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Rare RBC enzyme disorders

Rare RBC enzyme disorders
Literature review current through: Jan 2024.
This topic last updated: Sep 28, 2023.

INTRODUCTION — Mature red blood cells (RBCs) are anucleate (thereby incapable of cell division), devoid of ribosomes (thereby incapable of protein synthesis), and lacking in mitochondria (thereby incapable of oxidative phosphorylation). Despite these limitations, RBCs survive 100 to 120 days in the circulation and effectively deliver oxygen.

This occurs because RBCs have the enzyme-mediated metabolic machinery necessary to produce energy (ATP) and specialized metabolic pathways to protect against external oxidant stresses. In the absence of normal enzyme function, RBC survival is shortened, a manifestation of the hereditary nonspherocytic hemolytic anemias (HNSHAs).

RBC enzyme disorders fall into three mechanistic categories:

Deficiencies of glycolytic enzymes

Enzyme deficiencies affecting the hexose monophosphate (HMP) shunt and glutathione metabolism

Enzyme abnormalities affecting purine and pyrimidine metabolism

This topic reviews the very rare congenital RBC enzyme disorders that cause hemolysis. The two most common RBC enzyme disorders are discussed separately:

G6PD deficiency – (See "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Gene test interpretation: G6PD".)

PK deficiency – (See "Pyruvate kinase deficiency".)

From a clinical perspective, the possibility of one of these disorders is considered after the common causes of hemolytic anemia are eliminated. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)

PATHOPHYSIOLOGY

Overview of RBC metabolism — The main function of erythrocytes is oxygen transport, and to do this, red blood cells (RBCs) need to withstand physical, chemical, and oxidative stress. This requires energy (in the form of adenosine triphosphate [ATP]) and reducing power (in the form of reduced glutathione). RBCs use metabolic pathways to generate ATP, ensure membrane integrity, keep hemoglobin in the reduced state, and maintain a sufficient supply of reduced glutathione to protect the RBC from oxidative damage [1]. RBC metabolic pathways and the connections between them are illustrated in the figure (figure 1).

Metabolic pathways can be considered in three broad categories:

Glucose metabolism – Glucose is the main metabolic substrate. It is metabolized by two major pathways, glycolysis and the hexose monophosphate (HMP) shunt. Under normal conditions, approximately 90 percent of glucose flows through glycolysis, with approximately 10 percent being channeled through the HMP pathway. However, the fraction of glucose entering the HMP pathway can increase significantly under conditions of increased oxidative stress. (See 'Glycolysis pathway' below and 'HMP pathway' below.)

The major products of glycolysis are ATP (a source of energy for numerous RBC membrane and metabolic reactions), reduced nicotinamide adenine dinucleotide (NADH), a necessary cofactor for methemoglobin reduction by cytochrome b5 reductase, and 2,3-bisphosphoglycerate (2,3-BPG; an important intermediate that modulates hemoglobin-oxygen affinity) (figure 1).

Glutathione production – Reduced glutathione (GSH) protects the cell from oxidative damage. The glutathione pathway generates glutathione and the initial reactions of the hexose monophosphate (HMP) shunt maintain it in a reduced state. (See 'Glutathione metabolism' below.)

Nucleotide metabolism – Mature RBCs are incapable of de novo purine or pyrimidine synthesis, although many enzymes of nucleotide metabolism are present. The main role of purine metabolic enzymes is to sustain the RBC adenine pool, which is used to make ATP. (See 'Nucleotide metabolism' below.)

The mechanism of hemolysis associated with RBC enzymopathies is complex and incompletely understood. It is thought that reduced ATP stores and decreased reducing capacity ultimately lead to membrane damage and abnormalities in protein function that cause RBCs to be prematurely destroyed in the spleen, a form of extravascular hemolysis [1]. (See "Diagnosis of hemolytic anemia in adults", section on 'Site of RBC destruction'.)

Genetics (list of genes) — Genes are listed here and summarized in the table (table 1).

Glycolysis

PKLR Encodes the RBC form of pyruvate kinase (PK). (See "Pyruvate kinase deficiency".)

HK1 Encodes hexokinase isoform 1. (See 'Hexokinase (HK) deficiency' below.)

GPI Encodes glucose-6-phosphate isomerase. (See 'Glucosephosphate isomerase (GPI) deficiency' below.)

PFKM Encodes one of the isoforms of phosphofructokinase. (See 'Phosphofructokinase (PFK) deficiency' below and "Phosphofructokinase deficiency (glycogen storage disease VII, Tarui disease)".)

ALDOA Encodes aldolase (muscle and RBC form). (See 'Aldolase deficiency' below.)

TPI1 Encodes triosephosphate isomerase. (See 'Triosephosphate isomerase (TPI) deficiency' below.)

PGK1 – Encodes phosphoglycerate kinase (PGK). (See 'Phosphoglycerate kinase (PGK) deficiency' below.)

Hexose monophosphate (HMP) shunt and glutathione metabolism

G6PD Encodes glucose-6-phosphate dehydrogenase (G6PD). (See "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

GSR Encodes glutathione reductase. (See 'Glutathione reductase (GSR) deficiency' below.)

GPX1 Encodes glutathione peroxidase (GPx), RBC form. (See 'Glutathione peroxidase (GPx) deficiency' below.)

GCLC – Encodes the catalytic subunit of gamma-glutamyl-cysteine synthetase (GCS). (See 'Gamma-glutamyl-cysteine synthetase (GCS) deficiency' below.)

GSS – Encodes glutathione synthetase (GSS). (See 'Glutathione synthetase (GSS) deficiency' below.)

Purine and pyrimidine metabolism

NT5C3A Encodes pyrimidine 5' nucleotidase (P5'N). (See 'Pyrimidine 5' nucleotidase (P5'N) deficiency' below.)

ADA Encodes adenosine deaminase (ADA). (See 'Adenosine deaminase (ADA) excess' below and "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)

AK1 Encodes adenylate kinase (AK). (See 'Adenylate kinase (AK) deficiency' below.)

DIAGNOSTIC EVALUATION

When to suspect — An RBC enzyme disorder may be suspected in a child or adult with non-immune (Coombs-negative) hemolytic anemia in whom the other more common causes of hemolysis have been excluded. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)

Inheritance – Most of the rare glycolytic enzymopathies have an autosomal recessive pattern of inheritance. Heterozygotes almost always are hematologically normal, although their RBCs contain less than normal levels of enzyme activity. It once was thought that hemolysis occurred only in those individuals who were homozygous for the enzyme deficiency. However, true homozygosity for a given enzyme variant is known to be less common and usually restricted to a consanguineous kindred. The vast majority of hemolytic anemias due to enzyme deficiencies are a consequence of compound heterozygosity for two different variants; this accounts for the diverse biochemical and clinical heterogeneity of their clinical features.

Exceptions to autosomal recessive inheritance:

Phosphoglycerate kinase (PGK) deficiency is X-linked. (See 'Phosphoglycerate kinase (PGK) deficiency' below.)

A dominantly acting variant in the ADA gene causes increased adenosine deaminase activity; transmission is autosomal dominant. (See 'Adenosine deaminase (ADA) excess' below.)

Clinical findings – Hemolysis can cause chronic anemia, reticulocytosis, and indirect hyperbilirubinemia. The physical examination may show pallor, jaundice, and/or splenomegaly.

Hemolysis is usually recognized in childhood, although diagnosis in adolescents and adults is not uncommon. Frequently, there is a history of neonatal jaundice, often requiring an exchange transfusion, and rarely causing kernicterus. The magnitude of chronic anemia varies. There may be accelerated hemolysis with nonspecific infections or transient aplastic crises associated with parvovirus infection.

Some enzyme deficiencies, such as pyruvate kinase (PK) deficiency, have findings isolated to the RBCs; in others, the enzyme deficiency affects multiple cell types, and hemolytic anemia is accompanied by multisystem disease (eg, phosphofructokinase [PFK], aldolase, triosephosphate isomerase [TPI], and phosphoglycerate kinase [PGK]) (table 1). (See "Overview of hemolytic anemias in children", section on 'Diagnostic approach' and "Diagnosis of hemolytic anemia in adults", section on 'History and physical examination'.)

CBC, blood smear, and hemolysis testing

CBC – The complete blood count (CBC) usually shows anemia, which may be mild or absent if compensated by brisk reticulocytosis. Other cell counts are generally normal.

Blood smear – There are no specific morphologic abnormalities in most anemias due to rare enzyme deficiencies.

Anisocytosis and poikilocytosis are common, and there may be polychromasia due to reticulocytosis.

Heinz bodies (collections of denatured globin chains attached to the RBC membrane) can form with oxidant injury. These are seen only after blood is treated with a supravital stain such as brilliant cresyl blue.

Basophilic stippling (picture 1) may be present in pyrimidine 5' nucleotidase (P5'N) deficiency. (See 'Pyrimidine 5' nucleotidase (P5'N) deficiency' below.)

Hemolysis – Hemolysis causes increased reticulocyte count, increased bilirubin, increased lactate dehydrogenase (LDH), and decreased haptoglobin.

Many of these rare enzyme deficiencies cause chronic hemolysis. Just as in glucose-6-phosphate dehydrogenase (G6PD) deficiency, some rare deficiencies of glutathione synthetic enzymes cause intermittent hemolysis triggered by oxidant stress. (See 'Overview of RBC metabolism' above.)

Hemolysis is non-immune; the Coombs test (direct antiglobulin test [DAT]) is negative. (See "Diagnosis of hemolytic anemia in adults", section on 'Cause not obvious - start with Coombs test'.)

Osmotic fragility testing is not useful; if performed, the incubated osmotic fragility may be abnormal in some glycolytic enzymopathies. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Osmotic fragility or ektacytometry' and "Hereditary spherocytosis", section on 'Confirmatory tests'.)

Exclude other hemolytic anemias — Rare RBC enzyme disorders are typically considered after a patient is diagnosed with hemolytic anemia and other more common causes of non-immune hemolysis are excluded. These include drug-induced hemolysis, hemoglobinopathies, membrane/cytoskeleton disorders, and more common enzyme deficiency such as G6PD deficiency and PK deficiency. For some patients, it may be reasonable to evaluate for several of these disorders simultaneously, such as with a gene panel.

Other common non-immune hemolytic anemias include:

Drug-induced hemolysis – Drug-induced hemolysis is an acquired form of hemolysis. Hemolysis and anemia may be mild or severe, and certain oxidant drugs may trigger hemolysis regardless of an underlying disorder of glutathione metabolism. Unlike rare enzyme disorders, drug-induced hemolysis responds to drug discontinuation. (See "Drug-induced hemolytic anemia" and "Warm autoimmune hemolytic anemia (AIHA) in adults".)

Hemoglobinopathies – Hemoglobinopathies are heritable disorders. They include sickle cell disease, thalassemia, and Hb C, D, and E disorders. Like rare RBC enzyme disorders, they cause non-immune hemolysis. Unlike the rare enzyme disorders, they have classic morphologic changes on the blood smear, and hemoglobin analysis demonstrates the abnormal hemoglobin. Molecular testing may be required to demonstrate alpha thalassemia. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

RBC membrane and cytoskeletal disorders – These are heritable disorders. They include hereditary spherocytosis, elliptocytosis, and stomatocytosis. Like the rare RBC enzyme disorders, they cause non-immune hemolysis. Unlike the rare enzyme disorders, they have classic morphologic changes on the blood smear and well characterized alterations in RBC osmotic fragility, eosin-5'-maleimide (EMA) binding, or ektacytometry. (See "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

Thrombotic microangiopathies – Thrombotic microangiopathies (TMAs) include heritable and acquired disorders. They are characterized by microangiopathic hemolysis, with schistocytes on the blood smear. Unlike the rare enzyme disorders, TMAs are generally accompanied by thrombocytopenia, often severe, and other specific findings related to the underlying cause. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Congenital dyserythropoietic anemias (CDAs) – CDAs are rare heritable disorders. They are characterized by ineffective erythropoiesis and abnormal bone marrow morphology, especially multinuclear erythroblasts. Like rare enzyme disorders, they can cause non-immune hemolysis with splenomegaly. Unlike the rare enzyme disorders, in CDA there is evidence of ineffective erythropoiesis (ie, the reticulocyte count is low for the degree of anemia), and iron overload may be present. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Congenital dyserythropoietic anemia'.)

G6PD and PK deficiency – G6PD deficiency and PK deficiency are heritable RBC enzyme deficiencies. G6PD deficiency is common, and PK deficiency is rare but more common than the disorders discussed herein. Like the rare enzyme disorders, they cause non-immune hemolysis. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Pyruvate kinase deficiency".)

Genetic versus biochemical testing — In virtually all cases, a specific assay of RBC enzyme activity and/or genetic (molecular) testing are necessary to make the diagnosis. Benefits of obtaining a specific diagnosis include ending a diagnostic odyssey, facilitating testing of first-degree relatives, and informing plans for monitoring and treatment.

The specific sequence of testing depends on which tests are most readily available. As an example, at some academic centers that have biochemical testing on site, initial biochemical testing is done to narrow the diagnosis, followed by molecular testing for confirmation or final diagnosis. In practices that do not have easy access to biochemical testing, an initial gene panel may be more practical and can be followed by biochemical testing if necessary. If a familial disorder or combination of gene variants is known and an individual with chronic hemolysis has that pair of variants, biochemical testing may be unnecessary.

Biochemical enzyme assays and molecular studies are complementary, especially in difficult cases in which enzyme assays demonstrate low levels of activity relative to other RBC enzymes or in which molecular testing shows two pathogenic variants or a variant of uncertain significance (VUS). Advantages and disadvantages of enzyme assays and molecular testing are summarized in the table (table 2).

Enzyme assays – Historically, direct enzyme assays have been considered the gold standard for the diagnosis of RBC metabolic disorders. In many patients, direct enzyme analysis is adequate for initial diagnosis, with molecular testing serving as a confirmatory test.

However, biochemical testing may be falsely negative in individuals who have recently received a transfusion, since transfused RBCs have normal enzyme activity. Reticulocytes tend to have higher enzyme activity as well, and a high reticulocyte count may result in normal enzyme activity in some cases, particularly G6PD, pyruvate kinase (PK), hexokinase, and 5' nucleotidase deficiencies [1]. This problem can be circumvented by testing for another age-related enzyme in the same sample to determine if a deficiency is being masked.

Molecular testing – Over time, there has been an increased use of genetic testing and this is a moving target. A consensus "good practice" guideline published jointly by the British Society for Haematology and European Hematology Association noted that a large proportion of individuals with rare anemias are misdiagnosed or undiagnosed when their evaluation is based purely on phenotype and traditional testing that does not incorporate next-generation sequencing (NGS) technologies that query multiple genes [2,3]. Another advantage to using gene panels for RBC disorders is that testing platforms frequently contain other genes that code for disorders with similar features to enzyme disorders, such as congenital dyserythropoietic anemias (CDAs). (See 'Exclude other hemolytic anemias' above.)

Molecular testing identifies specific pathogenic variants. It can be performed in transfused patients and used for prenatal diagnosis. Sample preparation and shipping are less complicated than for direct enzyme assays. Costs and availability have also shifted to favor genetic testing. Some laboratories offer a comprehensive hemolytic anemia gene panel. However, unless the patient is homozygous for a known variant, samples for molecular testing of the parents are needed to ascertain if the variants detected are in cis (on the same allele) or trans (on both alleles). Some patients have low enzyme activity with nonconfirmatory genetic testing, suggesting that molecular testing may miss variants outside the coding region. For these patients, diagnostic classification is challenging and in some cases may require whole genome sequencing.

VUSs create an additional diagnostic dilemma, as it is not clear whether these variants are pathogenic and related to disease. In these cases, enzyme assays would be required to characterize the anemia.

Where to obtain specialized testing

Genetic testing – Genetic testing is generally done using a gene panel that includes genes for most common (or in some cases, all known) metabolic enzymes. Testing is performed by several academic centers in North America and Europe, and testing may be available at low or no cost from certain commercial laboratories [4].

Biochemical testing – Biochemical assays with enzyme panels are available in academic and commercial laboratories in North America and Europe.

GENERAL PRINCIPLES OF MANAGEMENT — Management depends on the severity of hemolytic anemia. For most of these disorders, care is supportive and similar to other chronic hemolytic anemias.

Transfusions – RBC transfusions may be required if anemia is severe. Some individuals with chronic hemolytic anemia may tolerate a lower hemoglobin. (See "Red blood cell transfusion in infants and children: Indications" and "Indications and hemoglobin thresholds for RBC transfusion in adults".)

Folic acid – We generally suggest folic acid supplementation for individuals with chronic hemolytic anemia. A typical dose is 1 mg daily or a multivitamin containing folic acid.

Monitoring for gallstones – Cholelithiasis is common problem, and gallbladder ultrasound examinations are performed periodically (eg, every three to five years) or when symptoms or abnormalities such as gallbladder sludge develops. Gallstones can develop following splenectomy. If the individual requires abdominal surgery for another reason, it may be reasonable to evaluate for gallstones, in case the information might influence decisions about concurrent cholecystectomy. (See "Gallstones: Epidemiology, risk factors and prevention", section on 'Hyperbilirubinemia'.)

Splenectomy – Splenectomy usually is beneficial in severely anemic patients, since the spleen (along with the liver) participates in the destruction of enzymatically abnormal cells. In most cases, the response to splenectomy is only partial, although RBC transfusion requirements may decrease. (See "Elective (diagnostic or therapeutic) splenectomy".)

Monitoring for iron overload – Transfusion-dependent and transfusion-independent iron loading is a frequent complication in RBC glycolytic disorders. Routine monitoring is indicated, with ferritin and/or magnetic resonance imaging (MRI) once a child or young adult can cooperate. Optimal monitoring has not been determined for rare enzymopathies; practice similar to thalassemia would be reasonable. (See "Management of thalassemia", section on 'Assessment of iron stores and initiation of chelation therapy'.)

Avoid oxidant exposures – Exposure to chemicals and drugs, and foods (fava beans) with oxidant potential should be avoided, especially in individuals with disorders of glutathione metabolism. These are the same exposures that are avoided in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Inciting drugs, chemicals, foods, illnesses'.)

Additional management for nonhematologic consequences of glucose metabolism disorders and metabolic myopathies is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism" and "Approach to the metabolic myopathies".)

SPECIFIC DISORDERS

Disorders of glycolysis

Glycolysis pathway — Glycolysis is the source of energy-production in RBCs. RBCs conduct glycolysis anaerobically (without oxygen) using the Embden-Myerhof pathway, which converts glucose to pyruvate (and lactate), producing adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH) (figure 1). ATP provides energy for membrane ion channels and enzymes to function properly. This pathway uses the majority of the glucose in the cell. The rate-limiting enzymes are hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK).

The Rapoport-Luebering shunt is a branch pathway of anaerobic glycolysis that generates 2,3-diphosphoglycerate (2,3 DPG, also called 2,3 BPG), which regulates hemoglobin-oxygen affinity and oxygen delivery to the tissues. (See "Hemoglobin variants that alter hemoglobin-oxygen affinity", section on 'Regulation of hemoglobin oxygen affinity'.)

PK deficiency — PK deficiency is the most common glycolytic pathway disorder; it is discussed separately. (See "Pyruvate kinase deficiency".)

Hexokinase (HK) deficiency — HK catalyzes conversion of glucose to glucose-6 phosphate (figure 1). As the first enzyme in the glycolytic pathway, HK has a strategic role in the regulation of glucose consumption. The activity of HK declines rapidly as RBCs age; in older cells, HK activity is lower than any other glycolytic enzyme.

Pathophysiology – There are four hexokinase isozymes, each one is coded for by a different gene (HK1, HK2, HK3, HK4). The HK1 gene on chromosome 10 encodes RBC hexokinase [5]. This HK isozyme also is present in lymphocytes and platelets; however, deficiency of type I HK isozyme in lymphocytes is offset by an increase in the amount of type III isozyme [6]. Deficient HK activity may result from quantitative deficiency of an apparently normal enzyme or from abnormalities that affect substrate affinity or heat stability [7,8]. Specific pathogenic variants have been identified in an increasing number of cases of HK deficiency [9-13].

Epidemiology and inheritance – Inheritance of HK deficiency is autosomal recessive. At least 30 patients with HK deficiency have been described in families of European, Mediterranean, Scandinavian, and Asian ancestry [5,8,11].

Clinical features – Complications are not well characterized but are likely to be similar to other congenital hemolytic anemias. Disease severity varies from fully compensated hemolysis to hyperbilirubinemia requiring exchange transfusion (in approximately one-fourth of reported cases) or transfusion-dependent anemia. Symptoms may be more severe (out of proportion to the degree of anemia) due to low levels of erythrocyte 2,3-BPG [14,15]. Splenomegaly is common. Pigment gallstones may occur. There are no unique RBC features.

Diagnosis – Diagnosis is made by documenting decreased RBC HK activity on an enzymatic assay or a pathogenic variant in HK1 on genetic testing. Because HK is among the most age-dependent of RBC enzymes, enzyme activity must be considered in relation to the reticulocyte count or the activity of other age-dependent enzymes such as pyruvate kinase (PK) [7]. Given the rarity of HK deficiency, if a patient is found to have low enzyme activity, the diagnosis should be confirmed with molecular testing.

Management – Exchange transfusion may be needed in neonates; transfusions may be needed in older children and adults. Monitoring may be needed for complications such as gallstones and transfusion-independent iron loading. Splenectomy ameliorates but does not cure the hemolytic process [7]. Hemopoietic stem cell transplant has been described in a single patient [16]. General management recommendations are listed above. (See 'General principles of management' above.)

Glucosephosphate isomerase (GPI) deficiency — Glucosephosphate isomerase (GPI, also called glucose-6-phosphate isomerase) catalyzes the interconversion of fructose-6-phosphate and glucose-6-phosphate (figure 1).

Pathophysiology – GPI deficiency is caused by homozygous or compound heterozygous pathogenic variants in the GPI gene on chromosome 19 [17,18]. Multiple pathogenic variants in GPI have been identified, including missense mutations and gene deletions [17-24]. A single form of GPI is synthesized by all cells of the body, and abnormal forms of the enzyme are expressed in all tissues. However, because most disease variants result in enzyme instability, functional compromise occurs mainly in older RBCs [25].

Epidemiology and inheritance – Inheritance of GPI deficiency is autosomal recessive. Individuals who are heterozygous for a pathogenic variant in GPI have reduced GPI activity in RBCs but are hematologically normal without hemolysis. GPI deficiency is the second most common glycolytic enzyme disorder associated with hemolytic disease [26]. Since the first description of the disorder in 1968, fewer than 100 cases have been reported [19]. As with other glycolytic enzyme disorders, many more cases probably exist but are not published or listed in any rare disease registry.

Clinical features – The severity of hemolysis is quite variable. Hydrops fetalis with death in neonates has been reported [27,28]. Anemia and hyperbilirubinemia complicate the postnatal course in many patients [29]. Gallstones may develop. As with other congenital hemolytic anemias, the clinical course may be complicated by aplastic and hyperhemolytic episodes with infectious illness. In patients with hemolysis, RBC morphology is characterized by anisocytosis, poikilocytosis, polychromatophilia, and often nucleated RBCs. Transfusion-independent iron loading can occur [30].

Neuromuscular impairment (hypotonia, ataxia, dysarthria, intellectual disability) has occasionally been seen with some variants [19,31].

Publications from 2019 and 2022 reviewed the clinical and molecular features of individuals with GPI deficiency [32,33].

In the first review, involving 12 GPI-deficient individuals from 11 families (eight males, four females), the median age at diagnosis was 13 years (range, 1 to 51 years), and six new pathogenic variants in GPI were identified [32]. Anemia ranged from moderate to severe and improved with aging. Splenectomy, mainly performed in transfusion-dependent patients, ameliorated the anemia or extended the transfusion intervals. None of the patients had neurological impairment.

In the second review, involving 17 individuals, the median age at diagnosis was 5 years and the male to female ratio was 0.7:1 [33]. Severe neonatal jaundice occurred in 82 percent, and subtle neurological manifestations were seen in 13 percent. Homozygosity for the GPI exon 12 pathogenic variant c.1040G >A (p.R347H) was seen in 16 of the individuals (94 percent). Median hemoglobin was 6.3 g/dL, and the median mean corpuscular volume (MCV) was 130.2 fL. Splenectomy resulted in fewer transfusions.

Diagnosis – Diagnosis is made by documenting decreased RBC GPI activity on an enzymatic assay or detection of pathogenic variants of GPI in genetic testing [32].

Management – Chronic transfusions may be required. Splenectomy eliminates or reduces the transfusion requirement in most patients. Post-splenectomy hemoglobin concentrations are 8 to 10 g/dL. Similar to pyruvate kinase (PK)-deficiency, reticulocyte counts may increase dramatically (by 50 to 75 percent) postsplenectomy [34]. (See 'General principles of management' above.)

Phosphofructokinase (PFK) deficiency — Phosphofructokinase (PFK) catalyzes the phosphorylation of fructose-6-phosphate to fructose-1, 6-diphosphate, one of the rate limiting reactions of glycolysis (figure 1).

Pathophysiology – The PFK enzyme in RBCs is a tetrameric protein made up of varying combinations of muscle (M) type subunits and liver (L) type subunits [35-37]. The M type subunit is encoded by the PFKM gene on chromosome 1 [38,39]. The L type subunit is encoded by the PFKL gene on chromosome 21 [40]. The subunits are variably expressed in different tissues. Muscle and liver PFK are composed exclusively of M4 and L4 tetramers, respectively. PFK in RBCs contains equal amounts of M and L subtypes and all possible tetrameric variations (L4; L3M1; L2M2; L1M3; and M4) [37]. The variable structure of PFK in different tissues provides an explanation for the diversity of syndromes associated with deficiency states.

Epidemiology and inheritance – Inheritance of PFK deficiency is autosomal recessive. Prevalence depends on the clinical syndrome.

Clinical features – Diverse clinical syndromes can occur.

The first PFK-deficiency syndrome described was characterized by congenital nonspherocytic hemolytic disease and myopathy (Tarui's disease, glycogenosis type VII) [41]. At least 40 unrelated families have been identified with this very rare deficiency [42]. The myopathy is characterized by muscle fatigue and cramping with exercise and pathologically by increased muscle glycogen [43]. There is a mild compensated hemolytic anemia; the hemoglobin concentration can be normal or even increased.

A severe and fatal form of muscle PFK deficiency has been described in a preterm female infant, manifested at a corrected age of one month as floppy infant syndrome, congenital joint contracture, cleft palate, and duplication of the pelvicalyceal system [44]. She died at a corrected age of six months due to respiratory failure. An associated literature review of other infantile presentations found congenital hypotonia in 79 percent, arthrogryposis in 64 percent, encephalopathy in 36 percent, and cardiomyopathy in 21 percent.  

Myopathy and hemolytic disease both result from the total lack of M subunit expression. Biopsies of muscle reveal complete lack of PFK activity, while erythrocyte PFK activity is approximately 50 percent of normal. The RBC PFK in these patients is composed exclusively of L4 subunits [37,45]. The concentration of glycolytic intermediates proximal to PFK are increased, and those distal to the block are decreased. 2,3-BPG is decreased [46]; this presumably leads an unfavorable shift of the hemoglobin-oxygen affinity, thereby accounting for the mild erythrocytosis in some patients and absence of anemia despite shortened RBC survival in others.

PFK deficiency can also cause hemolysis without myopathy or with mild myopathic symptoms during ischemic exercise tolerance tests [47-49]. This syndrome is attributed to an unstable but catalytically active M subunit. Muscle cells are protected because of continued synthesis of the enzyme, whereas RBCs, which are incapable of protein synthesis, sustain early loss of enzyme activity [47].

Although myopathy without hemolysis has also been attributed to PFK deficiency, hemolytic disease may have been dismissed because of the absence of anemia related to the shift in hemoglobin-oxygen affinity [48]. Heterozygosity for deficiency in the L subunit is associated with approximately 50 percent PFK activity in RBCs, with no myopathic or hemolytic features [48,50,51].

Aldolase deficiency — Aldolase catalyzes the conversion of fructose-1, 6-diphosphate to dihydroxyacetone and glyceraldehyde-3-phosphate (figure 1).

Pathophysiology – Aldolase is a tetrameric protein; three tissue isoenzymes (A, B, and C) have been identified. Type A aldolase is the main isozyme in RBCs and muscle. It is encoded by the ALDOA gene located on chromosome 16. Various missense and nonsense mutations have been identified, each resulting in a thermolabile unstable enzyme [52-55].

Epidemiology and inheritance – Inheritance of aldolase deficiency is autosomal recessive. Aldolase deficiency is a very rare cause of hemolytic anemia that has been identified in seven kindreds.

Clinical features – Case reports have described various presentations in infants, children, and adults:

A child with mild hemolytic anemia, hepatomegaly with glycogen deposition, and psychomotor retardation [56].

Severe hemolytic anemia (hemoglobin 6 g/dL, 7 to 8 percent reticulocytes) without hepatomegaly or developmental delay [57].

Neonatal jaundice and jaundice during infancy, transfusion-dependent anemia, and myopathy with severe muscle weakness, exercise intolerance and rhabdomyolysis in association with fever and an upper respiratory infection [52].

Transfusion-dependent hemolytic anemia requiring splenectomy at age 3 years and myopathy with recurrent episodes of rhabdomyolysis [53].

Rhabdomyolysis following exercise or fever and chronic hemolytic anemia with high ferritin [58].

Triosephosphate isomerase (TPI) deficiency — Triosephosphate isomerase catalyzes the reversible isomerization of glyceraldehyde3-phosphate and dihydroxyacetone phosphate (figure 1).

Pathophysiology – TPI is encoded by a single structural gene (TPI1) located on the short arm of chromosome 12 [59]. There is only one TPI isozyme, and enzyme deficiency involves all body tissues. Enzyme activity is deceased in RBCs, leukocytes, muscle, and skin fibroblasts. Several different TPI pathogenic variants are recognized [60,61]. The enzyme abnormality in almost all cases is due to a G315C point mutation and a single amino acid substitution (Glu104Asp) that results in an unstable enzyme [60].

Studies in Drosophila of a new TPI1 pathogenic variant, R189Q, determined that this residue affects protein stability and coordinates the substrate-binding site with important catalytic residues [62]. Additional studies demonstrated that variants C41Y and E104D perturb the stability of the enzyme's quaternary structure, while variants I170V and V231M mainly disturb kinetic parameters, and variant G72A affects both enzyme stability and kinetics [63]. Additional Drosophila studies demonstrated that impaired TPI dimerization could elicit neurologic dysfunction via abnormal cycling of neuronal vesicles containing neurotransmitters [64].

Epidemiology and inheritance – Inheritance of TPI deficiency is autosomal recessive. Individuals who are heterozygous for a TPI1 pathogenic variant have 50 percent TPI activity in RBCs and are clinically unaffected. The prevalence of heterozygous TPI deficiency is relatively high (0.1 to 0.5 percent in White Americans and 5.5 percent in African Americans) [65]. Despite this estimate, fewer than 40 individuals with symptomatic disease have been identified [60]. The very low incidence of clinically significant homozygous TPI deficiency suggests incompatibility with fetal life.

Clinical features – TPI deficiency is a progressive, ultimately fatal multisystem disease. It presents in infancy or early childhood with chronic hemolytic anemia and neurologic features. Most affected individuals do not survive beyond early childhood [66]. Death from hemolytic anemia in the first week of life occurred in a sibling and a cousin of the patient described in the first reported case [67]. The degree of anemia is variable; there are no specific RBC morphologic abnormalities.

Neurologic features are progressive, including spasticity, hypotonia, motor retardation, weakness, and paraparesis [60]. One report described TPI deficiency with chronic hemolytic anemia in two male siblings, one of whom had hyperkinetic torsion dyskinesia, while the other had no neurological abnormalities [68-70]. In most cases, anemia and hyperbilirubinemia are noted at birth or during the first weeks of life [60,67].

A 2023 review of the literature and discussion of two cases described neonatal onset of hemolytic anemia, neurologic findings, susceptibility to infections, and respiratory failure, with the diagnosis made at approximately two years of age [71]. The affected individuals were homozygous for TPI1 variant E105D (c.315G>C). Although severely disabled, both patients received extensive supportive care including mechanical ventilation and were alive at the ages of seven and nine years. The literature review confirmed the newborn age of symptom onset, hemolytic anemia in all cases with a requirement for frequent blood transfusions, and neurologic symptoms (hypotonia, muscle weakness, muscle atrophy, delayed development milestones, loss of acquired functions); cardiomyopathy was absent. Increased susceptibility to infections was a common symptom, although no specific studies have addressed leukocyte function. Many patients died during infancy (from 21 months to 6 years), with one individual surviving to 20 years [70].

Diagnosis – Diagnosis is made by molecular testing. Biochemical TPI enzyme assays are not readily available. (See 'Genetic versus biochemical testing' above.)

Management – Most affected infants and children require periodic blood transfusions. Splenectomy appears to have no discernible benefit [67]. In a cell culture model of TPI deficiency, itavastatin and resveratrol increased triosephosphate isomerase protein levels, suggesting that impaired stability, rather than reduced catalytic activity, is a better predictor of disease severity [72]. These preliminary data may help understanding the complex disease pathogenesis and provide hints for therapeutic approaches, although further studies are needed.

Phosphoglycerate kinase (PGK) deficiency — Phosphoglycerate kinase (PGK) catalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate (figure 1).

Pathophysiology – This is one of two glycolytic reactions resulting in net adenosine triphosphate (ATP) generation from adenosine diphosphate (ADP). An alternative fate of 1,3-DPG is the formation of 2,3-DPG, a reaction catalyzed by 2,3-diphosphoglyceromutase (DPGM). 2,3-DPG is an important intermediate that enhances oxygen release from hemoglobin. (See "Structure and function of normal hemoglobins", section on 'Oxygen affinity'.)

PGK is encoded by a single structural gene (PGK1) on the X-chromosome [73]. Biochemical variants of PGK with abnormal kinetics and/or enzyme instability have been reported in several families, due to a variety of different missense mutations [74,75]. RBCs severely deficient in PGK predictably accumulate DHAP, have higher than normal concentrations of 2,3-DPG, and decreased concentrations of ATP.

Epidemiology and inheritance – Inheritance of PGK deficiency is unique among glycolytic enzymopathies in that it is X-linked [76]. Hereditary PGK deficiency is a rare cause of chronic hemolytic anemia [76].

Clinical features – Male hemizygotes with little or no enzyme activity are symptomatic with chronic hemolysis that can be severe, often requiring RBC transfusions [76-78]. In contrast, females, who are mosaic for the X chromosome, have a combination of normal and PGK-deficient RBCs, and there may be variable degrees of hemolysis [76,79]. Clinical exacerbations of hemolysis, most of which appear to be triggered by intercurrent infections, are responsible for recurrent episodes of jaundice.

Other reported cases include a new PGK1 pathogenic variant (I371K) resulting in multiple tissue involvement including hemolytic anemia, increased creatine kinase, respiratory distress, intellectual disability, and severe myopathy [80]. The enzyme showed highly perturbed catalytic properties combined with protein instability, thus accounting for the severe clinical expression of the disease

Another new variant, PGK-Barcelona, has been reported to cause chronic hemolytic anemia and progressive neurological impairment due to loss of enzyme thermal stability rather than reduced catalytic function [81]. In contrast, a mild clinical phenotype has been reported in a young male, and a literature review of 20 cases and 29 PGK1 variants found significant variability in clinical presentation, with two-thirds showing neurological symptoms and approximately one-half showing anemia or muscle symptoms [82].

Of far greater consequence than hemolysis is progressive neurologic deterioration. Some males experience apparent normal development until three to four years of age when motor regression, expressive aphasia, and emotional liability become apparent. Seizures and progressive extrapyramidal disease follow late in the first decade [76,77,83,84]. (See "Phosphoglycerate kinase deficiency and phosphoglycerate mutase deficiency", section on 'Clinical features'.)

Most PGK1 variants cause symptoms of both hemolysis and neurologic disease (PGK-Uppsala, PGK-Tokyo, PGK-Matsue, PGK-Michigan); however, there are exceptions. PGK-Shizuoka is characterized by hemolysis and muscle disease, while PGK-San Francisco has only hemolysis without other symptoms [85,86]. Another variant is characterized by neurologic and muscle disease with no hemolysis [87]. At the other extreme, recurrent exertional rhabdomyolysis producing kidney failure without associated neurologic or hematologic disease has been observed in PGK-Creteil [88]. The absence of hemolysis in this variant is confusing since PGK activity in RBCs was <3 percent of normal.

Management – Splenectomy obviates transfusion in most patients but does not fully correct the hemolytic process. A child with PGK deficiency was treated with hematopoietic stem cell transplant, with resolution of hemolysis and neurologic symptoms [89]. Additional aspects of management are presented separately. (See "Phosphoglycerate kinase deficiency and phosphoglycerate mutase deficiency", section on 'Phosphoglycerate kinase deficiency'.)

Disorders of the HMP shunt and glutathione metabolism — Almost all hemolytic episodes related to altered hexose monophosphate (HMP) shunt and glutathione metabolism are due to glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, another enzyme of the HMP shunt, 6-phosphogluconate dehydrogenase (6PGD), the closely linked reactions of glutathione metabolism (glutathione reductase [GSR], glutathione peroxidase [GPx]), and the glutathione synthetic pathway also are involved in protecting RBC against oxidant injury. Rare abnormalities in these enzymes have been reported in association with hemolysis.

HMP pathway — The HMP shunt pathway also known as the pentose phosphate pathway (PPP), is a side pathway of anaerobic glycolysis that starts with glucose-6-phosphate (G6P) and converts it to 6-phosphogluconate (6-PG) (figure 1). The HMP shunt metabolizes 5 to 10 percent of glucose in RBCs and protects the cells against oxidant injury. It is the only RBC source of reduced nicotinamide adenine dinucleotide phosphate (NADPH), a cofactor important in glutathione metabolism. NADPH serves as a cofactor for glutathione reductase, the enzyme that maintains glutathione in a reduced state. (See 'Glutathione metabolism' below.)

Glutathione metabolism — RBCs contain relatively high concentrations of reduced glutathione (GSH), a sulfhydryl containing tripeptide (glutamyl-cysteinyl-glycine) that functions as an intracellular reducing agent and protects RBCs from oxidant injury.

Oxidants such as superoxide anion (O2-) and hydrogen peroxide (H2O2) are produced by exogenous factors (drugs, infection) and also are formed within RBCs as a consequence of reactions of hemoglobin with oxygen. When these oxidants accumulate, they can oxidize hemoglobin and other proteins, leading to loss of function and RBC death.

Under normal circumstances, hemoglobin and other proteins do not get oxidized, since GSH, in conjunction with glutathione peroxidase (GPx), rapidly inactivates O2- and H2O2.

During the oxidant detoxification process, GSH is converted to oxidized glutathione (GSSG), and GSH levels fall. GSH levels must be maintained to protect against persistent oxidant injury, and this is accomplished by glutathione reductase (GSR), which catalyzes reduction of GSSG to GSH. This reaction requires the NADPH generated by G6PD in the first enzymatic reaction of the HMP shunt.

The tight coupling of the HMP shunt and glutathione metabolism is responsible for protecting intracellular proteins from oxidative assault.

RBCs actively synthesize glutathione in a simple two-step pathway (figure 1) in which gamma-glutamyl-cysteine synthetase (GCS) catalyzes formation of gamma-glutamyl-cysteine from glutamic acid and cysteine, and glutathione synthetase (GS) catalyzes formation of glutathione from gamma-glutamyl-cysteine and glycine.

Oxidized glutathione (GSSG) is reduced to glutathione (GSH) in the presence of NADPH by glutathione reductase (GSR) (figure 1) [90]. This enzyme requires flavin adenine dinucleotide (FAD) as a cofactor and, as a result, normal enzyme activity is dependent upon the dietary availability of the water soluble vitamin riboflavin (vitamin B2) [91]. (See "Overview of water-soluble vitamins", section on 'Vitamin B2 (riboflavin)'.)

G6PD deficiency — G6PD deficiency is discussed separately. (See "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Glutathione reductase (GSR) deficiency — Oxidized glutathione (GSSG) is reduced in the presence of NADPH by glutathione reductase (GSR) (figure 1).

Pathophysiology – GSR is encoded by the GSR gene. The GSR enzyme contains flavin adenine dinucleotide (FAD) as a prosthetic component, and as a result, normal enzyme activity is dependent on the dietary availability of riboflavin. Consequently, partial GSR deficiency is a relatively common feature of disorders that are compounded by suboptimal nutrition. The association between riboflavin induced GSR deficiency in most disease states is of no hematologic consequence [92].

Epidemiology and inheritance – Inheritance of GSR deficiency is unclear. Genetically determined GSR deficiency was documented in three siblings who were offspring of consanguineous parents [93]. A 2007 report from the same group described an infant with severe neonatal jaundice requiring exchange transfusion and phototherapy; she had biallelic variants in GSR [94]. Subsequently, there have been no new reported cases of hereditary GSR deficiency associated with hemolysis.

Clinical features – Despite near absence of erythrocyte GSR activity, the three reported siblings were hematologically normal except for episodes of hemolysis after the ingestion of fava beans. All three of the siblings acquired cataracts at an early age (24 to 32 years) [94].

Diagnosis – Genetic testing for GSR variants is available on RBC gene panels. (See 'Genetic versus biochemical testing' above.)

Glutathione (GSH) synthesis disorders — RBCs are capable of de novo GSH synthesis, which requires two critical enzymes (figure 1):

Gamma-glutamyl-cysteine synthetase (GCS), also called glutamate-cysteine ligase (GCL), catalyzes formation of gamma-glutamyl-cysteine from glutamic acid and cysteine.

Glutathione synthetase (GSS) catalyzes formation of GSH from glutamyl-cysteine and glycine.

In many tissues (but not RBCs) these two enzymes are part of the gamma glutamyl cycle, which is involved with the synthesis and degradation of GSH and also thought to have a role in amino acid transport across cell membranes. Hereditary hemolytic anemia characterized by reduced RBC GSH content occurs in patients with GCS or GSS deficiencies. The clinical picture of GCS or GSS deficiencies depends on the severity of enzyme deficiency and whether the gamma glutamyl cycle is affected in non-erythroid tissues [95].

All the glutathione synthesis disorders can cause 5-oxyproline accumulation, but systemic GSS deficiency causes the most severe metabolic acidosis [96]. (See 'Glutathione synthetase (GSS) deficiency' below.)

Gamma-glutamyl-cysteine synthetase (GCS) deficiency — GCS is also called gamma-glutamyl-cysteine ligase (GCL). It catalyzes the first step in GSH synthesis (figure 1).

Pathogenesis – Missense mutations have been reported in the GCLC and GCLM genes, which encode the two GCS subunits (heavy and light, respectively).

Epidemiology and inheritance – Inheritance of GCS deficiency is autosomal recessive. It is rare, with 10 individuals reported [97-99]. Their heterozygous relatives were unaffected.

Clinical features – Among 10 individuals with GCS deficiency and hemolysis, six had isolated hemolysis and four had hemolysis plus severe neurological disease [98-101]. The first two siblings described had mild chronic hemolytic anemia, intermittent jaundice, cholelithiasis, splenomegaly, severe neurologic dysfunction (spinocerebellar degeneration), and aminoaciduria [102,103]. GSH levels were approximately 5 percent of normal. Another patient was reported with markedly reduced GCS activity in RBCs, severely reduced GSH levels, and chronic hemolytic anemia but no neurologic disease [97].

An additional six children from two independent consanguineous families have been reported [99]; all presented with neonatal hemolytic anemia followed by mild chronic anemia but no neurological symptoms. They were all homozygous for GCLC c.1772G>A (S591N) and c.514T>A (S172T).

Diagnosis – Genetic testing for GCLC variants is available on RBC gene panels. (See 'Genetic versus biochemical testing' above.)

Management – There is no specific therapy for GCS deficiency. Supportive care should be similar to other congenital hemolytic disorders, including management of neonatal hyperbilirubinemia, transfusion support for aplastic crisis, periodic gallbladder ultrasound for bilirubin gallstones, and monitoring for iron overload.

Glutathione synthetase (GSS) deficiency — GSS catalyzes the second step in glutathione synthesis (formation of glutathione from glutamyl-cysteine and glycine) (figure 1).

Pathophysiology – GSS deficiency is caused by pathogenic variants in the GSS gene. Virtually no GSS activity is detected in homozygous-deficient individuals [102]. Acidosis is caused by the accumulation of 5-oxoproline, a metabolic product of gamma-glutamyl-cysteine. Abnormally large quantities of the dipeptide 5-oxoproline are produced because of the loss of feedback inhibition of gamma-glutamyl-cysteine synthetase by glutathione.

Epidemiology and inheritance – Inheritance of GSS deficiency is autosomal recessive. The disorder is rare.

Clinical features – GSS deficiency can cause isolated chronic hemolytic anemia or a generalized syndrome (due to enzyme deficiency in many tissues) characterized by mild hemolysis, severe metabolic acidosis, and neurologic deterioration.

Isolated hemolytic anemia has been described in several families [104-107]. Exposure to oxidant drugs and fava beans has resulted in temporary acceleration of hemolysis. Splenomegaly has been noted in approximately one-half of reported cases.

The second more generalized syndrome is characterized by mild hemolytic anemia, persistent metabolic acidosis presenting in the newborn period, and progressive cerebral and cerebellar degeneration [108]. Oxoprolinemia (increased 5-oxoproline, which can cause oxoprolinuria) can occur,

A severe case of GSS deficiency in a Japanese infant was characterized by hemolytic anemia, metabolic acidosis with 5-oxoprolinuria, progressive neurological symptoms, and recurrent bacterial infections [109]. An additional infant was reported with hemolytic anemia, metabolic acidosis, bilateral subependymal pseudocysts, increased echogenicity of the basal ganglia, and unilateral right femur agenesis [110]; the infant was homozygous for a previously unidentified variant in GSS (c.800G>A, R267Q). Additional severe cases have been reported with hemolytic anemia, metabolic acidosis, increased 5-oxoprolinemia, and respiratory distress, associated with two novel complex heterozygous pathogenic variants or with homozygosity for p.R125H (c.374G>A) [111,112]

Diagnosis – This disorder is suspected in patients with hemolytic anemia and markedly reduced RBC GSH content. Genetic testing for GSS variants is available on RBC gene panels. (See 'Genetic versus biochemical testing' above.)

Management – Therapy is rarely needed. Exposure to drugs and chemicals with oxidant potential should be avoided by individuals with chronic hemolytic anemia. Acetaminophen should be avoided in those with associated oxoprolinemia or oxoprolinuria [113]. In some cases, splenectomy has been effective in reducing anemia, although hemolysis may continue as manifested by persistent reticulocytosis [104]. (See 'General principles of management' above.)

Metabolic acidosis may occur in individuals with GSS deficiency and oxoprolinemia, and administration of an alkylating agent (oral sodium bicarbonate or citrate) may be needed [114]. Some clinicians have suggested vitamins C and E to be beneficial [115]. (See "Approach to the child with metabolic acidosis", section on 'Treatment' and "Approach to the adult with metabolic acidosis", section on 'Overview of therapy'.)

Abnormalities of purine and pyrimidine metabolism

Nucleotide metabolism — Mature RBCs are incapable of de novo purine or pyrimidine synthesis, although they contain many enzymes of nucleotide metabolism (figure 1). The RBC nucleotide salvage pathways predominantly function to supply adenosine to the RBC for use in generating adenosine triphosphate (ATP).

Initial interest in RBC nucleotide metabolism was stimulated by blood bank concerns related to ATP and 2,3-DPG loss during storage of RBCs. Several studies demonstrated that inosine, adenosine, and adenine each could minimize loss of organic phosphates and thereby improve viability of stored blood. These studies defined an important role for purine nucleotide metabolism in maintaining energy pools of stored RBC, and this has had a major impact on the science of transfusion medicine. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Collection and storage procedures'.)

In certain immune and metabolic disorders due to inborn errors of purine metabolism, RBCs share the same enzymatic deficiency without any adverse effect on RBC function or viability. The RBC enzyme abnormalities in these cases can serve as a marker of disease in other tissues, and in some cases, assay of enzyme activity in RBCs is used for diagnostic purposes [116]. The two most common disorders in which RBCs are used as this type of diagnostic tool are adenosine deaminase (ADA) deficiency associated with severe combined immune deficiency and purine nucleoside phosphorylase deficiency associated with impaired T-cell immunity [117,118].

In other cases, RBC purine and pyrimidine enzyme disorders have been associated with inherited hemolytic syndromes, and these cases have further identified the important role of nucleotide metabolism in mature RBCs. These disorders are discussed below.

Pyrimidine 5' nucleotidase (P5'N) deficiency — Ribosomal RNA in normal reticulocytes is degraded to 5' nucleotides. The enzyme P5'N further catalyzes the degradation of cytidine and uridine mononucleotides to the corresponding nucleoside and inorganic phosphate. Whereas the mononucleotides are impermeable to the RBC membrane, after metabolism by P5'N, the nucleosides can passively diffuse from the cell. P5'N thus rids maturing reticulocytes of pyrimidine degradation products of RNA without compromising the purine (adenine) nucleotide pool necessary for energy-dependent reactions.

Another enzyme, thymidylate nucleotidase, is thought to catalyze the degradation of thymidine monophosphate in a similar manner. This is supported by the observation that P5'N deficient cells exhibit brisk nucleotidase activity when thymidine and deoxyuridine monophosphates are used as substrates [119-121].

Pathophysiology – Normally, RBC nucleotides are almost entirely adenine nucleotides. However, in P5'N deficiency, up to 80 percent of the nucleotide pool may be pyrimidine nucleotides. The gene encoding P5'N (NT5C3A) is located on chromosome 7. Over 20 different pathogenic variants in NT5C3A have been reported [122].

Reticulocytes deficient in P5'N accumulate large quantities of cytidine and uridine compounds, increasing the total nucleotide pool to more than five times that in normal RBCs [119,123]. As a consequence of impaired ribosomal degradation, intracellular aggregates form in P5'N deficient cells, and these appear as basophilic stippling on Wright-stained peripheral blood smears (picture 1).

Cases of P5'N deficiency formerly were classified as "high ATP syndromes" owing to the erroneous assumption that the large amount of nucleotide was adenine phosphate rather than pyrimidine phosphate [124,125].

The P5'N enzyme is readily inactivated by heavy metals such as lead, and it has been proposed that the basophilic stippling in lead poisoning is secondary to acquired P5'N deficiency [126]. As blood lead levels approach 200 mcg/dL of packed RBCs, P5'N activity decreases to levels comparable to those associated with the homozygous deficiency state, intracellular pyrimidine nucleotides accumulate, and basophilic stippling can be demonstrated [119,127].

The molecular bases of P5'N deficiency have been investigated by studying the biochemical properties of the wild-type and 4 mutant forms of the enzyme [128]. All mutations were found to affect the catalytic properties of the P5'N enzyme and/or impair the protein stability, particularly D87V and N179S. In contrast, L131P and G230S show only moderate alterations in enzyme activity despite a substantial change in kinetic and thermostability parameters, suggesting that reductions in P5'N activity caused by mutations can be compensated.

Two cases of P5'N deficiency in brothers of Polish origin have been deeply studied by using genome, transcriptome, and functional analysis [129]. They were heterozygous for very rare pathogenic variant involving a deletion in NT5C3A (c.444_446delGTT), resulting in deletion of a single amino acid residue (p.F149del); this decreased enzymatic activity of P5'N and reduced the purine/pyrimidine ratio by 2.5-fold.

Epidemiology and inheritance – P5'N deficiency is an autosomal recessive disorder. Heterozygous individuals are hematologically unaffected; homozygous individuals with less than 5 to 10 percent of normal P5'N activity are affected. This is a rare disorder, yet it is the most common enzyme abnormality affecting nucleotide metabolism [26,120,122]. Over 60 patients representing a wide geographic distribution have been reported, with a predisposition for people of Mediterranean, Jewish, and African ancestry [120,130].

Clinical features – Affected individuals have lifelong mild to moderate hemolytic anemia associated with splenomegaly and intermittent jaundice. A unique finding on the blood smear is marked basophilic stippling (picture 1). (See 'CBC, blood smear, and hemolysis testing' above.)

Diagnosis – The high percentage of pyrimidine nucleotides in RBCs with P5'N deficiency is the basis for a simple screening test that uses ultraviolet spectroscopy to demonstrate a shift in the absorption spectrum of RBC lysates [131]. Genetic testing for NT5C3A variants is available on RBC gene panels. (See 'Genetic versus biochemical testing' above.)

Management – Transfusions usually are not required. Splenectomy is followed by a modest increase in hemoglobin concentration but affords no significant benefit [124,131,132].

Adenosine deaminase (ADA) excess — Adenosine is a common substrate for two different enzymes, adenosine kinase (ADK) and adenosine deaminase (ADA). The binding constant for adenosine is much lower for ADK than for ADA, and thus, metabolism normally proceeds through ADK, with phosphorylation of adenosine to form adenosine monophosphate (AMP) (figure 1). In the presence of plasma adenosine, ADK helps maintain the RBC adenine nucleotide pool [121,133]. The enzyme ADA catalyzes the deamination of adenosine to form inosine.

Pathogenesis – A pathogenic variant that causes hyperactive ADA and depletes adenine has been associated with hemolytic anemia in case reports [134]. ADA activity is increased by 60 to 100-fold [135]. Adenosine triphosphate (ATP) content in RBCs is reduced [135,136]. The decrease in adenine nucleotides presumably occurs because elevated ADA activity, despite the higher Km for adenosine, effectively competes with normal levels of ADK, thereby producing a relative deficiency of ADK activity [132,137]. The purified ADA enzyme exhibits normal biochemical properties, and the disorder appears to be due to excess production of a structurally normal enzyme [138,139]. The synthesis of ADA is directed by a gene on chromosome 20, but the specific genetic variant has not been identified.

In contrast with these rare patients with a marked excess of enzyme activity and hemolytic anemia, individuals with Diamond-Blackfan anemia (DBA) have a much smaller increase in enzyme activity (two- to fourfold) [140,141]. Assessing RBC ADA activity has been a screening test for DBA for over 20 years. Abnormal RBC ADA activity should be evaluated by genetic testing. (See "Diamond-Blackfan anemia".)

In contrast to ADA excess, hereditary ADA deficiency is associated with autosomal recessive severe combined immunodeficiency (SCID). Since RBCs are also deficient, RBC ADA assays can be used for diagnosis. RBC adenine nucleotide content is increased in severe ADA deficiency, but this has no adverse effects on RBCs and there is no anemia. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)

Epidemiology and inheritance – Hyperactive ADA activity is autosomal dominant [135]. It is rare and has been described in a few families including a large kindred of English-Irish ancestry and in a Japanese family [136].

Clinical features – Clinical features include mild to moderate anemia (anemia is very mild in most individuals), reticulocytosis, and hyperbilirubinemia. No other tissues share in enzyme excess, and there are no other systemic effects. There are no distinguishing clinical, hematologic, or morphologic features.

Diagnosis – The specific diagnosis can be suspected if RBC ADA activity is markedly increased.

Management – Usually no specific therapy is indicated since anemia is often mild.

Adenylate kinase (AK) deficiency — AK catalyzes the interconversion of adenine nucleotides (AMP+ATP → 2 ADP) (figure 1).

Pathogenesis – In RBCs, AMP is formed in two reactions: the ADK-mediated phosphorylation of adenosine and the APRT (adenine phosphoribosyltransferase)-mediated phosphorylation of PRPP (phosphoribosyl diphosphate). AK is the enzyme reaction in mature RBC that can convert AMP to ADP, and thus it appears to have a critical role in salvaging AMP and protecting the adenine nucleotide pool [142]. There are three isozymes: AK1, AK2, and AK3 [143]; AK1 is the isozyme in RBCs, muscle and brain. In cases of AK deficiency with chronic hemolysis, molecular analysis reveals missense mutations, nonsense mutations, and/or deletions [18,143-146].

Epidemiology and inheritance – Adenylate kinase deficiency is autosomal recessive. There are no hematologic abnormalities associated with heterozygous AK deficiency. AK deficiency has been described in a few different kindred distributed worldwide [142,144-150].

Clinical features – A moderate to severe chronic nonspherocytic hemolytic anemia has been reported in almost all affected individuals [1]. Developmental delay has been reported in some cases with severe erythrocyte AK deficiency [144,145,147,148]; this may reflect that AK1 is the isozyme in both RBC and brain.

Diagnosis – RBC gene panels include AK1 as a target gene. (See 'Genetic versus biochemical testing' above.)

Management – Splenectomy is sometimes beneficial [148,151]. (See 'General principles of management' above.)

LIKELY CLINICALLY INSIGNIFICANT

Glycolytic enzymopathies of doubtful clinical significance — Hemolysis has been associated with deficiencies of other glycolytic enzymes, but the causal relationship between enzymopathy and reported hematologic disturbances is far from clear. These enzyme abnormalities include [26]:

Glyceraldehyde-3-phosphate dehydrogenase (G3PD) deficiency

2,3-diphosphoglyceromutase (2,3-DPGM) deficiency

Enolase deficiency

Lactate dehydrogenase (LDH) deficiency

Diphosphoglyceromutase (DPGM) deficiency does not cause hemolysis but is associated with low RBC 2,3 DPG, a left shifted oxygen dissociation curve, and compensatory erythrocytosis [152]. In most cases, this is an autosomal recessive disorder. (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera".)

6-phosphogluconate dehydrogenase (6PGD) deficiency — 6PGD (not to be confused with glucose-6-phosphate dehydrogenase [G6PD]) catalyzes the conversion of 6-phosphogluconate to pentose-5-phosphate and carbon dioxide, which is coupled to the generation of NADPH from NADP. 6PGD is another source of NADPH in the RBC.

Deficiency of 6PGD is well documented, although it appears to have little or no significance for RBC viability. Presumably this reflects the fact that NADPH is generated by the proximal enzyme, G6PD, suggesting that the second dehydrogenase may not be necessary for cell integrity.

Glutathione peroxidase (GPx) deficiency — Glutathione peroxidase (GPx) catalyzes the oxidation of reduced glutathione (GSH) by peroxides, including hydrogen peroxide and organic hydroperoxides (figure 1). GPx is only one of the cellular mechanisms available to detoxify peroxides, and under physiologic conditions, catalase and non-enzymatic reduction of oxidants by GSH also may be important for oxidant detoxification. (See 'Glutathione metabolism' above.)

There is a general consensus that GPx deficiency is probably not a cause of hemolysis or other hematologic problems, as many healthy individuals, particularly those of Jewish or Mediterranean ancestry, have reduced GPx activity without evidence of hemolysis [153]. Low GPx activity without hemolysis has also been observed in healthy people with Selenium (Se) deficiency (Se being an integral cofactor for GPx) [154]. From a clinical perspective, because of the questionable role of GPx, any patient with hemolytic anemia and reduced GPx activity should be extensively evaluated for other causes of hemolysis.

Rare cases of hemolysis in association with moderate deficiency of erythrocyte GPx activity were reported years ago in adults and children [155]. One of the most persuasive was that of a 9 month-old girl with chronic nonspherocytic hemolytic anemia and GPx activity of 17 percent, while her hematologically normal parents had GPx activity of 51 to 66 percent [156]. It is not known whether this specific enzyme defect was responsible for the patient's chronic hemolytic anemia.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)

SUMMARY AND RECOMMENDATIONS

Function of RBC metabolic enzymes – RBCs lack nuclei, ribosomes, and mitochondria, yet they survive in the circulation and deliver oxygen to peripheral tissues for 100 to 120 days. Specialized metabolic pathways (figure 1) produce adenosine triphosphate (ATP) and generate reduced glutathione that protects RBCs from oxidative damage. Genes in these pathways are listed above. (See 'Overview of RBC metabolism' above and 'Genetics (list of genes)' above.)

When to suspect – Hereditary hemolytic anemia due to a RBC enzyme deficiency may be suspected in a child or adult with Coombs-negative hemolysis after exclusion of other hemolytic anemias. Most of these anemias have findings associated with chronic hemolysis; some have syndromic features. The blood smear is typically unremarkable, with poikilocytosis and polychromasia (due to reticulocytosis). Heinz bodies can form with oxidant injury. Basophilic stippling (picture 1) may be present in pyrimidine 5' nucleotidase (P5'N) deficiency. (See 'When to suspect' above and 'CBC, blood smear, and hemolysis testing' above and 'Exclude other hemolytic anemias' above.)

Diagnostic testing – Genetic and biochemical testing can both be used for diagnosis and are often complementary (table 2). Resources for obtaining testing are listed above. (See 'Genetic versus biochemical testing' above and 'Where to obtain specialized testing' above.)

Management – Management is largely supportive, with transfusion if needed for severe anemia. For chronic hemolysis, we suggest folic acid (Grade 2C). A typical dose is 1 mg daily or a multivitamin containing folic acid. Medications and substances with oxidant potential are avoided, especially for deficiencies in glutathione metabolism. Monitoring for iron overload and pigment gallstones may be appropriate. Splenectomy is reserved for severe cases. Individuals with increased 5-oxoproline may require bicarbonate, citrate, or lactate to control metabolic acidosis. (See 'General principles of management' above and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Management' and "Approach to the child with metabolic acidosis", section on 'Treatment' and "Approach to the adult with metabolic acidosis", section on 'Overview of therapy'.)

Specific disorders – Disorders are summarized in the table (table 1) and discussed above.

Glycolysis – Disorders of glycolysis (glucose metabolism) include pyruvate kinase (PK) deficiency, hexokinase (HK) deficiency, glucosephosphate isomerase (GPI) deficiency, phosphofructokinase (PFK) deficiency, aldolase deficiency, triosephosphate isomerase (TPI) deficiency, and phosphoglycerate kinase (PGK) deficiency. (See 'Disorders of glycolysis' above and "Pyruvate kinase deficiency".)

Hexose monophosphate (HMP) shunt and glutathione metabolism – Disorders of the HMP shunt and glutathione metabolism include glucose-6-phosphate dehydrogenase (G6PD) deficiency, glutathione reductase (GSR) deficiency, gamma-glutamyl-cysteine synthetase (GCS) deficiency, and glutathione synthetase (GSS) deficiency. (See 'Disorders of the HMP shunt and glutathione metabolism' above and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Nucleotide metabolism – Disorders of purine and pyrimidine metabolism include P5'N deficiency, adenosine deaminase (ADA) excess, and adenylate kinase (AK) deficiency. (See 'Abnormalities of purine and pyrimidine metabolism' above.)

Questionable clinical significance – Certain glycolytic disorders, as well as 6-phosphogluconate dehydrogenase (6PGD) deficiency and glutathione peroxidase (GPx) deficiency, do not appear to reproducibly cause hemolytic anemia. (See 'Likely clinically insignificant' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

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Topic 7128 Version 26.0

References

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