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1.
Oxid Med Cell Longev ; 2020: 7145656, 2020.
Article in English | MEDLINE | ID: mdl-32655772

ABSTRACT

Skin aging has been associated with a higher dietary intake of carbohydrates, particularly glucose and galactose. In fact, the carbohydrates are capable of damaging the skin's vital components through nonenzymatic glycation, the covalent attachment of sugar to a protein, and subsequent production of advanced glycation end products (AGEs). This review is focused on the role of D-galactose in the development of skin aging and its relation to oxidative stress. The interest in this problem was dictated by recent findings that used in vitro and in vivo models. The review highlights the recent advances in the underlying molecular mechanisms of D-galactose-mediated cell senescence and cytotoxicity. We have also proposed the possible impact of galactosemia on skin aging and its clinical relevance. The understanding of molecular mechanisms of skin aging mediated by D-galactose can help dermatologists optimize methods for prevention and treatment of skin senescence and aging-related skin diseases.


Subject(s)
Galactose/toxicity , Oxidative Stress/physiology , Skin Aging/drug effects , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Cellular Senescence/drug effects , Collagen/metabolism , Galactosemias/etiology , Galactosemias/metabolism , Galactosemias/pathology , Galactosemias/therapy , Glycosylation , Humans , Oxidative Stress/drug effects , Skin/drug effects , Skin/metabolism , Skin/pathology , Skin Aging/pathology
2.
Int J Mol Sci ; 20(20)2019 Oct 22.
Article in English | MEDLINE | ID: mdl-31652573

ABSTRACT

Classical galactosaemia (CG) (OMIM 230400) is a rare inborn error of galactose metabolism caused by the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12). Primary ovarian insufficiency (POI) is the most common long-term complication experienced by females with CG, presenting with hypergonadotrophic hypoestrogenic infertility affecting at least 80% of females despite new-born screening and lifelong galactose dietary restriction. In this review, we describe the hypothesized pathophysiology of POI from CG, implications of timing of the ovarian dysfunction, and the new horizons and future prospects for treatments and fertility preservation.


Subject(s)
Fertility Preservation/methods , Galactose/genetics , Galactosemias/etiology , Female , Galactose/metabolism , Galactosemias/pathology , Galactosemias/therapy , Humans
3.
Genet Med ; 21(6): 1286-1294, 2019 06.
Article in English | MEDLINE | ID: mdl-30451973

ABSTRACT

PURPOSE: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. METHODS: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. RESULTS: The highest blood galactose levels observed in each patient were 17.3-41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between ß- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients' peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. CONCLUSION: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.


Subject(s)
Carbohydrate Epimerases/genetics , Galactosemias/etiology , Galactosemias/genetics , Alleles , Base Sequence , Carbohydrate Epimerases/metabolism , Child, Preschool , Female , Galactose/metabolism , Genetic Variation , Humans , Infant , Male
4.
Genet Med ; 20(1): 3-11, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29261178

ABSTRACT

Disclaimer: These ACMG Standards and Guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these Standards and Guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Galactosemias are inherited disorders of galactose metabolism due to deficiency in one of the three enzymes involved in the Leloir pathway: galactose-1-phosphate uridyltransferase, galactokinase, and uridine diphosphate (UDP)-galactose-4'-epimerase. Galactose-1-phosphate uridyltransferase deficiency, or classic galactosemia, is the most frequent and the most severe of the three enzyme deficiencies; it is characterized by failure to thrive, liver failure, susceptibility to sepsis, and death, if untreated. Newborn screening for classic galactosemia has been implemented in all of the United States, while screening for galactokinase deficiency and UDP-galactose-4'-epimerase deficiency is not universal. Early identification and treatment of galactosemia leads to improved outcome. This document reviews the laboratory methods and best practices for the diagnosis of galactosemia.


Subject(s)
Galactosemias/diagnosis , Genetic Testing , Molecular Diagnostic Techniques , Clinical Laboratory Techniques/methods , Clinical Laboratory Techniques/standards , Galactose/metabolism , Galactosemias/etiology , Galactosemias/metabolism , Genetic Testing/methods , Genetic Testing/standards , Humans , Metabolic Networks and Pathways , Mutation , Prenatal Diagnosis , Reproducibility of Results
6.
Biochim Biophys Acta ; 1832(8): 1279-93, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23583749

ABSTRACT

Type I galactosemia is a genetic disorder that is caused by the impairment of galactose-1-phosphate uridylyltransferase (GALT; EC 2.7.7.12). Although a large number of mutations have been detected through genetic screening of the human GALT (hGALT) locus, for many it is not known how they cause their effects. The majority of these mutations are missense, with predicted substitutions scattered throughout the enzyme structure and thus causing impairment by other means rather than direct alterations to the active site. To clarify the fundamental, molecular basis of hGALT impairment we studied five disease-associated variants p.D28Y, p.L74P, p.F171S, p.F194L and p.R333G using both a yeast model and purified, recombinant proteins. In a yeast expression system there was a correlation between lysate activity and the ability to rescue growth in the presence of galactose, except for p.R333G. Kinetic analysis of the purified proteins quantified each variant's level of enzymatic impairment and demonstrated that this was largely due to altered substrate binding. Increased surface hydrophobicity, altered thermal stability and changes in proteolytic sensitivity were also detected. Our results demonstrate that hGALT requires a level of flexibility to function optimally and that altered folding is the underlying reason of impairment in all the variants tested here. This indicates that misfolding is a common, molecular basis of hGALT deficiency and suggests the potential of pharmacological chaperones and proteostasis regulators as novel therapeutic approaches for type I galactosemia.


Subject(s)
Galactosemias/enzymology , Proteostasis Deficiencies/enzymology , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/chemistry , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/metabolism , Galactosemias/etiology , Galactosemias/genetics , Humans , Kinetics , Models, Molecular , Mutagenesis, Site-Directed , Mutation , Protein Binding , Protein Denaturation , Proteostasis Deficiencies/etiology , Proteostasis Deficiencies/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/genetics
7.
Dis Model Mech ; 6(1): 84-94, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22773758

ABSTRACT

Classic galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research, the mechanisms that underlie pathophysiology in classic galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we describe application of our fly genetic model of galactosemia to the question of whether oxidative stress contributes to the acute galactose sensitivity of GALT-null animals. Our first approach tested the impact of pro- and antioxidant food supplements on the survival of GALT-null and control larvae. We observed a clear pattern: the oxidants paraquat and DMSO each had a negative impact on the survival of mutant but not control animals exposed to galactose, and the antioxidants vitamin C and α-mangostin each had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested but, interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose sensitivity of GALT-null Drosophila and, by extension, suggest that reactive oxygen species might also contribute to the acute pathophysiology in classic galactosemia.


Subject(s)
Galactosemias/genetics , Galactosemias/metabolism , Animals , Antioxidants/pharmacology , Ascorbic Acid/pharmacology , Cysteine/metabolism , Dimethyl Sulfoxide/toxicity , Disease Models, Animal , Drosophila Proteins/deficiency , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/drug effects , Drosophila melanogaster/enzymology , Drosophila melanogaster/genetics , Galactose/metabolism , Galactose/toxicity , Galactosemias/drug therapy , Galactosemias/etiology , Galactosephosphates/metabolism , Gene Expression/drug effects , Gene Knockout Techniques , Genes, Insect , Glutathione/metabolism , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Humans , Mutation , Oxidative Stress/drug effects , Paraquat/toxicity , Reactive Oxygen Species/metabolism , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/deficiency , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/genetics , Xanthones/pharmacology
8.
Clin Chim Acta ; 411(19-20): 1506-10, 2010 Oct 09.
Article in English | MEDLINE | ID: mdl-20547145

ABSTRACT

BACKGROUND: Three different types of galactosemia have been described, and the most common form occurs due to a deficiency in the galactose-1-phosphate uridyltransferase (GALT) enzyme activity. METHODS: To investigate the molecular defects of the GALT gene, PCR-direct sequencing was performed with genomic DNA from 18 Korean patients with reduced GALT activity. RESULTS: Of the 18 patients tested, 13 (72.2%) had previously reported variants: Duarte variant (12 patients), p.R201H (1 patient), and g.A1962G. In addition, we identified six novel sequence variations by PCR-direct sequencing: five sequence variations in coding regions (p.H31R, p.L116I, p.Q169H, p.H186P and p.R333R), and one in an intron (g.2621A>G). Of 100 normal individuals tested, 4 were heterozygous for the Duarte variant, which indicates a Duarte allele frequency of 2%. Biochemical characteristics of the novel genetic alterations were determined: enzyme activity for exonic alterations and splicing for intron. CONCLUSION: The genetic constitution of the GALT gene is responsible for galactosemia in the Korean population.


Subject(s)
Galactosemias/genetics , Genetic Variation , UTP-Hexose-1-Phosphate Uridylyltransferase/deficiency , UTP-Hexose-1-Phosphate Uridylyltransferase/genetics , DNA Mutational Analysis , Exons/genetics , Galactosemias/etiology , Genome, Human , Humans , Infant , Infant, Newborn , Introns/genetics , Korea
10.
BJOG ; 117(2): 156-62, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19843045

ABSTRACT

Over the past 15 years there have been changes in the care of children and adolescents paralleling increased longevity of those with chronic illnesses and increased survival after childhood cancer and organ transplantation. A broad understanding of holistic management and long-term risks is required. Optimisation of pubertal progress and normalisation of bone and hormonal health by the end of puberty will reduce the impact of later adult bone loss in chronic disease conditions. Psychosocial issues related to both precocious and delayed puberty can have profound effects on family function.


Subject(s)
Hypothalamo-Hypophyseal System/physiopathology , Ovarian Diseases/complications , Adolescent , Adult , Autoimmune Diseases/diagnosis , Autoimmune Diseases/genetics , Child , Child, Preschool , Chronic Disease , Female , Galactosemias/etiology , Growth Disorders/etiology , Humans , Hypogonadism/physiopathology , Hypothalamic Diseases/complications , Hypothalamic Diseases/physiopathology , Neoplasms/drug therapy , Neoplasms/radiotherapy , Ovarian Diseases/physiopathology , Pregnancy , Puberty/drug effects , Puberty/physiology , Puberty/psychology , Puberty, Precocious/physiopathology , Survivors , Turner Syndrome/drug therapy , Turner Syndrome/physiopathology , Uterus/growth & development , Young Adult
11.
Pediatr Int ; 51(2): 276-82, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19405932

ABSTRACT

BACKGROUND: Portosystemic shunt is one of the main causes of persistent hypergalactosemia without enzyme deficiency, but the diagnostic imaging strategy has not yet been established. The purpose of the present study was to establish a diagnostic imaging strategy. METHODS: A retrospective investigation of the clinical and imaging findings of 10 children with persistent hypergalactosemia without enzyme deficiency detected by screening was undertaken. RESULTS: Abnormal ultrasonography (US) findings were detected in all eight patients with liver disorders. In three patients with citrin deficiency, the combination of fatty liver on US and laboratory evidence of cholestasis led to the diagnosis. In three patients with portosystemic shunt, US on sedation clearly depicted the shunt vessels. The extent was more easily understood on contrast computed tomography (CT). Per-rectal portal scintigraphy with N-isopropyl-p-I-123 iodoamphetamine and lung perfusion scintigraphy with (99m)Tc macroaggregated albumin were useful for evaluation of portal shunt index and assessment of pulmonary arteriovenous shunt. One patient underwent transarterial coil embolization. In two patients with hepatic tumor, the lesions and its vascularity were clearly demonstrated on US and dynamic CT. In one patient, small shunt index on per-rectal portal scintigraphy suggested no need for treatment. The other patient was treated with a combination of steroid, radiation, and interventional radiology. The etiology remained unknown in two children. CONCLUSIONS: In the assessment of hypergalactosemia, US is the modality of choice. CT is a useful tool for more detailed evaluation of the abnormalities found on US. Per-rectal portal scintigraphy and pulmonary perfusion scintigraphy play an important role in the evaluation of portosystemic shunt. Interventional radiology is sometimes effective.


Subject(s)
Diagnostic Imaging , Galactosemias/diagnosis , Citrullinemia/complications , Citrullinemia/epidemiology , Embolization, Therapeutic , Fatty Liver/epidemiology , Galactosemias/etiology , Humans , Lung/diagnostic imaging , Magnetic Resonance Imaging , Portasystemic Shunt, Surgical , Radiography, Interventional , Radionuclide Imaging , Retrospective Studies , Tomography, X-Ray Computed
12.
Am J Physiol Endocrinol Metab ; 293(4): E1036-44, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17666488

ABSTRACT

Dysmetabolic state in diabetes may lead to augmented synthesis of extracellular matrix (ECM) proteins. In the endothelial cells, we have previously demonstrated that glucose-induced fibronectin (FN) production and that of its splice variant, EDB(+)FN, is regulated by protein kinase B (PKB, also known as Akt). In this study, we investigated the role of Akt1 in ECM protein production in the organs affected by chronic diabetic complications. We studied Akt1/PKBalpha knockout mice and wild-type control littermates. To avoid confounding effects of systemic insulin, we used 30% galactose feeding to induce hyperhexosemia for 8 wk starting at 6 wk of age. We investigated FN mRNA, EDB(+)FN mRNA, and transforming growth factor (TGF)-beta mRNA expression, Akt phosphorylation, Akt kinase activity, and NF-kappaB and AP-1 activation in the retina, heart, and kidney. Renal and cardiac tissues were histologically examined. Galactose feeding caused significant upregulation of FN, EDB(+)FN, and TGF-beta in all tissues. FN protein levels paralleled mRNA. Such upregulation were prevented in Akt1-deficient galactose-fed mice. Galactose feeding caused ECM protein deposition in the glomeruli and in the myocardium, which was prevented in the Akt knockout mice. NF-kappaB and AP-1 activation was pronounced in galactose-fed wild-type mice and prevented in the galactose-fed Akt1/PKBalpha-deficient group. In the retina and kidney, Ser473 was the predominant site for Akt phosphorylation, whereas in the heart it was Thr308. Parallel experiment in streptozotocin-induced diabetic animals showed similar results. The data from this study indicate that hyperhexosemia-induced Akt/PKB activation may be an important mechanism leading to NF-kappaB and AP-1 activation and increased ECM protein synthesis in the organs affected by chronic diabetic complications.


Subject(s)
Fibronectins/biosynthesis , Galactosemias/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Animals , Diabetes Complications/genetics , Diabetes Complications/metabolism , Diabetes Complications/pathology , Extracellular Matrix/metabolism , Fibronectins/genetics , Galactosemias/etiology , Galactosemias/genetics , Galactosemias/pathology , Gene Expression Regulation , Mice , Mice, Inbred C57BL , Mice, Knockout , Proto-Oncogene Proteins c-akt/genetics , Transcription Factors/metabolism , Transforming Growth Factor beta/genetics
15.
J Inherit Metab Dis ; 27(2): 279-80, 2004.
Article in English | MEDLINE | ID: mdl-15243984

ABSTRACT

A patient affected by Fanconi-Bickel syndrome detected by neonatal screening for galactosaemia is reported. Molecular studies of the GLUT2 gene led to the identification of a novel mutation of the glucose transporter.


Subject(s)
Fanconi Syndrome/diagnosis , Fanconi Syndrome/genetics , Galactosemias/diagnosis , Galactosemias/genetics , Monosaccharide Transport Proteins/genetics , Fanconi Syndrome/complications , Galactosemias/etiology , Gene Deletion , Glucose Transporter Type 2 , Humans , Infant, Newborn , Male , Neonatal Screening
16.
J Inherit Metab Dis ; 27(1): 11-8, 2004.
Article in English | MEDLINE | ID: mdl-14970742

ABSTRACT

The aetiology of hypergalactosaemia in 100 neonates detected by screening using the Paigen method is discussed. Hypergalactosaemia was transient in 94 cases and persistent in 6. The aetiology among transient cases was unknown in 55, delayed closure of the ductus venosus in 19, heterozygous UDP-galactose 4-epimerase (GALE) deficiency in 16, and heterozygous galactose-1-phosphate uridyltransferase (GALT) deficiency in 6. The aetiology among persistent cases was hepatic haemangioendothelioma with portovenous shunting in 2, and patent ductus venosus with hypoplasia of the intrahepatic portal vein, citrin deficiency, homozygous GALE deficiency, and heterozygous GALE deficiency in one patient each. The abnormalities of the portal system were identified ultrasonographically at the initial consultation and measurements of the total bile acid and alpha-fetoprotein concentrations were helpful in resolving the differential diagnosis. The causes of hypergalactosaemia varied, but a major cause was portosystemic shunt. Evaluation of patients with hypergalactosaemia should not be limited to enzymatic analysis, but should also include hepatic imaging, especially ultrasonography. Additionally, determination of total bile acids and alpha-fetoprotein is helpful in identifying the aetiology of hypergalactosaemia in infants.


Subject(s)
Galactosemias/diagnosis , Mass Screening , Portal Vein/diagnostic imaging , Ultrasonography, Doppler, Color , Acute Disease , Bile Acids and Salts/blood , Chronic Disease , Galactose/administration & dosage , Galactosemias/blood , Galactosemias/diet therapy , Galactosemias/etiology , Hemangioendothelioma/complications , Heterozygote , Humans , Infant, Newborn , Liver Neoplasms/complications , Metabolism, Inborn Errors/genetics , Portal System/abnormalities , Portal System/diagnostic imaging , Severity of Illness Index , UDPglucose 4-Epimerase/deficiency , UDPglucose 4-Epimerase/genetics , UTP-Hexose-1-Phosphate Uridylyltransferase/deficiency , alpha-Fetoproteins/analysis
17.
Annu Rev Nutr ; 23: 59-80, 2003.
Article in English | MEDLINE | ID: mdl-12704219

ABSTRACT

In humans, the absence of galactose-1-phosphate uridyltransferase (GALT) leads to significant neonatal morbidity and mortality which are dependent on galactose ingestion, as well as long-term complications of primary ovarian failure and cognitive dysfunction, which are diet independent. The creation of a knockout mouse model for GALT deficiency was aimed at providing an organism in which metabolic challenges and gene manipulation could address the enigmatic pathophysiologic questions raised by humans with galactosemia. Instead, the mouse represents a biochemical phenotype without evidence of clinical morbidity. The similarities and differences between mice and humans with galactosemia are explored from metabolite, enzyme, and process points of view. The mouse both produces and oxidizes galactose in a manner similar to humans. It differs in brain accumulation of galactitol. Future directions for exploration of this enigmatic condition are discussed.


Subject(s)
Galactosemias/etiology , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/deficiency , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/genetics , Animals , Disease Models, Animal , Galactose/metabolism , Galactosemias/enzymology , Galactosemias/genetics , Galactosemias/metabolism , Gene Expression Regulation, Enzymologic , Humans , Liver/enzymology , Mice , Mice, Knockout
18.
Hum Reprod ; 18(2): 276-82, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12571162

ABSTRACT

BACKGROUND: In rats, prenatal exposure to high concentrations of galactose may contribute to a condition that is equivalent to the premature ovarian failure (POF) component of human galactosaemia. We investigated if development of POF under experimental galactosaemia-like conditions was attributed to impaired germ cell migration. METHODS: Pregnant rats were fed pellets supplemented with, or without, 35% galactose from day 3 of conception continuing through parturition. Between days 12-15, embryos from one uterine horn were dissected out. Primordial germ cells (PGC) were histochemically localized and counted on the basis of binding of Dolichos biflorus agglutinin, a lectin specific for terminal N-acetylgalactosamine (GalNAc), to the surface glycoconjugate of the germ cells. The embryos from the other uterine horn were maintained until parturition. Liver activity of uridine diphosphate galactose 4-epimerase, the enzyme involved at multiple steps in the process of synthesis of GalNAc, was assayed in 1-2 day old female pups. RESULTS: The numbers of PGC at the day-specific sites on all days of examination were significantly lower (P

Subject(s)
Galactose/administration & dosage , Galactose/adverse effects , Galactosemias/etiology , Germ Cells/drug effects , Prenatal Exposure Delayed Effects , Primary Ovarian Insufficiency/etiology , Animals , Cell Count , Cell Movement/drug effects , Dose-Response Relationship, Drug , Female , Galactosemias/complications , Germ Cells/pathology , Gonads/pathology , Liver/enzymology , Male , Pregnancy , Rats , UDPglucose 4-Epimerase/antagonists & inhibitors , UDPglucose 4-Epimerase/metabolism
19.
Med Hypotheses ; 60(1): 123-8, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12450779

ABSTRACT

Classic galactosemia is due to the deficiency of galactose-1-phosphate uridyl transferase and is transmitted as an autosomal recessive disorder. Patients suffering from classic galactosemia display acute symptoms such as poor growth, feeding difficulties, jaundice, hepatomegaly etc., which disappear when the individual is on galactose free diet. However, these patients continue to suffer from defects such as neurological disturbances and ovarian dysfunction, due to the accumulation of galactose-1-phosphate, which is a normal intermediate of galactose metabolism. The biochemical mechanism of galactose-1-phosphate mediated toxicity is still an enigma. Recent experiments strongly suggest that galactose-1-phosphate is also a substrate for inositol monophosphatase (IMPase). Phosphatidylinositol bisphosphate [PI(P)2] dependent signaling serves as a second messenger for several neurotransmitters in the brain. Therefore, the brain is critically dependent on IMPase for the supply of free inositol in order to sustain [PI(P)2] signaling. Circumstantial evidence strongly supports the possibility that being a substrate, galactose-1-phosphate could modulate IMPase function in vivo. The implication of this idea is discussed in relation to classic galactosemia as well as bipolar disorder, which has been thought to be due to the hyper-activation of [PI(P)2] mediated second messenger pathways(s).


Subject(s)
Galactosephosphates/metabolism , Models, Biological , Phosphoric Monoester Hydrolases/metabolism , Galactosemias/etiology , Galactosemias/metabolism , Humans , Phosphatidylinositols/metabolism , Second Messenger Systems , Substrate Specificity
20.
J Inherit Metab Dis ; 24(1): 72-8, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11286386

ABSTRACT

Congenital porto left renal venous (PRV) shunt was found to be the cause of galactosaemia in four galactosaemic neonates detected by mass screening (Paigen method). The patients did not have hereditary galactosaemias and were diagnosed as having galactosaemia of unknown cause, because porto-systemic venous (PS) shunts had not been recognized. At the time of diagnosis, hypergalactosaemia was not severe (0.44-0.55 mmol/L; 8-10 mg/dl) and plasma concentration of total bile acids (TBA) did not suggest a PS shunt (46-50 micromol/L). However, slightly but consistently increased concentrations of galactose and TBA strongly suggested the presence of a PS shunt, and careful ultrasonographic investigation revealed PRV shunt. We conclude that PRV shunt should be suspected in patients with hypergalactosaemia of unknown cause.


Subject(s)
Galactosemias/etiology , Portal Vein/abnormalities , Renal Veins/abnormalities , Female , Heart Defects, Congenital/complications , Humans , Infant , Infant, Newborn , Male , Portal Vein/diagnostic imaging , Renal Veins/diagnostic imaging , Ultrasonography , Vascular Fistula/complications , Vascular Fistula/diagnostic imaging
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