A Novel Pathogenic Sense Variant in Exon 7 of the HK1 Gene in a Patient with Hexokinase Deficiency and Gilbert Syndrome

Abstract

Background: Hexokinase (HK) deficiency is a rare autosomal recessively inherited disease manifested by chronic nonspherocytic hemolytic anemia. Most patients present with a mild to severe course of the disease (fetal hydrocephalus, neonatal hyperbilirubinemia, severe anemia). We reviewed 37 cases of patients with hexokinase deficiency described so far, focusing on the severity of the disease, clinical presentation, treatment applied, and genetic test results.

Methods: We present a 10-year-old girl who initially presented with symptoms of weakness, excessive fatigue, and yellowing of the skin and sclerae. Genetic testing detected the (TA)7 variant in both alleles of the UGT1A1 gene and diagnosed Gilbert's disease. In the follow-up, red cell hemolysis was observed. The diagnosis was extended, and tests for red cell enzymopathy were performed and a reduced level of hexokinase-0.65 IU/gHb (normal 0.78-1.57) was found. Next-generation sequencing revealed a new sense-change variant in exon 7 in the hexokinase gene not previously reported in databases.

Results: Up to this date, only around 37 cases of hexokinase deficiency associated with hereditary nonspherocytic hemolytic anemia have been documented around the world. Diagnosing hexokinase deficiency involves clinical evaluation, laboratory testing, and genetic analysis. Management focuses on treating symptoms and preventing complications; there is no cure for the underlying enzyme deficiency. In patients with severe anemia, the treatment is multiple blood transfusions followed by iron chelation therapy.

Conclusions: Understanding and diagnosing hexokinase deficiency is critical for providing appropriate care and improving the quality of life for affected individuals.

Keywords: HK1 gene; children; hemolytic anemia; hexokinase deficiency; next-generation sequencing.