Hereditary Hemolytic Anemia with Increased Red Cell Adenosine Deaminase (45- to 70-fold) and Decreased Adenosine Triphosphate

Valentine, William N.; Paglia, Donald E.; Tartaglia, Anthony P.; Gilsanz, Florinda

doi:10.1126/science.836588

Cited by 162 publications

(44 citation statements)

References 24 publications

(10 reference statements)

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“…One case of anemia arising from superactive adenosine deaminase has been reported (15). The patient had approximately 40-70 times the normal activity.…”

Section: Discussionmentioning

confidence: 99%

Developmental disorder associated with increased cellular nucleotidase activity

Page

Fontanesi

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Four unrelated patients are described with a syndrome that included developmental delay, seizures, ataxia, recurrent infections, severe language deficit, and an unusual behavioral phenotype characterized by hyperactivity, short attention span, and poor social interaction. These manifestations appeared within the first few years of life. Each patient displayed abnormalities on EEG. No unusual metabolites were found in plasma or urine, and metabolic testing was normal except for persistent hypouricosuria. Investigation of purine and pyrimidine metabolism in cultured fibroblasts derived from these patients showed normal incorporation of purine bases into nucleotides but decreased incorporation of uridine. De novo synthesis of purines and cellular phosphoribosyl pyrophosphate content also were moderately decreased. The distribution of incorporated purines and pyrimidines did not reveal a pattern suggestive of a deficient enzyme activity. Assay of individual enzymes in fibroblast lysates showed no deficiencies. However, the activity of cytosolic 5 -nucleotidase was elevated 6-to 10-fold. Based on the possibility that the observed increased catabolic activity and decreased pyrimidine salvage might be causing a deficiency of pyrimidine nucleotides, the patients were treated with oral pyrimidine nucleoside or nucleotide compounds. All patients showed remarkable improvement in speech and behavior as well as decreased seizure activity and frequency of infections. A double-blind placebo trial was undertaken to ascertain the efficacy of this supplementation regimen. Upon replacement of the supplements with placebo, all patients showed rapid regression to their pretreatment states. These observations suggest that increased nucleotide catabolism is related to the symptoms of these patients, and that the effects of this increased catabolism are reversed by administration of uridine.

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“…One case of anemia arising from superactive adenosine deaminase has been reported (15). The patient had approximately 40-70 times the normal activity.…”

Section: Discussionmentioning

confidence: 99%

Developmental disorder associated with increased cellular nucleotidase activity

Page

Fontanesi

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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“…It is present in virtually all mammalian cells, and is known to occur in several isoenzymatic and molecular forms (Hirchhorn and Ratech, 1980). A deficiency of ADA activity is associated with a form of severe combined immunodeficiency disease (SCID) (Giblet et al, 1972;Valentine et al, 1977). Also, a 40-to 70-fold increase of its activity is associated with a form of chronic nonspherocytic hemolytic disease (Daddona et al, 1978).…”

Section: Introductionmentioning

confidence: 99%

A Product Inhibition Study on Adenosine Deaminase by Spectroscopy and Calorimetry

Saboury¹,

Divsalar²,

Jafari³

et al. 2002

BMB Reports

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Kinetic and thermodynamic studies have been made on the effect of the inosine product on the activity of adenosine deaminase in a 50 mM sodium phosphate buffer, pH 7.5, at 27 o C using UV spectrophotometry and isothermal titration calorimetry (ITC). A competitive inhibition was observed for inosine as a product of the enzymatic reaction. A graphical-fitting method was used for determination of the binding constant and enthalpy of inhibitor binding by using isothermal titration microcalorimetry data. The dissociation-binding constant is equal to 140 µM by the microcalorimetry method, which agrees well with the value of 143 µM for the inhibition constant that was obtained from the spectroscopy method.

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“…Several pieces of evidence do support the existence of a regulatory locus controlling expression of ADA. Thus, Valentine has reported autosomal dominant inheritance of a 50-fold increase in ADA activity of erythrocytes, but normal activity in lymphocytes and fibroblasts (27,28 (24). However, we cannot rule out the possibility that GM 4396 is homozygous for ADAs and additionally has a mutation at a regulatory locus.…”

Section: Resultsmentioning

confidence: 99%

Genetic heterogeneity in partial adenosine deaminase deficiency.

Hirschhorn¹,

Martiniuk²,

Roegner-Maniscalco³

et al. 1983

J. Clin. Invest.

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A B S T R A C T Inherited deficiency of the enzyme adenosine deaminase (ADA) results in a syndrome of severe combined immunodeficiency (SCID). Children with ADA--SCID lack ADA in all cells and tissues. In contrast, a "partial" deficiency of ADA has been described in six immunologically normal children from four different "families." These children lack ADA in their erythrocytes but retain variable amounts of activity in their lymphoid cells.We have examined ADA activity in lymphoid line cells from four of these children, who are unrelated, for evidence of genetic heterogeneity. One child, who is Caucasian, has an enzyme with increased electrophoretic mobility, a diminished isoelectric point (pl 4.8 vs. Nl = 4.9) and very low activity (2.3 vs. Nl = 82.9±12.9 nmol/mg protein per min); as a second child has an enzyme with normal electrophoretic mobility but increased isoelectric point (pI = 5.0), markedly diminished heat stability at 56°C (tl/2 = 4.2' vs. Nl = 40') and low activity (12.1); a third has an enzyme with only diminished heat stability (t1/2 = 6.5'), no detectable abnormality in charge and almost normal activity (41.9); while the fourth exhibits only diminished ADA activity (25.0) with no striking qualitative abnormalities.Thus, we have found evidence for three different mutations at the structural locus for ADA in three of these individuals, (a) an acidic, low activity heat stable mutation (b) a basic, somewhat higher activity, heat labile mutation, and (c) a relatively normal activity

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Hereditary Hemolytic Anemia with Increased Red Cell Adenosine Deaminase (45- to 70-fold) and Decreased Adenosine Triphosphate

Cited by 162 publications

References 24 publications

Developmental disorder associated with increased cellular nucleotidase activity

Developmental disorder associated with increased cellular nucleotidase activity

A Product Inhibition Study on Adenosine Deaminase by Spectroscopy and Calorimetry

Genetic heterogeneity in partial adenosine deaminase deficiency.

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