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704 Part VI: The Erythrocyte Chapter 47: Erythrocyte Enzyme Disorders 705

hemolytic anemia. Mutations in the X chromosome-linked gene may gene. Patients with mild GS deficiency display mild hemolytic anemia
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cause mild to severe chronic hemolysis, neurologic dysfunction, and as their only symptom. In contrast, patients with a moderate deficiency
myopathy. Approximately 40 patients with PGK deficiency have been usually present in the neonatal period with metabolic acidosis, 5-
369
reported. 369,370 Most patients manifest either hemolytic anemia in com- oxoprolinuria, and mild to moderate hemolytic anemia. In addition to
bination with neurologic symptoms, including mental retardation, sei- these symptoms, patients with the third and most severe type develop
zures, progressive decline of motor function, and developmental delay, progressive neurologic symptoms such as psychomotor retardation,
or isolated myopathy. 370–372 The combination of all clinical manifesta- mental retardation, seizures, ataxia, and spasticity. 5-Oxoprolinuria
tions is a rare event, described in only 2 families. 373,374 Splenectomy has results from accumulation of γ-glutamylcysteine because of decreased
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been reported to be beneficial but does not correct the hemolytic pro- feedback inhibition of GCL by the decreased levels of GSH. Impor-
cess. 341,369 Marrow transplantation has been performed to prevent the tantly, 5-oxoprolinuria may have other causes. 398,399 Experiments in rats
manifestation of severe neurologic symptoms. 375 show that acute administration of 5-oxoproline induces oxidative dam-
Twenty-two unique mutations have been identified. 370,371 Most age in the brain, a mechanism that may be involved in the neurologic
of these mutations (80 percent) are missense mutations. Most of the symptoms of severe GS deficiency. 400
encoded amino acid changes heavily affect the protein’s thermal sta- The diagnosis of GS deficiency has been established in more than
bility and to a different extent catalytic efficiency. 371,376 In an attempt 70 patients from 50 families, 396,397,401,402 of whom approximately 25 per-
401
to correlate the genotype to the phenotype, it was found that amino cent died in childhood. Thirty-two mutations are identified as being
acid changes grossly impairing protein stability but moderately affect- associated with GS deficiency. Based on the nature of the mutation, and
ing kinetic properties were associated mostly with hemolytic anemia taking into account GS activity and GSH levels it seems possible to pre-
and neurological symptoms. Mutations perturbing both catalysis and dict a mild versus a more severe phenotype. The structural effects of a
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heat stability were associated with myopathy alone, whereas muta- number of missense mutations have been determined. 197
tions faintly affecting molecular properties of PGK correlated with a A long-term followup study showed that early diagnosis, correc-
wide range of clinical symptoms. Yet, the precise reason for the dif- tion of acidosis, and early supplementation with antioxidants vitamins
376
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ferent clinical manifestations of mutations of the same gene remains C and E improve survival and long-term outcome. For these reasons it
unknown, suggesting the involvement of yet unknown alternate func- has been argued that GS deficiency should be included in the newborn
tion of this enzyme, environmental, metabolic, genetic and/or epige- screening program. 401
netic factors. 372,376 Complete deficiency of GS has shown to be lethal in mice, whereas
Bisphosphoglycerate Mutase Deficiency Bisphosphoglycerate heterozygous animals survive with no distinct phenotype. 403
mutase deficiency is a very rare disorder. Only three affected families Glutathione Reductase Deficiency Only two families with
have been characterized. Bisphosphoglycerate mutase deficiency appears hereditary GR deficiency have been described and characterized. 404,405
to be inherited as an autosomal recessive disorder. However, some het- The complete absence of GR in the red cells of members of one fam-
erozygous relatives have had a borderline high hemoglobin concen- ily was associated with only rare episodes of hemolysis, possibly caused
tration, 377,378 and in one single affected patient only one mutation was by fava beans. GR deficiency was caused by homozygosity for a large
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identified. Erythrocytosis was the predominant feature of the clinically genomic deletion. GR deficiency in the other family was caused by com-
380
normal probands, likely resulting from reduced 2,3-BPG levels and, pound heterozygosity for a nonsense mutation, and a missense mutation
consequently, the increased oxygen affinity of hemoglobin (Chap. 57). affecting a highly conserved residue. GR in red cells was undetectable,
Glutamate Cysteine Ligase Deficiency GCL deficiency is associ- but some residual activity was found in the patient’s leucocytes. 404
ated with mild hereditary nonspherocytic hemolytic anemia that may be In vitro studies on members of one of the GR deficiency families
fully compensated. Drug- and infection-induced hemolytic crises may has provided experimental evidence that GR deficiency may protect
occur as a consequence of strongly reduced GSH levels. As of this writ- from malarial infection by enhancing phagocytosis of ring-infected red
ing, eight cases of GCL deficiency had been described, belonging to six blood cells. 406
unrelated families. 381–388 In approximately half of the patients with GCL Adenylate Kinase Deficiency AK deficiency has been reported
deficiency, the hemolytic anemia was accompanied by impaired neuro- in 12 unrelated families and 7 different mutations have been identi-
388
logical function. Six patients have been characterized at the molecular fied. 263,407–412 In all but one case, 263,413 the deficiency was associated with
level and five different mutations have been reported. 385–388 In all these moderate to severe hemolytic anemia. In some of the patients, men-
cases, the causative mutation affected the catalytic subunit of GCL. The tal retardation and psychomotor impairment was also observed. 410,414
clinically observed mutations have been mapped to a homology model Studies on a number of recombinant proteins revealed strongly altered
of the human enzyme, based on the crystal structure of GCL of Sacchar- catalytic properties or protein stability resulting from mutation. In
241
omyces cerevisiae, thus explaining the molecular basis of GSH depletion contrast, patient’s cells sometimes displayed considerable residual enzy-
as a result of GCL deficiency. Complementary expression studies in matic activity. The activation of expression of other isozymes, that is,
192
mice showed that these GCL mutations impair glutathione produc- AK2 and AK3, has been proposed as one of the factors contributing to
tion by reducing the activity of the catalytic subunit of GCL. Addition this apparent discrepancy. 412
of the modifier subunit was able to largely restore enzymatic activity, Adenosine Deaminase Hyperactivity An increased activity of
thereby underscoring the critical role of GCLM. Complete deficiency ADA is associated with hereditary nonspherocytic hemolytic anemia.
389
of GCLC has shown to be lethal in mice, 390,391 whereas GCLM-null It is the only red cell enzyme disorder that is inherited in an autoso-
415
mice are viable and show no overt phenotype despite strongly reduced mal dominant disorder. Adenosine deaminase hyperactivity results in
GSH levels, including a reduction of more than 90 percent in red blood depletion of red cell ATP. 415,416 Few cases with a 30- to 70-fold increase in
cells. Upon exposure to oxidative stress, however, red blood cells from activity have been described. The molecular mechanism of this disorder
392
such mice undergo massive hemolysis with fatal outcome. 393 has not been identified but the markedly increased amounts of ADA
Glutathione Synthetase Deficiency GS deficiency is the most mRNA in affected individuals indicate that the red blood cell–specific
394
417
common abnormality of red cell glutathione metabolism. Three dis- overexpression occurs at the mRNA level, causing an overproduction
395
tinct clinical forms of GS deficiency can be distinguished, most likely of a structurally normal enzyme. ADA hyperactivity probably results
418
reflecting different mutations or epigenetic modifications in the GS from a cis-acting mutation in the vicinity of the ADA gene. 419

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