Glucose Phosphate Isomerase (GPI) deficiency
Q and A --- CASE STUDIES --- DIAGNOSIS --- THERAPY

Q and A (Answers by Dr. Andy Zoeller)
 

1. Is it possible to make F6PI (since there is no enzyme to turn G6PI into F6PI) synthetically and then inject it into a patient?

The isomerase, GPI converts G6P to F6P.  GPI can go both ways in that it can covert G6P to F6P as well as the reverse (F6P to G6P), so the reaction is reversible. I don't think that F6P can get into cells (across their outer membranes). Feeding fructose (not F6P) may be more likely to bypass the enzymatic block. I know that liver cells can take up fructose and phosphorylate it (to F1P) and use it for energy, but I don't know if that is the case for other organs or red blood cells. I think the liver is unique in this respect.  I will look around about other tissues or organs.

2. Do we know what enzyme is missing and is it possible to make it synthetically?

We know that the glucose-6-phosphate isomerase [GPI; the enzyme that converts glucose-6-phosphate (G6P) to fructose-6-phosphate F6P] is defective.  Even if you made it synthetically, it would not be useful.  You would have to try to get a good copy of the DNA that codes for that protein (GPI) into the cells.  They've been trying this for years with other inborn diseases with very limited success.

3. Is it absence of F6PI or too much of G6PI that leads to anemia?

This is a good question.  It is a very complex issue, it could be either, and we really don't know.  GPI maintains a certain ratio of G6P to F6P in the cell.  Since glucose (G) is always coming into the cells and getting converted to G6P (phosphorylated) it tends to go in the direction of making F6P.

We see a 10-fold increase in G6P levels in our cultured cell line that is deficient in GPI. We suspect that the accumulation of G6P is a problem for GPI deficiency, especially with those who have a severe deficiency (less than 20% of the normal range).   We see a decrease in lipid biosynthesis in our cells; if a cell can't make lipids normal, which are required to make normal membranes, they would have problems.  We also see that if we put extra glucose into the culture medium of our GPI-deficient cells in an effort to force glucose use, it kills the cells (while not affecting the cells with normal GPI activity).  This tells us that some glucose-derived compound accumulates in the cell that is toxic in these GPI-deficient cells.


CASE STUDIES


2. Amoxicillin-induced hemolytic anemia in a child with glucose 6-phosphate isomerase deficiency.

Rossi F.  Ruggiero S.  Gallo M.  Simeone G.  Matarese SM.  Nobili B.

Annals of Pharmacotherapy.  44(7-8):1327-9, 2010 Jul-Aug.

OBJECTIVE: To describe the first case of amoxicillin-induced nonimmune hemolytic anemia in a child with glucose-6-phosphate isomerase (GPI) deficiency.

CASE SUMMARY: A 3-year-old boy with GPI deficiency was admitted for upper respiratory tract infection and fever. The patient was treated with a standard dose of amoxicillin (50 mg/kg/day). On hospital admission, the child had a chronic moderately low hemoglobin level (8.6 g/dL), but within 24 hours of the first amoxicillin dose, the hemoglobin level markedly decreased (5.8 g/dL), the reticulocyte level increased (58%), and the urine darkened. Results of the direct and indirect Coomb's tests were negative and the acute hemolytic phase ended spontaneously 8 days after amoxicillin withdrawal (hemoglobin 9.5 g/dL, reticulocytes 22%).

DISCUSSION: All previous cases of amoxicillin-induced hemolytic anemia have been attributed to an immune mechanism. Given the absence of anti-reticulocyte antibodies (Coomb's test), we suggest that the amoxicillin-induced hemolytic anemia in our patient occurred via a nonimmune mechanism favored by the child's GPI deficiency. Based on a MEDLINE search, we believe this to be the first report of amoxicillin-induced nonimmune hemolytic anemia in a child with GPI deficiency. GPI deficiency has been associated with well-compensated chronic hemolytic anemia that can become clinically relevant consequent to the administration of drugs. GPI deficiency can lead to impairment of the system that removes free radicals generated by amoxicillin, thereby resulting in oxidation of hemoglobin and destabilization of red cell membranes, with acute hemolysis and severe hemoglobinuria. The Naranjo probability score was consistent with a probable relationship between the hemolytic anemia and amoxicillin therapy.

CONCLUSIONS: This report reinforces the hypothesis that a drug-sensitivity reaction is closely related to a genetically transmitted enzyme deficiency.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=20516363

 

4. Red cell glucose phosphate isomerase (GPI): a molecular study of three novel mutations associated with hereditary nonspherocytic hemolytic anemia.

Repiso A.  Oliva B.  Vives-Corrons JL.  Beutler E.  Carreras J.  Climent F.

Human Mutation.  27(11):1159, 2006 Nov.

Molecular characteristics of red blood cell (RBC) glucose phosphate isomerase (GPI) deficiency are described in two Spanish patients with chronic nonspherocytic hemolytic anemia. One patient, with residual GPI activity in RBCs of around 7% (GPI-Catalonia), is homozygous for the missense mutation c.1648A>G (p.Lys550Glu) in exon 18. The other patient, with residual activity in RBCs of around 20% (GPI-Barcelona), was found to be a compound heterozygote for two different missense mutations: c.341A>T (p.Asp113Val) in exon 4 and c.663T>G (p.Asn220Lys) in exon 7. Molecular modeling using the human crystal structure of GPI as a model was performed to determine how these mutations could affect enzyme structure and function. (c) 2006 Wiley-Liss, Inc.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=17041899

 

5. Glucose phosphate isomerase deficiency: enzymatic and familial characterization of Arg346His mutation.

Repiso A.  Oliva B.  Vives Corrons JL.  Carreras J.  Climent F.

Biochimica et Biophysica Acta.  1740(3):467-71, 2005 Jun 10.

Homozygous glucose phosphate isomerase (GPI) deficiency is one of the most important genetic disorders responsible for chronic non-spherocytic hemolytic anemia (CNSHA), a red blood cell autosomal recessive genetic disorder which causes severe metabolic alterations. In this work, we studied a patient with CNSHA due to an 82% loss of GPI activity resulting from the homozygous missense replacement in cDNA position 1040G>A, which leads to substitution of the protein residue A346H mutation. The enzyme is present in a dimeric form necessary for normal activity; the A346H mutation causes a loss of GPI capability to dimerize, which renders the enzyme more susceptible to thermolability and produces significant changes in erythrocyte metabolism.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=15949716

 

6. Combined glucose-6-phosphate dehydrogenase and glucosephosphate isomerase deficiency can alter clinical outcome.

Clarke JL.  Vulliamy TJ.  Roper D.  Mesbah-Namin SA.  Wild BJ.  Walker JI.  Will AM.  Bolton-Maggs PH.  Mason PJ.  Layton DM.

Blood Cells Molecules & Diseases.  30(3):258-63, 2003 May-Jun.

Glucosephosphate isomerase (GPI) deficiency in humans is an autosomal recessive disorder, which results in nonspherocytic hemolytic anemia of variable clinical expression. A 4-year-old female with severe congenital hemolytic anemia had low red cell GPI activity of 15.5 IU/g Hb (50% of normal mean) indicating GPI deficiency. Subsequent DNA sequence analysis revealed a novel homozygous 921C to G mutation in the GPI gene sequence, predicting a Phe307 to Leu replacement. Strikingly, the red cell GPI activity in this patient was higher than that found in a second patient expressing the same GPI variant, with a more severe clinical phenotype. We propose that the hemolysis in the first patient may be modified by an accompanying deficiency of glucose-6-phosphate dehydrogenase (G6PD). The proband's red cell G6PD activity was reduced at 4.5 IU/g Hb (50% of normal mean) and molecular studies revealed heterozygosity for the G6PD Viangchan mutation and a skewed pattern of X-chromosome inactivation, producing almost exclusive expression of the mutated allele. The G6PD Viangchan variant is characterised by severe enzyme deficiency, but not chronic hemolysis. This study suggests that the metabolic consequences of a combined deficiency of GPI and G6PD might be responsible for a different clinical outcome than predicted for either defect in isolation.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=12737943

 

7. Glucosephosphate isomerase (GPI) deficiency mutations associated with hereditary nonspherocytic hemolytic anemia (HNSHA).

Beutler E.  West C.  Britton HA.  Harris J.  Forman L.

Blood Cells Molecules & Diseases.  23(3):402-9, 1997 Dec.

Five unrelated patients with hereditary glucosephosphate isomerase (GPI) deficiency resulting in nonspherocytic hemolytic anemia were studied. Three new mutations were found in the coding region of the GPI gene: two patients were heterozygous for 223 A-->G (R75G) and 898 G-->C(R300P), respectively and one was homozygous for 1415G-->A(R472H). Surprisingly, 2 previously reported mutations, 286 C-->T and 1039 C-->T, were found in 2 and 3 patients respectively. Until now only 4 of 18 GPI mutations had been found more than once in unrelated patients and these 4 in only 2 patients each. Eleven of the 20 known point mutations have occurred at CpG "hot spots" and the 286 C-->T and 1039 C-->T are among these. The 489 G/A polymorphism in the GPI coding region was used to demonstrate unequivocally that the 1039 C-->T mutation occurred in both haplotypes and therefore probably originated more than once. Because no common GPI mutation has been found we suggest that heterozygosity for GPI confers little if any selective advantage. Copyright 1997 The Blood Cells Foundation.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=9446754

 

8. Glucose phosphate isomerase deficiency: biochemical and molecular genetic studies on the enzyme variants of two patients with severe haemolytic anaemia.

Huppke P.  Wunsch D.  Pekrun A.  Kind R.  Winkler H.  Schroter W.  Lakomek M.

European Journal of Pediatrics.  156(8):605-9, 1997 Aug.

Biochemical and molecular genetic studies were performed on the enzyme variants of two patients compound heterozygous for glucose phosphate isomerase (GPI) deficiency, both suffering from severe haemolytic anaemia. The enzymes of case 1 (GPI 'Zwickau') and case 2 (GPI 'Nordhorn' [25]), revealed reduced GPI activity and remarkable thermolability. Glucose-6-phosphate (Gluc-6-P) concentration was elevated 2.3 times in case 1 and 3.8 times in case 2. Sequencing the patients' GPI genes showed four different point mutations, two of them involving highly conserved amino acids. The c1039 C-->T substitution, found in the gene of GPI 'Zwickau', has been described recently [30] and causes an Arg 347-->Cys substitution close to the putative catalytic site. The second mutation in this case is a novel c1538 G-->A substitution causing a Trp-->stop mutation at position 513 apparently resulting in premature RNA degradation thus resulting either in a complete lack of protein or a protein which does not show GPI activity. In the gene of GPI 'Nordhorn' a c1028 A-->G mutation was discovered, also previously described [1, 9] causing a Gln 343-->Trp substitution. The second mutation was a novel splice site mutation at the border of intron 15 to exon 16: IVS15-(-2) A-->C which leads to an aberrant splicing of exon 16, thus resulting either in a truncated and most likely inactive enzyme or in no protein at all. CONCLUSION: Biochemical and molecular genetic studies performed with the enzyme variants GPI 'Zwickau' and GPI 'Nordhorn' showed that in both cases the simultaneous occurrence of a single amino acid substitution affecting the active site, together with a nonsense mutation leading to the loss of major parts of the enzyme probably explains the severe clinical course of the disease.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=9266190

 

9. Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia.

Kanno H.  Fujii H.  Hirono A.  Ishida Y.  Ohga S.  Fukumoto Y.  Matsuzawa K.  Ogawa S.  Miwa S.

Blood.  88(6):2321-5, 1996 Sep 15.

We report here two new cases of glucose phosphate isomerase (GPI) deficiency associated with hemolytic anemia and present the results of molecular analysis of the five Japanese GPI variants. A Japanese girl (GPI Fukuoka) had an episode of prolonged neonatal jaundice and at 3 years of age was admitted due to acute hemolytic crisis occurring with upper respiratory tract infection. Red blood cell (RBC) GPI activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level of RBCs was slightly decreased. A 54-year-old Japanese man (GPI Iwate) was hospitalized due to chronic active hepatitis, and compensated hemolysis was noted. RBC GPI activity of the proband was decreased to 18.8%, and the GSH content was about half of the normal mean value. Sequencing of the reticulocyte GPIcDNA showed homozygous missense mutations 1028CAG-->CGG (343Gln-->Arg), 14ACC-->A7C (5Thr-->lle), 671ACG-->A7G (224Thr-->Met), and 1615GAC-->AAC (539Asp-->Asn) in GPI Narita, GPI Matsumoto, GPI Iwate, and GPI Fukuoka, respectively. We also identified GPI Kinki as a compound heterozygote of 1124ACA-->AGA(375Thr-->Arg)/ 1615GAC-->AAC(539Asp-->Asn). Our findings, together with the previous results of other investigators, showed that the GPI gene mutations so far identified were heterogeneous, although most GPI variants had common biochemical characteristics such as heat instability and normal kinetics. Several amino acid substitutions were identified in the proximity of the catalytically important amino acid residues such as Ser/Asp 159/160, Asp341, and Lys518, which have been identified in the structural analysis of the pig GPI. The molecular characterization of human GPI variants, therefore, may provide new insights into the genotype-phenotype correlation of GPI deficiency as well as the structure-function relationship of this enzyme.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=8822954

 

10.The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia.

Xu W.  Beutler E.

Journal of Clinical Investigation.  94(6):2326-9, 1994 Dec.

DNA was isolated from four unrelated glucose phosphate isomerase-deficient patients. Seven new mutations in the coding region were found: 247 C-->T, 671 C-->T, 818 G-->A, 833 C-->T, 1039 C-->T, 1459 C-->T, and 1483 G-->A. Three patients were compound heterozygotes, and one patient was a homozygote of 247 C-->T/247 C-->T. Six mutations were found to involve highly conserved amino acids of glucose phosphate isomerase, suggesting that these residues are crucial for the maintenance of biological activity. Two polymorphic sites were also identified, 489 A-->G and 1356 G-->C, which do not produce a change in the amino acid sequence.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med3&AN=7989588

 

11. Glucose phosphate isomerase (GPI) "Morcone": a new variant from Italy.

Alfinito F.  Ferraro F.  Rocco S.  De Vendittis E.  Piccirillo G.  Sementa A.  Colombo MB.  Zanella A.  Rotoli B.

European Journal of Haematology.  52(5):263-6, 1994 May.

Here we report the 4th Italian case of glucose phosphate isomerase (GPI) deficiency. The propositus is a young man suffering from chronic haemolytic anaemia since birth with occasional transfusion requirement. Biochemical characterization of the defective enzyme revealed increased affinity for F-6-P, decreased affinity for G-6-P and marked thermoinstability. Electrophoretic mobility appeared normal. GPI from both parents showed similar but less pronounced biochemical alterations. The variant described here seems to be different from those previously reported. Thus, we propose the provisional name of GPI "Morcone". [References: 22]

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med3&AN=8020625

 

12. GPI Mount Scopus--a variant of glucosephosphate isomerase deficiency.

Shalev O.  Shalev RS.  Forman L.  Beutler E.

Annals of Hematology.  67(4):197-200, 1993 Oct.

Glucosephosphate isomerase (GPI) deficiency is an unusual cause of hereditary nonspherocytic hemolytic anemia. The disease, inherited as an autosomal recessive disorder, is most often manifested by symptoms and signs of chronic hemolysis, ameliorated by splenectomy. We recently diagnosed GPI deficiency in a 23-year-old Ashkenazi Jewish man who displayed the typical clinical course of this disorder. The biophysical characteristics of the GPI variant are slow electrophoretic mobility, presence of only one of the two bands normally present, and extreme thermolability. To the best of our knowledge, this is the first report of GPI deficiency in a patient of Jewish descent, and we propose to designate this enzyme variant "GPI Mount Scopus".

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med3&AN=8218542

 

13. Combination of congenital nonspherocytic haemolytic anaemia and impairment of granulocyte function in severe glucosephosphate isomerase deficiency. A new variant enzyme designated GPI Calden.

Neubauer BA.  Eber SW.  Lakomek M.  Gahr M.  Schroter W.

Acta Haematologica.  83(4):206-10, 1990.

In two siblings, children of non-consanguineous parents, glucosephosphate isomerase (GPI) deficiency was found to be the cause of recurrent haemolytic crises. Characterization of the variant enzyme found in both individuals revealed low specific activity in erythrocytes and leucocytes, increased electrophoretic mobility and pronounced thermolability. Evaluation of the electrophoretic data allows the conclusions that these siblings are compound heterozygous carriers of GPI deficiency. The new variant was designated GPI Calden. Further investigations revealed that isolated granulocytes of both siblings show marked reduction of bactericidal activity and decreased production of superoxide anion. With rare exceptions, deficiency of this enzyme was supposed to cause congenital nonspherocytic haemolytic anaemia only. Here we report on two siblings presenting with the characteristic haemolytic anaemia and a significant decrease in granulocyte function, both presumably as the result of GPI deficiency. Our data indicate that impairment of granulocyte function might be a more general feature of severe GPI deficiency than formerly noted.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med3&AN=2115718

 

14. Clinical symptoms and biochemical properties of three new glucosephosphate isomerase variants.

Eber SW.  Gahr M.  Lakomek M.  Prindull G.  Schroter W.

Blut.  53(1):21-8, 1986 Jul.

Glucosephosphate isomerase deficiency as the cause of macrocytic congenital nonspherocytic hemolytic anemia is described in three unrelated families. The biochemical properties of the variant glucosephosphate isomerases indicate that the patients have new variants, designated as GPI Kiel, GPI Hamburg, and GPI Homburg. The severity of the clinical symptoms depended on the amount of residual GPI activity and the biochemical properties of the variant enzyme. Thus the patient with GPI Kiel (34% residual activity) whose variant GPI was slightly unstable showed a mild chronic hemolytic anemia. The patient with GPI Homburg (7% residual activity) whose variant enzyme was stable and had a reduced specific activity, suffered from severe congenital hemolytic anemia and neuromuscular symptoms. Due to the special properties of GPI Homburg, we assume that both the hematological and neuromuscular symptoms of the patient with GPI Homburg are caused by his GPI deficiency. The twins with GPI Hamburg (27% residual activity) had a distinctly unstable variant enzyme and had suffered from hemolytic crises since birth. Only GPI Homburg showed an altered electrophoretic mobility and an increased affinity for fructose-6-phosphate. The other two variants had normal values.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med2&AN=3719111

 

15. Generalised glucosephosphate isomerase (GPI) deficiency causing haemolytic anaemia, neuromuscular symptoms and impairment of granulocytic function: a new syndrome due to a new stable GPI variant with diminished specific activity (GPI Homburg).

Schroter W.  Eber SW.  Bardosi A.  Gahr M.  Gabriel M.  Sitzmann FC.

European Journal of Pediatrics.  144(4):301-5, 1985 Nov.

A new glucosephosphate isomerase (GPI) variant is described which is characterised by very low specific activity in erythrocytes, granulocytes and muscle tissue, nearly normal stability, normal kinetic properties and a decreased electrophoretic mobility. The propositus suffers from a complex syndrome involving erythrocytes (congenital haemolytic anaemia), granulocytes (decreased production of superoxide anion and reduced bactericidal activity in vitro) and the neuromuscular system (myopathy, mental retardation). It is suggested that the clinical syndrome results from generalised GPI deficiency due to a decreased specific activity of the variant enzyme, which cannot be compensated by an increase of de-novo synthesis of GPI protein even in cells exhibiting active protein synthesis such as granulocytes and muscle cells.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med2&AN=4076245

 

16. Ultrastructural and histochemical abnormalities of skeletal muscle in a patient with a new variant (type Homburg) of glucosephosphate isomerase (GPI) deficiency.

Bardosi A.  Eber SW.  Roessmann U.

Clinical Neuropathology.  4(2):72-6, 1985 Mar-Apr.

Ultrastructural and enzyme histochemical muscle abnormalities are described in a case with a new variant (type Homburg) of glucosephosphate isomerase (GPI) deficiency, associated with congenital nonspherocytic hemolytic anemia and muscle weakness. The enzyme is thermostable in contrast to other described variants. The muscle fibers showed decreased GPI activity, ultrastructural abnormalities, including giant mitochondria, and a diffuse increase of glycogen. The functional alteration of muscle tissue is due to a stable enzyme protein with decreased specific activity.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med2&AN=3995809

 

17. Glucose-6-phosphate isomerase deficiency-Nahariya: extreme in vitro and in vivo lability of the mutant enzyme.

Rijksen G.  Jansen G.  Manaster J.  Ezekiel E.  Streichman S.  Staal GE.

Israel Journal of Medical Sciences.  20(6):529-34, 1984 Jun.

A glucose-6-phosphate isomerase deficiency is described in an Arab boy suffering from chronic hemolytic anemia. The patient was probably true homozygous for the defect. The residual enzyme activity in his red blood cells (RBC) was approximately 30% of normal. The most striking enzyme abnormality observed was an extreme heat lability: upon incubation at 45 C, greater than 90% of activity was lost within 15 min. Furthermore, an increased affinity for the substrate glucose-6-phosphate was shown. The lability of the enzyme was also shown to exist in vivo by separating the patient's RBC into four fractions of different cell age by centrifugation on a discontinuous density gradient. This in vivo lability of the enzyme is believed to be the main cause of the hemolytic diathesis. Remarkably, the residual activity of the enzyme in the RBC of obligate heterozygotes was comparable to that in the patient. However, their enzyme activity was only slightly more labile than that in normal RBC and consequently no signs of hemolysis were noticed.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med2&AN=6469574

 

18. A case of congenital nonspherocytic hemolytic anemia associated with glucosephosphate isomerase (GPI) deficiency-GPI 'Kinki'.

Takegawa S.  Fujii H.  Miwa S.  Ohba Y.  Yamauchi H.  Miyata H.

Nippon Ketsueki Gakkai Zasshi - Acta Haematologica Japonica.  46(1):11-7, 1983 Feb.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med2&AN=6858560

 

19. Glucosephosphate-isomerase type Kaiserslautern. A new variant causing congenital nonspherocytic hemolytic anemia.

Arnold H.  Hasslinger K.  Witt I.

Blut.  46(5):271-7, 1983 May.

In a 13-year-old German girl a GPI deficiency was found to be the cause of a chronic nonspherocytic hemolytic anemia with recurrent hemolytic crises. The hemolytic crises usually occurred after a feverish infection. Only once did the patient require blood transfusion during a crisis. Examination of the family indicated that the patient is doubly heterozygous for the deficiency. The investigation of the biochemical properties of the deficient enzyme revealed an altered electrophoretic migration, a pronounced thermolability, an increased affinity for G-6-P and slightly changed pH optima for both substrates. The described properties of the deficient GPI indicate that we are dealing with a new variant designated GPI-Kaiserlautern.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med2&AN=6839028

 

20. Red cell glucosephosphate isomerase deficiency: two new mutant enzymes.

Zanella A.  Izzo C.  Fagnani G.  Zanuso F.  Perroni L.  Mariani M.  Colotti MT.  Sirchia G.

Haematologica.  65(5):564-84, 1980 Oct.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med2&AN=6780416

 

21. Augsburg-type glucosephosphate isomerase deficiency. A new variant causing congenital nonspherocytic hemolytic anemia in a German family.

Arnold H.  Lohr GW.  Hasslinger K.  Podgajny T.

Blut.  40(2):107-15, 1980 Feb.

In a 1-year-old German boy a GPI deficiency was found to be the cause of a chronic nonspherocytic hemolytic anemia with recurrent hemolytic crises. Because of consanguinity of the parents, the patient is true homozygote. The investigation of the biochemical properties of the deficient enzyme revealed an altered electrophoretic behavior, pronounced thermolability, an increased affinity for G6P, an increased affinity for the competitive inhibitor 6-PG, and slightly changed pH optima for both substrates. Electrophoresis after freezing and thawing the hemolysate indicates that the genetic modification of the subunit involves the mechanism of transforming the main band into the secondary bands. The properties of the new deficient GPI indicate a new variant designated GPI Augsburg.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med2&AN=7353078

 

22. Congenital haemolytic anaemia resulting from glucose phosphate isomerase deficiency: genetics, clinical picture, and prenatal diagnosis.

Whitelaw AG.  Rogers PA.  Hopkinson DA.  Gordon H.  Emerson PM.  Darley JH.  Reid C.  Crawfurd MA.

Journal of Medical Genetics.  16(3):189-96, 1979 Jun.

Glucose phosphate isomerase (GPI) deficiency with severe haemolysis and hydrops fetalis was found in the first child of unrelated, healthy Caucasian parents. The child died at 3 hours. Both parents were found to have 50% of normal red cell GPI activity and qualitative tests on their red cells and white cells showed that each was heterozygous for a different GPI variant allele associated with enzyme deficiency. Tests on the placenta showed that the propositus was a 'compound' heterozygote. Examination of amniotic cells obtained by amniocentesis on the mother at 28 weeks in her second pregnancy led to the prenatal diagnosis of GPI deficiency. This second child, a 'compound' heterozygote at the GPI locus indistinguishable from the first, was successfully treated by immediate exchange transfusion and subsequent blood transfusions.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=469896

 

23. Erythrocyte membrane proteins in hereditary glucosephosphate isomerase deficiency.

Coetzer T.  Zail SS.

Journal of Clinical Investigation.  63(4):552-61, 1979 Apr.

Erythrocytes (approximately equal to 50% reticulocytes) obtained from a splenectomized patient with a thermolabile variant of glucosephosphate isomerase (GPI) deficiency showed a striking degree of crenation and decreased filterability through 3-micrometer Nuclepore filters (Nuclepore Corp., Pleasanton, Calif.). Membranes prepared by hypotonic lysis of such erythrocytes were found to contain a high molecular weight aggregate which was probably disulphide-bonded. The 10% most dense erythrocyte fraction showed an accentuation of aggregate formation while aggregates could not be detected in the 10% least dense erythrocyte fraction. The aggregate consisted mainly of spectrin (band 1) and a protein with the mobility of 4.2. "Extractability" of spectrin from these membranes was also markedly diminished. Incubation of the erythrocytes for 24 h in substrate-free medium caused more pronounced spectrin aggregation than in low or high reticulocyte controls. Incubation of low or high reticulocyte controls for 24 h in medium that contained glucose completely prevented the formation of the high molecular weight aggregate. GPI-deficient erythrocytes incubated with glucose in the medium showed an accentuation of membrane protein aggregate formation; however, this was almost completely reversed by the addition of adenine and inosine to the incubation medium or by the use of fructose, the intermediate just distal to the "block" in glycolysis, as the sole substrate. ATP and reduced glutathione levels in the GPI-deficient erythrocytes incubated with glucose were similar to that found in the low and high reticulocyte controls. Our findings suggest that only a proportion of erythrocytes (the older, more dense population of cells) are susceptible to the formation of disulphide-bonded aggregates, and that this is directly related to an impairment of substrate flow through the glycolytic sequence. The exact mechanism of aggregate formation in these erythrocytes remains to be elucidated.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=438320

 

24. 'GPI Roma', a new glucose phosphate isomerase deficient variant: in vivo occurrence of postsynthetic modifications of the mutant enzyme.

Isacchi G.  Cottreau D.  Mandelli F.  Papa G.  Ciccone F.  Kahn A.

Human Genetics.  46(2):219-26, 1979 Jan 25.

In a 5-year-old Italian girl with severe congenital hemolytic anemia, red cell GPI deficiency was proven, and found to be due to a new variant, 'GPI Roma.' The parents are first cousins and have been proven to be heterozygous for this variant. GPI Roma was slightly unstable to heat and exhibited a slightly increased Michaelis constant for fructose-6-phosphate. A single predominant fast-migrating GPI form existed in the patient's white blood cells, while the electrophoretic pattern in the red cells was composed, in addition to this 'fast band,' of a major band migrating as normal GPI and of an additional slow band. It is shown that this phenomenon may be ascribed to postsynthetic events modifying the charge of the mutant enzyme.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=422204

 

25. Molecular and functional anomalies in two new mutant glucose-phosphate-insomerase variants with enzyme deficiency and chronic hemolysis.

Kahn A.  Buc HA.  Girot R.  Cottreau D.  Griscelli C.

Human Genetics.  40(3):293-304, 1978 Feb 16.

Two new deficient glucose-phosphate-isomerase (GPI) variants have been described in patients suffering from severe chronic hemolytic anemias. The patients' parents were consanguineous, such that the patients were true homozygotes for the mutated GPI genes. In both cases the main cause of the defect in enzyme activity was molecular instability of the mutated GPI molecules, their catalytic activity being nearly normal. GPI 'Paris' was characterized by a slow electrophoretic migration and, above all, a drastically altered affinity for the substrates glucose-6-phosphate (decreased) and fructose-6-phosphate (increased). GPI 'Enfants malades' exhibited a slightly reduced electrophoretic mobility, an abnormal curve of the activity in function of pH, and an abnormal ratio of maximal velocity in the backward direction (fructose-6-phosphate leads to glucose-6-phosphate) to that in the forward direction (glucose-6-phosphate leads to fructose-6-phosphate). No clear relation could be proved between the kinetic abnormalities of the mutant GPI variants on the one hand and the metabolic changes of the GPI-deficient red cells and the severity of hemolysis on the other. Finally we emphasized the possible role of the impairment of hexosemonophosphate pathway in the reduction of viability of the GPI-deficient red cells.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=631848

 

26. A new variant of glucosephosphate isomerase deficiency with mild haemolytic anemia (GPI-MYTHO).

Galand C.  Torres M.  Boivin P.  Bourgeaud JP.

Scandinavian Journal of Haematology.  20(1):77-84, 1978 Jan.

A new case of glucosephosphate isomerase deficiency with mild haemolytic anaemia was observed in a 6-year-old girl. Deficient enzyme was characterized by a profoundly decreased activity in the red cells, a normal electrophoretic phenotype, normal isoelectric point, normal optimum pH, a molecular instability and a clearly decreased Michaelis constant for fructose-6-phosphate. Propositus was double heterozygote for a 'silent gene' inherited from the mother and an abnormal enzyme from the father. Because this abnormal enzyme has undescribed characteristics, it responds to a new variant for which we propose the name GPI-MYTHO.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=625628

 

27. Haemolytic anaemia associated with glucosephosphate isomerase (GPI) deficiency in a Black South African child.

Cayanis E.  Penfold GK.  Freiman I.  MacDougall LG.

British Journal of Haematology.  37(3):363-71, 1977 Nov.

Haemolytic anaemia in a Black South African child was found to be associated with reduced glucosephosphate isomerase activity in the red cells. Apart from the haemolytic anaemia, there was no other clinical evidence of dysfunction. Family studies pointed to an autosomal recessive mode of inheritance, with the symptomatic homozygous propositus having a marked enzyme deficiency and the asymptomatic heterozygotes showing intermediate levels of activity. Biochemical characterization showed that, apart from being thermolabile, the electrophoretic mobility and the kinetic properites of the variant enzyme were similar to those of the normal wild type.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=603768

 

28. Glucosephosphate isomerase deficiency type Liege: a new variant with congenital nonspherocytic hemolytic anemia.

Arnold H.  Dodinval-Versie J.  Lambotte C.  Lohr GW.  van der Hofstadt J.

Blut.  35(3):187-93, 1977 Sep 29.

GPI deficiency was detected in a three year old girl of Morrocan origin suffering, since birth, from hemolytic anemia. The defective GPI is very thermolabile and migrates on starch gel electrophoresis as a single band with a mobility of 96% of the normal main band. The purification of the patient's GPI resulted in a 16000-fold enriched preparation, free of any other enzyme activity. The yield was 35%. The purified enzyme was very unstable even at low temperature. The kinetic constants of the forward and backward reaction as well as the inhibitory constants of 2,3-DPG and 6-PG do not significantly differ from normal values. The biochemical properties of the patient's GPI indicate a new variant designated type Liege.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=912103

 

29. A new variant of glucosephosphate isomerase deficiency: GPI-Kortrijk.

Staal GE.  Akkerman JW.  Eggermont E.  van Biervliet JP.

Clinica Chimica Acta.  78(1):121-7, 1977 Jul 1.

A new case of glucosephosphate isomerase deficiency in a Belgian family is described. The activity of the enzyme was decreased to about 25-30% of the normal value. Characterization of the defect enzyme showed a decreased thermostability. Heating of the enzyme at 45 degrees C showed a loss of activity of 50% after 90 min. The pH-optimum and the KM-value for fructose 6-phosphate were normal. The electrophoretic pattern showed a faster migration. The variant described here differs from all known variants. Therefore we propose to give to this new variant the name GPI-Kortrijk.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=18297

 

30. Excessive hepatic glycogen storage in glucosephosphate isomerase deficiency.

van Biervliet JP.  Staal GE.

Acta Paediatrica Scandinavica.  66(3):311-5, 1977 May.

Excessive amounts of glycogen were found in liver and erythrocytes of a patient suffering from generalized glucosephosphate isomerase deficiency. A low carbohydrate diet, frequent meals and avoidance of peak carbohydrate challenges resulted in a significant decrease of liver volume without affecting the haematological condition. The possible mechanism of these findings are discussed.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=868511

 

31. Glucosephosphate isomerase deficiency, a new variant in a Dutch family. Case report.

Rotteveel JJ.  de Vaan GA.  Staal GE.  van Biervliet JP.  Schretlen ED.

European Journal of Pediatrics.  125(1):21-8, 1977 Apr 26.

The clinical course and the biochemical findings are reported from a patient suffering from glucosephosphate isomerase (G.P.I EC 5.3.1.9) deficiency type Nijmegen. This disorder decleares itself as a non-spherocytic hemolytic anemia, presenting in the neonatal period. In the patient hemolysis was of the same degree during the years. However, trivial infections could often trigger an increase in hemolysis requiring treatment by blood transfusions. Enzyme studies revealed that the GPI deficiency in this patient was caused by a double heterozygous state for two different GPI deficient alleles. The presence of one of these deficient alleles in the proband's parents and grandparents, was not accompanied by any sign of hemolysis, as for instance a shortened red-cell survival.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=870323

 

32. Haematological studies in a new variant of glucosephosphate isomerase deficiency (GPI Utrecht).

Helleman PW.  Van Biervliet JP.

Helvetica Paediatrica Acta.  30(6):525-36, 1976 Apr.

The haematological data in a 9-year-old Dutch child suffering from an unusual new variant of glucose-6-phosphate isomerase deficiency (GPI Utrecht) are discussed. Symptoms and signs differ in many respects from those generally observed in GPI deficiency, as mental retardation, drug sensitivity and increased susceptibility to infections were present. Extensive studies on mechanisms involved in drug-sensitive haemolytic anaemia did not reveal its causes. Though the defect was generalized, no disturbance in granulocyte and thrombocyte functions were detected.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=1270325

 

33. A new variant of glucosephosphate isomerase deficiency.

Van Biervliet JP.  Vlug A.  Bartstra H.  Rotteveel JJ.  de Vaan GA.  Staal GE.

Humangenetik.  30(1):35-40, 1975 Oct 20.

A new variant of glucose-6-phosphate isomerase deficiency is described. The enzyme kinetics and properties were studied. Genetic and electrophoretic data pointed to a double heterozygous state in the patient. These data are compared to the other variants described in the literature until now.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=1339

 

34. Glucosephosphate isomerase deficiency in a Dutch family.

Van Biervliet JP.

Acta Paediatrica Scandinavica.  64(6):868-72, 1975 Nov.

A mentally retarded girl with severe hemolytic anemia due to glucosephosphate isomerase deficiency is described. The deficiency was detected in erythrocytes, leukocytes, thrombocytes, liver and muscle tissues. Besides the glucosephosphate isomerase deficiency, a glutathione instability of unknown origin was found in the erythrocytes of the propositus.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=1189910

 

35. A new variant of glucosephosphate isomerase deficiency (GPI-Utrecht).

Van Biervliet JP.  Van Milligen-Boersma L.  Staal GE.

Clinica Chimica Acta.  65(2):157-65, 1975 Dec 1.

A new case of glucosephosphate isomerase deficiency is described in a Dutch family. The activity of the enzyme was decreased to 20-25% of the normal value. Characterization of the defect enzyme showed a pronounced thermolability. Heating of the enzyme at 45 degrees C showed a loss of activity of 90% after one hour. The pH-optimum and the electrophoretic migration were normal. The Km-value for F-6-P, the Ki for the competitive inhibitors 2,3-DPG and 6-PG were in the normal range. The variant described here differs from all known variants. Therefore we propose to give to this new variant the name of GPI-Utrecht.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=241517

 

36. Glucosephosphate isomerase (GPI) deficiency hereditary nonspherocytic hemolytic anemia. Report of the second case found in Japanese.

Miwa S.  Nakashima K.  Oda S.  Matsumoto N.  Ogawa H.

Nippon Ketsueki Gakkai Zasshi - Acta Haematologica Japonica.  36(1):70-3, 1973 Feb.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=4738993

 

37. Glucosephosphate isomerase (GPI) deficiency hereditary nonspherocytic hemolytic anemia. Report of the first case found in Japanese.

Miwa S.  Nakashima Y.  Oda S.  Oda E.  Matsumoto N.

Nippon Ketsueki Gakkai Zasshi - Acta Haematologica Japonica.  36(1):65-9, 1973 Feb.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=4738992

 

38. Fine structure of the spleen and liver in glucosephosphate isomerase (GPI) deficiency hereditary nonspherocytic hemolytic anemia. Selective reticulocyte destruction as a mechanism of hemolysis.

Matsumoto N.  Ishihara T.  Oda E.  Miwa S.  Nakashima K.

Nippon Ketsueki Gakkai Zasshi - Acta Haematologica Japonica.  36(1):46-54, 1973 Feb

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=4738991

GPI DIAGNOSIS


1. Unique phenotypic expression of glucosephosphate isomerase deficiency.

Paglia DE.  Paredes R.  Valentine WN.  Dorantes S.  Konrad PN.

American Journal of Human Genetics.  27(1):62-70, 1975 Jan.

Studies of a Mexican kindred present evidence for a unique phenotype of erythrocyte glucosephosphate isomerase, GPI Valle Hermoso. The proband was apparently the homozygous recipient of a mutant autosomal allele governing production of an isozyme characterized by decreased activity, marked thermal instability, normal kinetics and pH optimum, and normal starch gel electrophoretic patterns. Unlike previously known cases, leukocyte and plasma GPI activities were unimpaired. This suggested that the structural alteration primarily induced enzyme instability without drastically curtailing catalytic effectiveness, thereby allowing compensation by cells capable of continued protein synthesis. Age-related losses of GPI, however, were not evident by density-gradient fractionation of affected erythrocytes.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=1155451

 

2. Detection of phosphohexose isomerase deficiency in human fibroblast cultures.

Krone W.  Schneider G.  Schulz D.  Arnold H.  Blume KG.

Humangenetik.  10(3):224-30, 1970.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=5475507

 

3. Inherited glucosephosphate isomerase deficiency. A review of known variants and some aspects of the pathomechanism of the deficiency.

Arnold H.

Blut.  39(6):405-17, 1979 Dec.

Since the first report of GPI deficiency in 1967 many patients from all over the world have been described. The patients suffer from a typical nonspherocytic hemolytic anemia with hemolytic crises during acute infections. The disease is inherited as an autosomal recessive, half of the patients are homozygotic, the others are double heterozygotes. The biochemical properties of the deficient enzymes vary widely. Thus, many well characterized enzymes have been designated as different variants. The modification of physicochemical properties surpasses kinetic aberrations. All defective variants are more or less unstable. The activity diminishes progressively, leading to a rise in G6P concentration and in red cells after aging in vitro to a dramatic impairment of glycolysis and concomittant hemolysis. The cause of the metabolic block is the diminished GPI activity itself and not an inhibition of hexokinase by the high G6P. [References: 54]

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=391302

 

4. Decreased deformability of erythrocytes in haemolytic anaemia associated with glucosephosphate isomerase deficiency.

Schroter W.  Tillmann W.

British Journal of Haematology.  36(4):475-84, 1977 Aug.

Deformability of erythrocytes from four patients with different types of glucosephosphate isomerase (D-glucose-6-phosphate ketoisomerase, GPI) deficiency has been determined by cell filtration. Young as well as whole erythrocyte populations had a markedly increased rigidity and an abnormally strong attachment of haemoglobin to the inner surface of isolated membranes. Acidic environment may enhance membran rigidity in vitro and also during passage of the erythrocytes through the spleen. The decrease of deformability at a pH of 6.8 was most pronounced in the splenectomized patients, and likewise in erythrocytes from the splenic artery, which were obtained from one patient during splenectomy. It is suggested that the metabolic environment of the spleen, with its low pH, impairs the deformability of GPI-deficient erythrocytes and predisposes them to splenic sequestration. The clinical improvement of all patients following splenectomy which is accompanied by an increase of the erythrocyte survival time and by unchanged reticulocyte counts, is in accordance with this view.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=19031

 

5. Hereditary glucosephosphate isomerase deficiency. A review. 

Paglia DE.  Valentine WN.

American Journal of Clinical Pathology.  62(6):740-51, 1974 Dec.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=4611197

 

6. Glucose phosphate isomerase deficiency with congenital nonspherocytic hemolytic anemia: a new variant (type Nordhorn). I. Clinical and genetic studies.

Schroter W.  Koch HH.  Wonneberger B.  Kalinowsky W.  Arnold A.  Blume KG.  Huther W.

Pediatric Research.  8(1):18-25, 1974 Jan.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=4809302

 

7. Electrophoretic and kinetic studies of glucosephosphate isomerase (GPI) in two different Japanese families with GPI deficiency.

Nakashima K.  Miwa S.  Oda S.  Oda E.  Matsumoto N.

American Journal of Human Genetics.  25(3):294-301, 1973 May.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=4704861

GPI THERAPY

1. Glucose-6-phosphate isomerase deficiency.

Kugler W.  Lakomek M.

Bailliere's Best Practice in Clinical Haematology.  13(1):89-101, 2000 Mar.

Most of the metabolic needs of erythrocytes are covered by glycolysis, the oxidative pentose phosphate pathway and the glutathione cycle. Hereditary enzyme deficiencies of all these pathways have been identified, among which glucose-6-phosphate isomerase (GPI) deficiency is the second most frequent erythroenzymopathy in glycolysis, being associated with non-spherocytic haemolytic anaemia of variable severity. This autosomal recessive genetic disorder may be associated in some cases with neurological impairment. GPI is a dimeric enzyme that catalyses the reversible interconversion of fructose-6-phosphate and glucose-6-phosphate. Virtually all the mutant gene products reported are characterized by marked instability and normal substrate affinities, but altered catalytic activity and electrophoretic migration rates. At the nucleotide level, 29 mutations have been reported. This chapter reviews (a) the clinical pattern of the condition; (b) biochemical and molecular studies; (c) structure-function relationships; (d) the molecular basis of neurological dysfunctions sometimes associated with GPI deficiency; and (e) the correlation between the severity of the anaemia and the molecular defect. [References: 58]

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=10916680

 

2. Hemolytic anemias due to erythrocyte enzyme deficiencies.

Jacobasch G.  Rapoport SM.

Molecular Aspects of Medicine.  17(2):143-70, 1996 Apr.

Red blood cells can only fulfil their functions over the normal period of approximately 120 days with 1.7 x 10(5) circulatory cycles efficiently if they withstand external and internal loads. This requires ATP and redox equivalents, which have to be permanently regenerated by the energy and redox metabolism. These pathways are necessary to maintain the biconcave shape of the cells, their specific intracellular cation concentrations, the reduced state of hemoglobin with a divalent iron and the sulfhydryl groups of enzymes, glutathione and membrane components. If an enzyme deficiency of one of these metabolic pathways limits the ATP and/or NADPH production, distinct membrane alterations result causing a removal of the damaged cells by the monocyte-macrophage system. Most metabolic needs of erythrocytes are covered by glycolysis, the oxidative pentose phosphate pathway (OPPP), the glutathione cycle, nucleotide metabolism and MetHb reductase. Hereditary enzyme deficiencies of all these pathways have been identified; those that cause non-spherocytic hemolytic anemia are listed in Table 4. Their frequencies differ markedly both with respect to the affected enzyme and geographic distribution. Glucose-6-phosphate dehydrogenase enzymopathies (G6PD) are with more than 400 million cases by far the most common deficiency. The highest gene frequency has been found with 0.7 among Kurdish Jews. G6PD deficiencies are furthermore prevalent with frequencies of about 0.1 among Africans, Black Americans, and populations of Mediterranean countries and South East Asia. In Middle and Northern Europe the frequency of G6PD is much lower, and with approximately 0.0005, comparable with the frequency of pyruvate kinase (PK) enzymopathies, the most frequent enzyme deficiency in glycolysis in this area (Luzzatto, 1987; Beutler and Kuhl, 1990). The relationship between the degree of enzyme deficiency and the extent of metabolic dysfunction in red blood cells and other tissues depend on several factors: on the importance of the affected enzyme; its expression rate; the stability of the mutant enzyme against proteolytic degradation and functional abnormalities; the possibility to compensate the deficiency by an overexpression of the corresponding isoenzyme or by the use of an alternative metabolic pathway. Difficulties in estimating the quantitative degree of disorder in severe cases are due to the fact that these populations contain many reticulocytes, which generally have higher enzyme activities and concentrations of intermediates than erythrocytes. An alternative approach to predict metabolic changes is the analysis by mathematical modeling. Mathematical modeling of the main metabolic pathways of human erythrocytes has reached an advanced level (Rapoport et al., 1976; Holzhutter et al., 1985; Schuster et al., 1988). Models have been successfully employed to describe stationary and time-dependent metabolic states of the cell under normal conditions as well as in the presence of enzyme deficiencies. Figure 5 shows computational results of erythrocyte enzyme deficiencies. This analysis is based on the comprehensive mathematical model of the energy and redox metabolism for human erythrocyte presented in Fig. 6. Stationary states of the cell metabolism have been calculated by varying the activity of each of the participating enzymes by several orders of magnitude. To predict consequences of enzyme deficiencies a performance function has been introduced (Schuster and Holzhutter, 1995). It takes into account the homeostasis of three essential metabolic variables: the energetic state (ATP), the reductive capacity (reduced glutathione) and the osmotic state. From the data given in Fig. 5 one can conclude that generally the metabolic impairment resulting in deficiencies occurs earlier for enzymes with high control coefficients than for those catalyzing equilibrium reactions. On the other hand the flux curves of latter enzymes decrease more steeply below a critica

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=8813716

 

3. Hereditary hemolytic anemia associated with glucosephosphate isomerase (GPI) deficiency--a new enzyme defect of human erythrocytes.

Baughan MA.  Valentine WN.  Paglia DE.  Ways PO.  Simons ER.  DeMarsh QB.

Blood.  32(2):236-49, 1968 Aug.

http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med1&AN=5672849



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