Other defects of the enzymes of the glycolytic system

Compared with PK deficiency, the other defects of the glycolytic pathway are very rare. The main features of these disorders are summarized in Table 9.1.

Hexokinase

Hexokinase (HK1) catalyses the phosphorylation of glucose to G6P, the first step in the glycolytic pathway. The enzyme in the red cell differs from that in nucleated cells, which have oxidative respiration, by lacking a porin-binding domain that links the enzyme to the mitochondrial membrane. The red cell enzyme is derived from alternative splicing of the gene product. The enzyme provides a major rate-limiting step in glycolysis and has extensive allosteric interactions, being highly pH sensitive and regulated in its activity by its products, G6P, Pi, 2,3-DPG and disulphide compounds. The enzyme activity decays predictably with age of the normal red cell, and may be used as a comparator

Glucosephosphate isomerase

Glucosephosphate isomerase (GPI) catalyses the second step of the Embden-Meyerhof pathway, the interconversion of G6P to fructose 6-phosphate (F6P). The enzyme is also known as phos-phohexose isomerase, phosphoglucose isomerase, autocrine motility factor and neuroleukin (NLK). The names 'autocrine motility factor' and 'neuroleukin' indicate that the protein has other actions in other cells. The interconversion of the hexose phosphates is driven towards F6P by the rapid metabolism of that product along the metabolic pathway, so that the concentration of F6P in the red cell is low and drives the reaction towards its formation.

Glucosephosphate isomerase deficiency

Deficiency of GPI is one of the commonest causes of CNSHA after G6PD deficiency and PK deficiency. It is about as equally common as pyrimidine 5'-nucleotidase deficiency (see later). The mutations that give rise to GPI deficiency are very heterogeneous - out of the 20 characterized mutations, 14 appear in only a single family and 11 out of the 20 occur in compound heterozygotes. The clinical picture perhaps reflects this genetic heterogeneity. Most reported cases are of mild to moderate haemolytic anaemia, but in one Indian family stillbirths and hydrops occurred in several siblings before early delivery and exchange transfusion for hydrops allowed survival. The mutations described mainly affect the stability of GPI, which is perhaps why no associated anomalies are found in nucleated cells. In T lymphocytes, GPI

Table 9.1 Main features of glycolytic enzyme deficiencies.

(chromosome/inheritance)

Haematology

Other systems affected

Comment

Hexokinase (HKI)

10q11.2

CNSHA

None directly*

Very rare, occasional AD

AR

High O2 affinity

Glucose phosphate

19cen-q12

CNSHA

None directly*

Most common after

isomerase (GPI)

PK deficiency

AR

Phosphofructokinase

1(M) and 21(L)

Erythrocytosis

Dominated by

Tarui's disease, subunit

(PFK)

myopathy

genes

Complex

Minimal haemolysis

Fructose diphosphate

16q22-q24

CNSHA

Dysmorphism,

Very rare (three families)

aldolase (ALDOA)

myopathy

AR

Intermittent HA

Triose phosphate

12p13

CNSHA

Neuromuscular,

Neuromuscular defects

isomerase (TPI)

cardiac

dominate, sudden death,

Splx not helpful

AR

Infections

Phosphoglycerate

Xq13

CNSHA

CNS, myopathy,

Rare (28 families), variable

kinase (PGK)

rhabdomyolysis

systems involved

X-linked

Diphosphoglycerate

7q23-q34

Erythrocytosis

None

Very rare, low 2,3-DPG

mutase (DPG mutase)

AR

Glyceraldehyde-3-

12p13

None

None

Membrane protein band 6,

P-dehydrogenase

associated with HS, gene

syntenic with TPI

AD

Pyruvate kinase (PK)

1q21-q22 (PKLR)

CNSHA

None

Commonest CNSHA

AR rarely AD

AD, autosomal dominant; AR, autosomal recessive; CNSHA, congenital non-spherocytic haemolytic anaemia; Splx, splenectomy. ^Neurological signs may be secondary to hypoxia or ischaemia.

AD, autosomal dominant; AR, autosomal recessive; CNSHA, congenital non-spherocytic haemolytic anaemia; Splx, splenectomy. ^Neurological signs may be secondary to hypoxia or ischaemia.

acts as NLK, a lymphokine that induces the formation of antibody-secreting cells. It is also present in neutrophils, but there is no increase in infections in deficient subjects. In some severely deficient patients, neurological retardation has been thought to be related to hypoxia or ischaemia in utero rather than to direct metabolic effects.

Phosphofructokinase

Phosphofructokinase (PFK) catalyses a reaction in which F6P is phosphorylated to fructose-1,6-diphosphate, ATP being the donor of the phosphate group. Under normal physiological conditions, this may be the major rate-limiting step in glycolysis in the red cell. PFK is a tetramer, which in the red cell is a heterote-

tramer made up from M or L subunits. Two separate genes code for the two subunits. In muscle, PFK is a homotetramer (M4) and in liver a homotetramer (L4). In the red cell, there may be five isoenzymes composed of different numbers of L- and M-type subunits. A third subunit is found in platelets.

Phosphofructokinase deficiency

Deficiency of the M subunit leads to glycogen storage disease type 7 (Tarui's disease). It is characterized by muscle cramps and myoglobinuria on exertion. Shortened red cell viability may be a minor component of this disease. Evidence of haemolysis may be accompanied by mild erythrocytosis as a result of the decreased production of 2,3-DPG.

Fructose diphosphate aldolase A (ALDOA)

Fructose-1,6-diphosphate aldolase catalyses the conversion of fructose 1,6-diphosphate to glyceraldehyde 3-phosphate (Ga3P) and dihydroxyacetone phosphate (DHAP). There are three aldolases in human tissues (A, B and C), of which only A is expressed in the red cell. ALDOA is produced in the developing embryo and forms also the bulk of the enzyme in muscle, where it may be as much as 5% of the total cellular protein. In the red cell, the reaction catalysed by the enzyme is for all intents and purposes irreversible.

Fructose diphosphate aldolase A deficiency

The condition is extremely rare, with only three families having been definitely identified as having ALDOA deficiency. Two families have been described in which the propositus presented with CNSHA, mental retardation and dysmorphic features that are similar in the two families. In at least one family, the mutation produced an unstable enzyme. In a third patient, symptoms were mainly of myopathy, with weakness and premature fatigue. Anaemia and jaundice were intermittent and rhabdomyolysis occurred. There was severe deficiency of both muscle and red cell enzyme activity.

Triose phosphate isomerase

Triose phosphate isomerase (TPI) catalyses the interconversion of DHAP and Ga3P. In the glycolytic pathway of the red cell, all DHAP is converted to Ga3P, which is then metabolized down the glycolytic pathway, providing the ultimate two molecules of ATP for each molecule of glucose metabolized by that pathway. The enzyme is a homodimer, present in all tissues. In tissues other than the red blood cell, DHAP is an important precursor for the biosynthesis of ether glycerolipids (plasmalogens).

Triose phosphate isomerase deficiency

Triose phosphate isomerase deficiency produces a severe syndrome present from birth, consisting of CNSHA, a progressive neurological disorder with spasticity and CNS degeneration. Cardiac failure and sudden death due to arrhythmias are also features. Death occurs usually about 5 years of age. There is, as usual, some variation, and haemolysis without neurological degeneration, and the opposite, have been described. Splenec-tomy does not appear to be effective in modifying the haemolysis and does not influence the neurological complications. The diagnosis is made based on clinical suspicion, together with the appropriate enzyme assay. A number of point mutations that lead to the syndrome have been identified, but far and away the most predominant is Glu104Asp, a mutation linked by common haplotypes, suggesting descent from a common ancestor.

Phosphoglycerate kinase

Phosphoglycerate kinase (PGK) catalyses the reversible conversion of 1,3-DPG to 3-phosphoglycerate, generating one molecule of ATP for each molecule of 1,3-DPG metabolized by this pathway. It should be noted that two molecules of the 1,3-DPG are produced for each molecule of glucose metabolized by this pathway. PGKA, the active enzyme in the red blood cell, is the product of a gene on the X chromosome. The enzyme is monomeric and is expressed in all tissues (a testis has an additional PGKB gene coded on an autosome).

Phosphoglycerate kinase deficiency

In total, 28 families with PGK deficiency have been reported, and sequencing data are available for 16 families. Overall, 15 different PGK1 gene mutations have been identified. CNSHA occurred in 17 out of the 28 families, CNS disorders in 13 and myopathy with or without rhabdomyolysis in 13. All three systems were involved in only one of the families. Anaemia, when present, is usually well tolerated because of the increased concentration of 2,3-DPG produced by the increased flow of 1,3-DPG to 2,3-DPG via the Rapaport-Leubering shunt in the presence of the mutated PGK deficiency. Splenectomy has been effective in some cases of severe anaemia, but less so in others.

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