Glucose phosphate isomerase deficiency demasked by whole-genome sequencing: a case report.

BACKGROUND: Glucose-6-phosphate isomerase deficiency is a rare genetic disorder causing hereditary nonspherocytic hemolytic anemia. It is the second most common glycolytic enzymopathy in red blood cells. About 90 cases are reported worldwide, with symptoms including chronic hemolytic anemia, jaundice, splenomegaly, gallstones, cholecystitis, and in severe cases, neurological impairments, hydrops fetalis, and neonatal death. CASE PRESENTATION: This paper details the case of the first Danish patient diagnosed with glucose-6-phosphate isomerase deficiency. The patient, a 27-year-old white female, suffered from lifelong anemia of unknown origin for decades. Diagnosis was established through whole-genome sequencing, which identified two GPI missense variants: the previously documented variant p.(Thr224Met) and a newly discovered variant p.(Tyr341Cys). The pathogenicity of these variants was verified enzymatically. CONCLUSIONS: Whole-genome sequencing stands as a potent tool for identifying hereditary anemias, ensuring optimal management strategies.

Rare hereditary red blood cell enzymopathies associated with hemolytic anemia - pathophysiology, clinical aspects, and laboratory diagnosis.

Hereditary red blood cell enzymopathies are genetic disorders affecting genes encoding red blood cell enzymes. They cause a specific type of anemia designated hereditary nonspherocytic hemolytic anemia (HNSHA). Enzymopathies affect cellular metabolism, which, in the red cell, mainly consists of anaerobic glycolysis, the hexose monophosphate shunt, glutathione metabolism, and nucleotide metabolism. Enzymopathies are commonly associated with normocytic normochromic hemolytic anemia. In contrast to other hereditary red cell disorders such as membrane disorders or hemoglobinopathies, the morphology of the red blood cell shows no specific abnormalities. Diagnosis is based on detection of reduced specific enzyme activity and molecular characterization of the defect on the DNA level. The most common enzyme disorders are deficiencies of glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PK). However, there are a number of other enzyme disorders, often much less known, causing HNSHA. These disorders are rare and often underdiagnosed, and the purpose of this review. In this brief review, we provide an overview of clinically relevant enzymes, their function in red cell metabolism, and key aspects of laboratory diagnosis.