoglycan decorin, and suggests that several of the enzymes involved in proteoglycan synthesis may function as a multienzyme complex. The common occurrence of hypergonadotropic hypogonadism in patients with galactosemia or carbohydrate-deficient glycoprotein protein syndrome, due to defective N-linked glycosylation, suggests that ovarian function is particularly dependent on proper glycan-synthesis. A host of other concepts await discovery as a fuller contingent of human disorders of glycan synthesis achieves recognition.

Anemia, Dyserythropoietic, Congenital↗
PubMed1999

Given the benefits of breastfeeding, are there any contraindications?

There are many benefits to the infant to be breastfed and to the mother to breastfeed. There are, however, a few conditions where the tremendous benefit may be outweighed by maternal infection, disease, drugs, or contaminants as these are rare. HIV is the only infection that is an absolute contraindication in developed countries. Galactosemia is the only infant disease and there are a few medications that are contraindicated.

Breast Feeding↗
PubMed1999

[Genes and ovarian insufficiency].

Premature ovarian failure is defined as hypoestrogenism with elevated gonadotropins, occurring before the age of 40. The prevalence of this syndrome is 3% of the women population. In most cases its etiology remains unknown. In theory, ovarian failure may occur by the following mechanisms: the pool of primordial follicule is too low; the atresia ou apoptosis is increased in the ovarian follicle; the follicle maturation is interrupted. In the past few years, several genes have been implicated in the pathogenesis of human or murine premature ovarian failure. Those genes can be classified according to the potential mechanisms previously described. Atm and c-kit gene code for proteins involved in maintaining the pool of primordial follicles. Genes located on the X chromosome, genes involved in blepharophimosis, in galactosemia code for proteins involved in follicular atresia. The gonadotropins, their receptors, GDF9 and connexin 37 are involved in follicle maturation. A better understanding of the family of genes involved in oocyte and follicular atresia should allow a better understanding of premature ovarian failure. Up to now, the better care for those patients is to give them hormonal replacement therapy and suggest oocyte donation when they desire to be pregnant.

Adult↗
PubMed1999

[Premature ovarian insufficiency].

Premature ovarian failure is defined as amenorrhea with hypo-oestrogenism and elevated gonadotrophins occurring before the age of 40 years. In theory, ovarian failure may occur because of a decreased pool of primordial follicles, because ovarian apoptosis is increased or accelerated or because the follicle maturation is interrupted before the preovulatory stage. The mechanisms inducing premature ovarian failure have been described in a few number of cases. Atm or c-kit gene mutations induce a very low pool of primordial follicles. In chromosome X abnormalities, chemotherapy, galactosemia and blepharophimosis syndrome apoptosis is increased. Follicle maturation is interrupted in FSH and LH receptor mutations or in autoimmunity. However, in most cases, the etiology remains idiopathic. A better knowledge in genes involved in ovarian apoptosis should enhance our understanding of premature ovarian failure. Meanwhile, the best treatment is to give hormonal replacement therapy and send the patient to oocyte donation program when they desire to be pregnant.

Adult↗
PubMed1999

Evaluating newborn screening program data systems--Georgia, 1998.

All 50 states and the District of Columbia conduct newborn screening (NBS) programs that annually screen approximately 4 million infants for metabolic and other disorders to prevent mental retardation, disability, and death. In 1998, Georgia newborns were screened for eight disorders: phenylketonuria, galactosemia, tyrosinemia, homocystinuria, hypothyroidism, maple syrup urine disease, congenital adrenal hyperplasia, and sickle cell disease. Appropriate data that reflect progress toward achieving short- and long-term goals are necessary to assess the effectiveness of NBS and to inform public health policy decisions about which disorders to add or delete from screening. This report summarizes findings from an evaluation of data systems for metabolic and endocrine disorders in the Georgia NBS program and assesses the ability to measure progress toward short- and long-term goals. Although the data indicate that the program typically received specimens of sufficient quality for testing in a timely manner, additional data are needed to assess fully the effectiveness of the NBS program in identifying disorders.

Databases, Factual↗
PubMed2000

Analysis of concentration and (13)C enrichment of D-galactose in human plasma.

BACKGROUND: A stable-isotope dilution method for the sensitive determination of D-galactose in human plasma was established. METHODS: D-[(13)C]Galactose was added to plasma, and the concentration was measured after D-glucose was removed from the plasma by treatment with D-glucose oxidase and the sample was purified by ion-exchange chromatography. For gas chromatographic-mass spectrometric analysis, aldononitrile pentaacetate derivatives were prepared. Monitoring of the [MH-60](+) ion intensities at m/z 328, 329, and 334 in the positive chemical ionization mode allowed the assessment of 1-(12)C-, 1-(13)C-, and U-(13)C(6)-labeled D-galactose, respectively. The D-galactose concentration was quantified on the basis of the (13)C-labeled internal standard. RESULTS: The method was linear (range examined, 0.1-5 micromol/L) and of good repeatability in the low and high concentration ranges (within- and between-run CVs <15%). The limit of quantification for plasma D-galactose was <0.02 micromol/L. Measurements in plasma of postabsorptive subjects yielded D-galactose concentrations (mean +/- SD) of 0.12 +/- 0.03 (n = 16), 0.11 +/- 0.04 (n = 15), 1.44 +/- 0.54 (n = 10), and 0.17 +/- 0.07 (n = 5) micromol/L in healthy adults, diabetic patients, patients with classical galactosemia, and obligate heterozygous parents thereof, respectively. These data were considerably lower (3- to 18-fold) than the values of a conventional enzymatic assay. The procedure was also applied successfully in a stable-isotope turnover study to evaluate endogenous D-galactose formation. CONCLUSIONS: The present findings establish that detection of D-galactose from endogenous sources is feasible in human plasma and show that erroneously high results may be obtained by enzymatic methods.

Adolescent↗
PubMed1999

Management of chronic liver disease.

Childhood liver disorders have, in general, mode of presentations which are distinct from that in adult population. It is due to varying etiology and natural history of the liver diseases in childhood. Chronic hepatitis B and C can be managed with alpha interferon. Remission rates in children have been reported to be between 20-58%. Recently available lamuvidine has also been used in combination with interferon therapy. Oral chelation therapy and liver transplantation have radically affected the outcome of patients with Wilson's disease. Corticosteroids and immunosuppressive therapy are effective in reducing both morbidity and mortality due to auto-immune hepatitis. Offending carbohydrates are eliminated from the diet of patients with galactosemia and hereditary fructose intolerance. The most important and often neglected component of management of chronic liver diseases in childhood are nutritional management and prompt interventions for ascites, spontaneous bacterial peritonitis, portal hypertension and hepatic encephalopathy. With definitive etiological and histological assessment and institution of specific as well as supportive therapy, children with chronic liver disease can have a prolonged survival with improved quality of life. Several of them can potentially receive the liver transplant as and when it becomes available.

Adolescent↗
PubMed2000

[Mutations causing puberty disturbances in girls].

A survey of literature has been presented relating to the disturbance of girls puberty in presence of gene mutations in membrane GnRH receptors and gonadotropins receptors as well as point mutations in the gonadotropins. The paper also presents the role of mutations in genes involving in steroid hormones production in girls ovaries and adrenal cortex and in the mother placenta. Furthermore also data concern the mutations indirectly influences on the mechanism of puberty as galactosemia or activating in gene G-alpha in absence interaction between gonadotropins and their receptors were presented.

Adolescent↗