Bisphosphoglycerate Mutase Deficiency
Bisphosphoglycerate mutase (BPGM) regulates the concentration of 2,3-BPG in RBCs. 2,3-BPG is an important modifier of RBC oxygen delivery. 2,3-BPG binds to the hemoglobin tetramer and allosterically converts hemoglobin to a low oxygen affinity state, resulting in a rightward shift of the oxygen dissociation curve. BPGM is a multifunctional enzyme with both synthase and phosphatase activity. The synthase activity of BPGM converts 1,3-bisphosphoglycerate to 2,3 BPG, which is then metabolized to 3-phosphoglycerate (3-PGA), an intermediate of the glycolytic pathway, by BPGM-phosphatase (see Fig. 1). Deficiency of BPGM results in decreased levels of 2,3-BPG. The consequent left shift of the oxygen dissociation curve increases hemoglobin affinity for oxygen, thus resulting in decreased delivery of oxygen into the peripheral tissues and compensatory erythrocytosis.
Fig1. PRINCIPAL COMPONENTS OF THE ERYTHROCYTE METABOLISM WITH CLINICAL RELEVANCE. Shown are glycolysis, glutathione production (purple shaded area), pentose shunt (orange shaded area), and Rapoport-Luebering shunt (blue shaded area). 1,3-BPG, 1,3-bisphosphoglycerate; 2,3-BPG, 2,3-bisphosphoglycerate; 6PG, 6-phosphogluconate; ADP, adenosine diphosphate; ATP, adenosine triphosphate; DHAP, dihydroxy acetone phosphate; GSH, reduced glutathione; GSSG, oxidized glutathione; NAD, oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; NADP, oxidized form of nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate.
BPGM deficiency is rare and only two families have been comprehensively studied. In a family in France, four siblings were compound heterozygotes for two different BPGM mutations and had erythrocytosis, markedly decreased 2,3-BPG levels and undetectable BPGM activity. Some of their heterozygote relatives had a milder decrease of 2,3-BPG levels and a mild erythrocytosis. Other affected individuals have also been reported, although they have not have been as well characterized.
Cytochrome b5 Reductase Deficiency
b5R deficiency can cause erythrocytosis in association with chronic methemoglobinemia; this entity is described below.
Prolyl Hydroxylase 2 Deficiency
Prolyl hydroxylase 2 is part of the oxygen sensing pathway regulating HIFs. This enzyme is the principal component of hypoxia sensing, binds to alpha subunits of HIFs and initiates their degradation, and thus down regulates HIF-regulated genes including erythropoietin. Loss-of-function mutations of the gene encoding prolyl hydroxylase 2, EGLN1, cause dominantly inherited erythrocytosis. Mutations of other genes in this pathway including von Hippel-Lindau (VHL) and EPAS1 mutations (encodes HIF2α) also cause congenital erythrocytosis.
