Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• British journal of haematology, 2024-05, Vol.204 (5), p.2040-2048

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2024

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Summary 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. The hexokinase 1 gene (HK1) encodes the hexokinase 1 enzyme, which plays a key role in red blood cell energy production. Biallelic pathogenic variants in HK1 cause hexokinase 1 deficiency and hereditary non‐spherocytic haemolytic anaemia (HNSHA). The clinical phenotype of hexokinase 1 (HK1)‐related HNSHA varies from mild chronic haemolytic anaemia to severe infantile‐onset disease. HK1 promoter variant c.‐193A>G combined with intragenic loss‐of‐function variants, such as c.372+1G>A, c.2361_2362del or c.2599C>T, is associated with predominantly mild HNSHA. Homozygous HK1 c.2599C>T p.(His867Tyr) missense variant results in severely hampered HK1 enzyme function and infantile‐onset HNSHA requiring regular red blood cell transfusions.