Leader the Molecular Basis of Disorders of Red Cell Enzymes

J Clin Pathol 1999;52:241–244 241 Leader J Clin Pathol: first published as 10.1136/jcp.52.4.241 on 1 April 1999. Downloaded from The molecular basis of disorders of red cell enzymes Mary F McMullin The mature red cell has no nucleus or for example a missense mutation in codon 510 organelles and therefore cannot synthesise pro- (CGA;Arg → CAA;Gln) is reported in 30% of tein or lipids. It is totally dependent on glycoly- cases in Northern European and United States sis to convert glucose into an energy source. populations. Despite patients having the same Glucose is phosphorylated by hexokinase to genetic abnormality there can be wide variation glucose-6-phosphate. This is the substrate for in the clinical expression of the disease. Thus anaerobic glycolysis which proceeds through other genetic or environmental factors influ- the Embden-Meyerhof pathway to pyruvate ence the phenotype.5 Molecular diagnosis is with production of ATP (fig 1). Some of the now nearly routine and carrier detection and glucose-6-phosphate may also be processed by prenatal diagnosis is feasible. oxidative glycolysis in the pentose phosphate pathway (fig 2). Around 20 enzymes facilitate these two major pathways and deficiency of any of these enzymes may cause haemolytic anaemia. The incidence of deficiency varies Glucose from over 400 million cases worldwide in HK Pentose phosphate glucose-6-phosphate dehydrogenase (G6PD) Glucose-6-P pathway deficiency to single case report in some of the (oxidative GPI other enzymes. I shall discuss the molecular glycolysis) basis of some of these enzyme deficiencies in Fructose-6-P this review. PFK Fructose-1,6-P http://jcp.bmj.com/ Deficiency of enzymes involved in the Aldolase Embden-Meyerhof pathway PYRUVATE KINASE DEFICIENCY TPI Pyruvate kinase (PK) catalyses the conversion DHAP G-3-P of phosphoenolpyruvate (PEP) to pyruvate. NAD G3PD The enzyme exists as four isoenzymes. PR-L is NADH 1,3-BPG 2,3 BPGM expressed in the liver and PK-R in red cells. on October 2, 2021 by guest. Protected copyright. 2,3 BPG These two forms are encoded by a single gene, ADP PGK PK-LR, located at 1q21 but tissue specific pro- ATP 2,3 BPGP 3-PG moters generate mRNAs with diVerent 5' end PGM sequences. PK-M1 is the form in muscle and 2-PG brain, and PK-M2 is present in fetal and most adult cells including white blood cells and Enolase 2-PEP platelets. It is encoded by the PK-M gene ADP located at 15q22 and the isoforms are pro- ATP PK duced by alternative splicing. During erythroid Pyruvate diVerentiation the PK-M2 form is progressively LDH 1 replaced by PK-R. Lactate Department of In PK deficiency PK-R is functionally defec- Haematology, The tive. PK deficiency presents as a non- Figure 1 The Embden-Meyerhof pathway for anaerobic Queen’s University of glycolysis in the erythrocyte. Boxed enzymes cause Belfast, Institute of spherocytic haemolytic anaemia which can be haemolytic disease when deficient. ADP,adenosine Clinical Science, Royal anything from mild compensated haemolysis to diphosphate; ATP,adenosine triphosphate; DHAP, severe anaemia. Approximately 400 patients dihydroxyacetone phosphate; G-3-P, Victoria Hospital, glyceraldehyde-3-phosphate; G3PD, Grosvenor Road, with the deficiency have been described and glyceraldehyde-3-phosphate dehydrogenase; GPI, glucose Belfast BT12 6BA, UK the inheritance is autosomal recessive. Nearly phosphate isomerase; HK, hexokinase; LDH, lactate M F McMullin 100 gene mutations have been identified.2–6 dehydrogenase; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; PFK, phosphofructokinase; PGK, Correspondence to: The majority are missense mutations but splic- phosphoglycerate kinase; PGM, phosphoglycerate mutase; Dr McMullin. ing mutations, insertions, and deletions also PK, pyruvate kinase; TPI, triosephosphate isomerase; email: occur. The mutations are widely distributed 1,3-BPG, 1,3-bisphosphoglycerate; 2-PG, [email protected] 2-phosphoglycerate; 2-PEP,2-phosphoenolpyruvate; 2,3 throughout the gene. Although most mutations BPG, 2,3-biphosphoglycerate; 2,3 BPGM, Accepted 23 October 1998 occur only once, some appear relatively often; 2,3-biphosphoglycerate mutase; 3-PG, 3-phosphoglycerate. 242 McMullin PHOSPHOFRUCTOKINASE DEFICIENCY H2O2 H2O Phosphofructokinase (PFK) catalyses the conversion of fructose-6-phosphate to fructose 1-6 J Clin Pathol: first published as 10.1136/jcp.52.4.241 on 1 April 1999. Downloaded from phosphate. Over 35 cases of PFK deficiency GSH peroxidase have been reported. There are diVerent genes for the diVerent PFK proteins in muscle (PFK-M), liver (PFK-L), and platelets (PFK- GSH GSSG P). It is a multisystem disease, the expression of which varies owing to the variable expression in the tissues. Manifestations include haemolytic GSSG reductase anaemia and myopathy. The commonest form is Tarui’s disease or glycogen storage disease type VII. At least 11 mutations of the PFK-M Glucose gene, which is located at 1cen-q32, have been NADP NADPH described—splicing defects, nucleotide deletions, and point mutations.1 G6P 6PG G6PD TRIOSEPHOSPHATE ISOMERASE DEFICIENCY Triosephosphate isomerase (TPI) catalyses the Pentose interconversion of dihydroxyacetone phos- Embden- phosphate 6PGD Meyerhof pathway phate and glyceraldehyde-3-phosphate. Over pathway (oxidative) 35 cases of TPI deficiency have been reported. (glycolytic) Pentose It presents as a multisystem disorder with pro- phosphate gressive neurological dysfunction, cardiomy- opathy, and increased susceptibility to infec- tion. AVected individuals die in early childhood. The inheritance is autosomal reces- Pyruvate sive but it is interesting, given the rarity of the disorder, that 5% of African Americans are Lactate heterozygotes. The gene is encoded at 12p13. Figure 2 The pentose phosphate pathway for red cell Although mutations have been described in oxidative glycolysis. G6P,glucose-6-phosphate; G6PD, single families, the majority of cases are due to glucose 6-phosphate dehydrogenase; GSH, glutathione; → GSSG, oxidised glutathione; H2O2, hydrogen peroxide; a missense mutation, GAG;Glu GAC;Asp, NADP,nicotinamide adenine dinucleotide phosphate; 6PG, in codon 104, in contrast to the genetic 6-phosphogluconolactone; 6PGD, 6-phosphogluconolactone heterogeneity of other disorders.10 There is evi- dehydrogenase. dence for a single origin for this mutation in a single ancestor.11 HEXOKINASE DEFICIENCY Hexokinase catalyses the first step in the PHOSPHOGLYCERATE KINASE DEFICIENCY http://jcp.bmj.com/ Embden-Meyerhof pathway, the conversion of Phosphoglycerate kinase (PGK) catalyses the glucose to glucose-6-phosphate. The enzyme is interconversion of 1,3 diphosphoglycerate and located at 10p11.2. Approximately 20 cases of 3-phosphoglycerate. Approximately 20 cases of hexokinase deficiency have been described and PGK deficiency have been described. Inherit- the patients present with non-spherocytic ance is X linked, the gene being located at haemolytic anaemia. It is an autosomal reces- Xq13. AVected males usually present with sive disorder. The molecular defect has been haemolytic anaemia and neurological abnor- on October 2, 2021 by guest. Protected copyright. described in at least one patient in whom there malities, including mental retardation and was a point mutation in one allele of the myopathy. Females have mild haemolytic anae- hexokinase gene and a deletion in the other mia owing to the lyonisation of the X chromo- allele producing clinical disease.7 some. At least nine mutations have been described, each resulting in a unique point mutation.12 GLUCOSE PHOSPHATE ISOMERASE DEFICIENCY Glucose phosphate isomerase (GPI) catalyses OTHER ENZYME DEFICIENCIES the conversion of glucose-6-phosphate to Deficiencies of the enzymes aldolase, enolase, fructose-6-phosphate. The GPI gene is located 2,3-bisphosphoglycerate mutase (2,3-BPGM), at 19cen-q13. Over 45 cases of GPI deficiency and lactate dehydrogenase (LDH) have all have been described, generally presenting with been reported in isolated cases, and haemolysis compensated haemolytic anaemia but in one has been described as part of the deficiency. case associated with hydrops fetalis and in two Molecular abnormalities have now been de- cases associated with mental retardation. The scribed in all of these deficiencies.1 inheritance is autosomal recessive and cases are compound heterozygotes or homozygotes. Ap- Abnormalities of erythrocyte nucleotide proximately 20 mutations have been described metabolism which are distributed throughout the gene.89 Nucleotide metabolic pathways are essential These are missense mutations, deletions, and for maintenance of the energy pool of red cells. nonsense mutations. GPI is identical to neu- Pyrimidine 5' nucleotidase (P5'N), adenosine roleptin, a neurotrophic factor for spinal and deaminase, and adenylate kinase are vital to sensory neurones, and may have a function nucleotide cycling, and abnormalities of these outside carbohydrate metabolism. enzymes are associated with decreased red cell The molecular basis of disorders of red cell enzymes 243 survival. P5'N is the most common of these The situation with the sporadic variety is dif- disorders but the precise molecular defect has ferent. The same mutation appears to have not been clarified because the gene has not arisen independently in cases in diVerent J Clin Pathol: first published as 10.1136/jcp.52.4.241 on 1 April 1999. Downloaded from been identified. areas.17 This suggests that mutations capable of Adenosine deaminase deficiency has been causing chronic haemolysis are restricted to a detected

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