Epidemiology

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is distributed worldwide with a high prevalence in populations of Africa, Southern Europe, the Middle East, Southeast Asia and parts of Oceania, as well as in areas to which migrations from these areas have taken place. The overall geographic distribution of G6PD deficiency and its heterogeneity, together with clinical field studies and in vitro culture experiments, strongly support the view that this common genetic trait has been selected by Plasmodium falciparum malaria, by virtue of

Table 12.7 Synopsis of red cell enzymopathies*.

Enzyme (abbreviation)

Isoenzyme3

Prevalence

Main clinical features

characteristic of of enzyme

associated with enzyme

Benefit from

Chromosomal

red cells

deficiency

deficiencyb

splenectomy

localization

Hexokinase (HK)

R(D

Very rare

HA

Partial

10q22

Glucose 6-phosphate isomerase (GPI)

Rare

HA, NM, CNS

Partial

19q1 3.1

Phosphofructokinase (PFK)9

M

Very rare

HA, myopathy

12 q 1 3

L

21 q22.3

Aldolase

A

Very rare

HA, myopathy

16q22-24

Triosephosphate isomerase (TPI)

Very rare

HA, CNS, NM,

None

12p13

Glyceraldehyde 3-phosphate dehydrogenase (GAPD)h

Very rare

HA

12p13.31 -p13.1

Diphosphoglycerate mutase (DPGM)

Very rare

Polycythemia

7q31-q34

Phosphoglycerate kinase (PGK)

1

Very rare

HA, CNS, NM

Partial

Xq13

Monophosphoglycerate mutase (PGAM-B)

B

10q25.3

Enolaseh

1 (a)

Very rare

HA

1 pter-p36.13

Pyruvate kinase (PK)

R'

Rare

HA

Partial

1 q21

Glucose 6-phosphate dehydrogenase (G6PD)

B

Common

HA

None

Xq28

Cytochrome B5 reductase

Rare

pseudo-cyanosis, CNS

22q13.31 -qter

Adenylate kinase (AK)

1

Very rare

HA, CNS

Partial

9q34.1

■y-Glutamylcysteine synthetase (GLC LC)'

Very rare

HA, CNS(?)

6p12

Glutathione synthetase (GSS)

Very rare

HA, CNS

20q11.2

Glutathione peroxidase (GSH-Px)

Very rare1"

?m

3q 11 -q 12

Pyrimidine 5' nucleotidase (P5'N1 )

Rare

HA

Partial

7p15-p14

Number of known mutations'*

Deletion-insertion

Number of exons Number of amino acidsd

5-UTR

Missense Nonsense

In frame With frameshift Affecting splicing Total

19 916(917)'

1

3-0

4

18 558

16 2

2

20

24 780

7 1

1-0

6

15

22 784

12 364

2

2

7 249

1

9 2

1-0

13

9 335

Continued

3

259

1

1-0

2

11

417

8

1-0

2

11

254

434

12

574'

2 90

9

3-3

7-6

12

132

13

515

122'

1

6-0

1

130

9

276k

18

5

3-0

5

31

7

194

2

1

3

16

637

3

3

12

474

14

1-0

1-0

1

17

201

10

286"

3

1

0-1

2

7

*We have listed in the table all enzymes In the Intermediary metabolism of red cells for which, to the best of our knowledge, the corresponding cDNA/gene has been cloned. Modified from Luzzatto L. and Notaro R. (1998) Red cell enzymopathies. In: Jameson JL (ed.) Principles of Molecular Medicine. Clifton, NJ: Humana Press, pp. 197-207. aNo entry In this column means that there are no known Isoenzymes; therefore, It is assumed that the same enzyme type Is present in all tissues. bCNS, central nervous system Involvement; HA, hemolytic anemia; NM, neuromuscular manifestations. cData available only for some patients.

including N-termlnal methionine, which Is cleaved off In most or all cases.

eEach Individual molecular change, If observed in more than one patient, has been counted only once.

'The HK-I gene encodes both the erythrold-speciflc (HK-R) and ubiquitous (HK-I) isoforms. HK-R transcription starts from the erythrold-speciflc promoter upstream exon I (exon II is missing In the erythrold HK-R mRNA). HK-I transcription starts from the ubiquitously expressed promoter upstream exon II.

9PFK In normal red cells consists of a mixture of the five tetramerlc species that can be formed from random association of the M (muscle) and L (liver) highly homologous subunlts (M4, M3L, M2L2, ML3and L4).

hSlnce no mutations have yet been reported, there Is no formal proof that HA associated with this enzyme deficiency Is due to mutation of the corresponding gene.

'The red cell form of PK, called R, Is produced by the gene encoding the L (liver) subunlt. Because a different promoter Is used, the size of liver PK Is 543 amino acids.

The 122 mlssense mutations Include two variants with normal activity, A and Sao Borja. Six variants have two mlssense mutations each and one variant has three different mlssense mutations.

The cytoplasmic form of this enzyme, present In red cells, differs from the microsomal form present In other cells because, as a result of an alternative splicing pathway, It lacks the first 25 N-termlnal amino acids. Therefore, In other cells the size of the enzyme Is 301 amino acids.

'y-Glutamylcystelne synthetase consists of two subunlts: a catalytic subunlt and a regulatory subunlt. Data for the catalytic subunlt are shown here. "There Is no clear evidence that Inherited deficiency of glutathione peroxidase exists.

"Two alternatively spliced forms are present In reticulocytes. The main protein Is the long 286 amino acid protein (the third exon Is spliced out); a longer protein contains 11 extra amino acids at Its C-terminus.

Glucose

Fig. 12.8 Intermediary metabolism in red cells

The diagram shows the glycolytic pathway and related reactions (not the complete metabolic machinery of the red cells). Enzymes are enclosed in rounded boxes. Abbreviations as in Table 12.7. Additional abbreviations: DPG, diphosphoglycerate; GSH, reduced glutathione; GSSG, glutathione; HbFe2+, hemoglobin; HbFe3+, methemoglobin; yGluCys, y-glutamylcysteine. From Luzzatto L, Notaro R. (1998) Red cell enzymopathies. In: Jameson JL (ed.). Principles of Molecular Medicine. Clifton, NJ: Humana Press.

-ADP

Glucose 6-phosphate ■

G6PD

6-phosphogluconate

NADP NADPH

Fructose 6-phosphate ATP

CpfO

" -ADP Fructose 1,6-bisphosphate

Aldolase

NADP NADPH

CpfO

" -ADP Fructose 1,6-bisphosphate

Aldolase

yGluCys

Pentose phosphates yGluCys

Dihydroxyacetone phosphate

Cytochrome B5

Oyœraldehyde reductase

3-phosphate

(Cytochrome B5 reductase tNAD + Pi

NADH 1,3-diphosphoglycerate ADP

3-phosphoglycerate

DPGM

DPGM

2,3-DPG

PGAM

2-phosphoglycerate Enolase k

Phosphoenolpyruvate - ATP

Pyruvate *

Lactate the fact that it confers relative resistance against this highly lethal infection.

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