Page 735 - Hematology_ Basic Principles and Practice ( PDFDrive )

622 Part V Red Blood Cells

with antioxidants such as vitamins C and E was reported to improve deficiency lead to a left-shifted hemoglobin-oxygen dissociation curve
survival and long-term outcome in some but not all affected patients. and a more symptomatic anemia than comparable levels of anemia
Patients with glutathione synthetase deficiency should avoid the seen in patients with other RBC disorders. Splenectomy may be
same agents known to precipitate acute hemolysis in patients with beneficial. A mouse model of HK deficiency demonstrates severe
G6PD deficiency. hemolytic anemia with extensive tissue iron deposition and marked
reticulocytosis.
Glutathione Reductase Deficiency
Phosphofructokinase Deficiency
Glutathione reductase (GR) restores intracellular GSH by reducing
GSSG in the presence of NADPH and flavine adenine dinucleotide Phosphofructokinase (PFK) catalyzes the rate-limiting phosphoryla-
(FAD), a derivative of the water-soluble vitamin riboflavin. Heredi- tion of fructose-6-phosphate by ATP to fructose-1,6-diphosphate.
tary GR deficiency has only been reported in two Dutch families. In Red cells contain both M and L subunits of PFK. PFK deficiency is
one consanguineous family, acute hemolytic anemia after ingestion an autosomal recessive disorder with approximately 100 cases and 23
of fava beans occurred; GR deficiency was caused by a large homo- mutant PFKM alleles reported. These mutations lead to an almost
zygous deletion. The second family had a compound heterozygous complete loss of PFK activity in muscle, but only partial loss of
mutation and a clinical phenotype of neonatal jaundice. activity in erythrocytes. Two common mutations are present in
Riboflavin is a cofactor of GR. Mild acquired GR deficiency is Ashkenazi Jews. The most common manifestation of PFK deficiency
common and occurs in malnourished individuals because of ribofla- is type VII glycogen storage disease (Tarui disease), which causes
vin deficiency but has no hematologic phenotype. muscle weakness and exercise intolerance, although a mild chronic
hemolytic anemia may also be present. In some patients, hemolysis
is present without muscle manifestations.
Glutathione Peroxidase Deficiency PFK deficiency in dogs is characterized by hemolytic crises with
strenuous exercise. Pfkm null mice show exercise intolerance, reduced
Glutathione peroxidase is a selenium-containing enzyme that reduces lifespan and progressive cardiac hypertrophy.
hydrogen peroxide to water. Although a polymorphism affecting the
activity of glutathione peroxidase and acquired decreased activity
because of selenium deficiency have been described, neither circum- Aldolase Deficiency
stance was associated with a clinical phenotype.
Aldolase reversibly cleaves fructose-1,6-diphosphate into glyceralde-
OTHER ENZYMOPATHIES OF THE hyde 3-phosphate and dihydroxyacetone phosphate. Aldolase defi-
ciency is a very rare cause of chronic nonspherocytic hemolytic
GLYCOLYTIC PATHWAY anemia; myopathy and mental retardation may also occur.
Glucose Phosphoisomerase Deficiency
Phosphoglycerokinase Deficiency
Glucose phosphoisomerase (GPI) deficiency is one of the three most
common RBC enzyme defects causing chronic hereditary nonsphero- Phosphoglycerokinase catalyzes the reversible conversion of
cytic hemolytic anemia (the other two are PK and P5′N1), with 1,3-bisphosphoglycerate to 3-phosphoglycerate, forming ATP in the
approximately 100 affected families described. GPI deficiency is an process. This reaction can be bypassed by the Rappaport-Luebering
autosomal recessive disorder, with most patients compound hetero- shunt. Deficiency of this X-chromosome encoded enzyme is variably
zygous for mutations that partially inactivate the enzyme. The severity associated with hemolytic anemia, mental retardation, and
of the hemolysis is variable. Splenectomy can improve the anemia, myoglobinuria.
eliminating transfusion requirements. Neonatal jaundice is common
and hydrops fetalis has been reported. Rarely, severe neuromuscular
symptoms, mental retardation and granulocyte dysfunction occur. Triosephosphate Isomerase Deficiency
These symptoms may be caused by nonerythroid functions of GPI,
including its actions as a neuroleukin, an autocrine motility factor, a Triosephosphate isomerase (TPI) catalyzes the reversible interconver-
nerve growth factor, and a differentiation and maturation mediator. sion of the triose phosphate isomers, dihydroxyacetone phosphate
It has also been suggested that disturbed glycerolipid biosynthesis in and glyceraldehyde 3-phosphate. TPI deficiency is a rare autosomal
GPI deficiency may have significant effects on membrane formation, recessive disorder characterized by chronic hemolytic anemia,
membrane function, and axonal migration. increased susceptibility to bacterial infections, cardiomyopathy and
progressive neuromuscular disease. Neonatal jaundice may also occur.
The neuromuscular disease is likely caused by the formation of toxic
Hexokinase Deficiency protein aggregates of glycated proteins formed by elevated byproducts
of dihydroxyacetone phosphate.
Hexokinase (HK), the red cell enzyme with the lowest activity in the Approximately 40 patients with several different mutations have
glycolytic pathway, catalyzes the initial step in the utilization of been reported; however, most patients have the same mutation and
glucose and thus is required for both glycolysis and the pentose shunt are descendants from a common British/French ancestor about 1000
and produces glucose 6-phosphate. The two HK isoenzymes, HK1 years ago. There is no effective therapy and most patients die in
and HKR, are the product of a single gene HK-1 by use of an childhood, although there are rare exceptions.
alternate translation initiation site. A single nucleotide polymorphism
in HK-1 was strongly associated with reduced hemoglobin and
hematocrit levels in a European population. HK deficiency is a rare OTHER ENZYMOPATHIES
cause of hereditary chronic nonspherocytic hemolytic anemia with
only few dozen cases in 19 families reported. Most patients are of Transaldolase Deficiency
northern European extraction, although one case was reported in a
Chinese individual. The molecular defect has been characterized in Transaldolase catalyzes the conversion of seduhepulose-7-phosphate
only four patients; two were homozygous. HK is proximal to the and glyceraldehyde-3-phosphate into erythrose-4-phosphate and
generation of 2,3-BPG and thus decreased levels of 2,3-BPG in HK fructose-6-phosphate. Transaldolase deficiency has been described in