Red Cell Glycolytic Enzyme Disorders Caused by Mutations: An Update

Abstract

Glycolysis is one of the principle pathways of ATP generation in cells and is present in all cell tissues; in erythrocytes, glycolysis is the only pathway for ATP synthesis since mature red cells lack the internal structures necessary to produce the energy vital for life. Red cell deficiencies have been detected in all erythrocyte glycolytic pathways, although their frequencies differ owing to diverse causes, such as the affected enzyme and severity of clinical manifestations. The number of enzyme deficiencies known is endless. The most frequent glycolysis abnormality is pyruvate kinase deficiency, since around 500 cases are known, the first of which was reported in 1961. However, only approximately 200 cases were due to mutations. In contrast, only one case of phosphoglycerate mutase BB type mutation, described in 2003, has been detected. Most mutations are located in the coding sequences of genes, while others, missense, deletions, insertions, splice defects, premature stop codons and promoter mutations, are also frequent. Understanding of the crystal structure of enzymes permits molecular modelling studies which, in turn, reveal how mutations can affect enzyme structure and function.

Diagnostic approaches for inherited hemolytic anemia in the genetic era

“…PK deficiencies are caused by PKLR mutations and are the most common cause of congenital non-spherocytic HA. Over 200 PKLR mutations have been described [6566]. Up to 70% of PK-deficient alleles carry a missense mutation followed by splicing and stop codon mutations (13% and 5%, respectively; www.lovd.nl/pklr) [50].…”

Deficiency of Nicotinamide Mononucleotide Adenylyltransferase 3 (Nmnat3) Causes Hemolytic Anemia by Altering the Glycolytic Flow in Mature Erythrocytes

“…It is well known that some of metabolic enzyme deficiencies can cause congenital hemolytic anemia in humans (49). Nmnat3 gt/gt mice exhibit a phenotype very similar to that of pyruvate kinase (PK)-deficient mice (50,51).…”

An infant with chronic hemolytic anemia

“…It is observed considerably rarely, although it is the second most common glycolytic enzyme disease following piruvate kinase deficiency (3). About 50 cases have been reported in the literature, though its frequency has not been clarified exactly (4). Glucose 6 phosphate which is increased because of deficiency of the enzyme inhibits hexokinase enzyme which transforms glucose to glucose 6 phosphate with negative feedback and thus the glycolysis and hexose monophosphate pathway is supressed.…”