Biallelic hexokinase 1 (HK1) variants causative of non-spherocytic haemolytic anaemia: A case series with emphasis on the HK1 promoter variant and literature review

Elli-Maija Ukonmaanaho*, Silvia Dell'Anna, Anna Hakonen, Ulla Wartiovaara-Kautto, Sakari Kakko, Minke A E Rab, Brigitte van Oirschot, Minna Kraatari-Tiri, Richard van Wijk, Elisa Rahikkala

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The hexokinase (HK) enzyme plays a key role in red blood cell energy production. Hereditary non-spherocytic haemolytic anaemia (HNSHA) caused by HK deficiency is a rare disorder with only 12 different disease-associated variants identified. Here, we describe the clinical features and genotypes of four previously unreported patients with hexokinase 1 (HK1)-related HNSHA, yielding two novel truncating HK1 variants. The patients' phenotypes varied from mild chronic haemolytic anaemia to severe infantile-onset transfusion-dependent anaemia. Three of the patients had mild haemolytic disease caused by the common HK1 promoter c.-193A>G variant combined with an intragenic HK1 variant, emphasizing the importance of including this promoter variant in the haemolytic disease gene panels. HK activity was normal in a severely affected patient with a homozygous HK1 c.2599C>T, p.(His867Tyr) variant, but the affinity for ATP was reduced, hampering the HK function. In cases of HNSHA, kinetic studies should be considered in the functional studies of HK. We reviewed the literature of previously published patients to provide better insight into this rare disease and add to the understanding of genotype-phenotype correlation.

Original languageEnglish
Pages (from-to)2040-2048
Number of pages9
JournalBritish Journal of Haematology
Volume204
Issue number5
Early online date28 Feb 2024
DOIs
Publication statusPublished - May 2024

Keywords

  • anaemia
  • haemolysis
  • hexokinase deficiency
  • HK1
  • promoter variant

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