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

PK deficiency may be also caused by mutations not directly involv- Homozygous GPI-deficient mice exhibit hematologic features
ing the PKLR gene as demonstrated by a deficiency of PK being one of resembling that of the human enzymopathies. In addition, other tissues
the key features of severe congenital hemolytic anemia caused by muta- are also affected, indicating a reduced glycolytic capability of the whole
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tions in the key erythroid transcription factor KLF1. 294 organism. Complete loss of GPI in mice is embryonically lethal. 337
There is evidence that PK deficiency provides protection against Phosphofructokinase Deficiency Because red cells contain
infection and replication of Plasmodium falciparum in human erythro- both PFK M and L subunits, mutations affecting either gene (PFKM or
cytes, 295,296 an effect possibly mediated by reduced ATP levels in PK- PFKL) will lead to a partially reduced red cell enzyme activity in PFK
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deficient red blood cells. This suggests that PK deficiency may confer deficiency. Mutations in the PFKM gene cause PFKM deficiency or gly-
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a protective advantage against malaria in human populations in areas cogen storage disease VII (Tarui disease). The disease is characterized
where this disease is endemic. In agreement with this, population stud- predominantly by mild to severe myopathy, in particular exercise intol-
ies on sub-Saharan African populations indicate that malaria is acting erance, cramps, and myoglobinuria. The associated hemolysis is usu-
as a selective force in the PKLR genomic region. 298–300 ally mild but may be absent. As of this writing, there has been only one
PK deficiency has also been recognized in mice, dogs, and multiple reported case in which an unstable L subunit was identified. This patient
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breeds of domestic cats. In all these animals, the deficiency causes exhibited no signs of myopathy or hemolysis. Approximately 100 cases
severe anemia and marked reticulocytosis, closely resembling human of PFK deficiency have been reported as of this writing, and 23 mutant
PK deficiency. Basenji dogs with PK deficiency completely lack PKLR PFKM alleles are reported. Approximately half of the reported muta-
enzymatic activity and, instead, only the PK-M2 isozyme is expressed in tions are missense mutations, the remaining mutations mostly affect
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their red blood cells. A unique feature of PK deficiency in dogs is the splicing. Intriguingly, PFK-deficient Ashkenazi Jews share two common
progressive development of myelofibrosis and osteosclerosis. Marrow mutations: a G>A base change affecting the donor splice site of intron
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fibrosis may occur in response to damage caused by iron overload, 5 (c.237+1G>A) and a single base deletion in exon 2 (c.2003delC). 33,339
although factors associated with marked erythropoiesis have also been The mode of action by which missense mutations cause disease is largely
proposed to play a role. Gene therapy approaches have been employed unknown. 33,340–347
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to cure PK deficiency in dogs. PK-deficient mice show delayed switch- PFK deficiency in dogs is characterized by the association of
ing from PK-M2 to PK-R, resulting in delayed onset of the hemolytic hemolytic crises with strenuous exercise. Pfkm null mice show exer-
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anemia. PK deficiency in mice has been rescued by expression of the cise intolerance, reduced life span, and progressive cardiac hypertrophy,
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human PK-R isozyme in murine hematopoietic stem cells. 307,308 suggesting that Tarui disease should be considered as a complex sys-
temic disorder rather than a muscle glycogenosis. 349,350
Other Enzyme Deficiencies Aldolase Deficiency At the time of this writing, only six patients
Hexokinase Deficiency Nineteen families with HK deficiency have with red cell aldolase deficiency had been described, four of whom were
been described as of the time of this writing 309–311 and only four patients characterized at the DNA level. All displayed moderate chronic hemo-
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have been characterized at the molecular level. 310–313 Two of these lytic anemia, either by itself or accompanied by myopathy, 352,353 rhab-
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patients were homozygous, either for a highly conserved substitution in domyolysis, psychomotor retardation, or mental retardation. 77,352
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the enzyme’s active site or a lethal out-of-frame deletion of exons 5 to Triosephosphate Isomerase Deficiency TPI deficiency is char-
8 of HK1. In one patient a regulatory mutation was identified in the acterized by hemolytic anemia, often accompanied by neonatal hyper-
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putative erythroid-specific promoter. In vitro, this mutation disrupted bilirubinemia requiring exchange transfusion. In addition, patients
binding of the AP-1 transcription factor complex, leading to strongly display progressive neurologic dysfunction, increased susceptibility to
decreased gene expression. 311 infection, and cardiomyopathy. Most affected individuals die before
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In mice, a mutation designated downeast anemia causes severe the age of 6 years, but there are remarkable exceptions. TPI deficiency
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hemolytic anemia with extensive tissue iron deposition and marked is the most severe disorder of glycolysis. Key in the pathophysiology
reticulocytosis, representing a mouse model of generalized HK of the severe neuromuscular disease is the formation of toxic protein
deficiency. 314 aggregates: accumulation of the substrate dihydroxyacetone phosphate
Glucosephosphate Isomerase Deficiency Glucosephosphate results in elevated levels of the toxic methylglyoxal, leading to the for-
isomerase deficiency is second to PK deficiency in frequency, with mation of terminal glycation of proteins, whereas mutation-induced
respect to glycolytic enzymopathies. To date, approximately 55 families changes in the quaternary structure of TPI lead to the formation of an
with glucosephosphate isomerase deficiency have been described world- aggregation-prone protein. 357,358 Therefore, it has been suggested that
wide. 315–320 Most of these patients are compound heterozygous for muta- TPI deficiency represents a conformational rather than a metabolic
tions that partially inactivate the enzyme. Most of the 31 GPI mutations disease. 357
reported to date are missense mutations. Mapping of these mutations to Approximately 40 patients and 19 different mutations have been
the crystal structure of the human enzyme and recombinant expression reported in TPI deficiency. 355,358–363 The most common mutation is the
of genetic variants has provided considerable insight in the molecular p.(Glu104Asp) amino acid change which is detected in approximately
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mechanisms causing hemolytic anemia in this disorder. 321,322 The major- 80 percent of patients, all descendants from a common ancestor. Stud-
ity of the mutations disrupt key interactions that contribute directly or ies on recombinant mutant TPI show that the p.(Glu104Asp) does not
indirectly to the architecture of the enzyme’s active site. In rare cases, affect catalysis. Instead, the mutation disrupts a conserved network of
321
GPI deficiency also affects nonerythroid tissues, causing severe neuro- buried water molecules, which prevents efficient formation of the active
muscular symptoms and granulocyte dysfunction. 323–328 The finding that TPI dimer, causing its dissociation in inactive monomers. 85
GPI also functions as a neuroleukin, an autocrine motility factor, a TPI-null mice die at an early stage of development. Hemolytic
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nerve growth factor, and a differentiation and maturation mediator anemia characterizes the only viable mouse model of TPI deficiency.
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has led to the hypothesis that the mutation-dependent loss of cytokine Studies on a Drosophila model recapitulating the neurologic phenotype
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function of GPI could account for the neuromuscular symptoms. An of TPI deficiency suggests that loss of an isomerase-independent
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alternative explanation involves disturbed glycerolipid biosynthesis in function of TPI underlies the neuropathogenesis in TPI deficiency. 368
GPI deficiency, which could have significant effects on membrane for- Phosphoglycerate Kinase Deficiency PGK deficiency is one
mation, membrane function, and axonal migration. 334,335 of the relatively uncommon causes of hereditary nonspherocytic
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