{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:51:52Z","timestamp":1793119912702,"version":"4.5.0"},"reference-count":33,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,7]],"date-time":"2024-12-07T00:00:00Z","timestamp":1733529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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\u2019s 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\u20140.65 IU\/gHb (normal 0.78\u20131.57) 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.<\/jats:p>","DOI":"10.3390\/genes15121576","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T06:16:14Z","timestamp":1733724974000},"page":"1576","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Novel Pathogenic Sense Variant in Exon 7 of the HK1 Gene in a Patient with Hexokinase Deficiency and Gilbert Syndrome"],"prefix":"10.3390","volume":"15","author":[{"given":"Magdalena","family":"Bartnik","sequence":"first","affiliation":[{"name":"Department of Paediatrics Hemato-Oncology and Paediatric Gastroenterology, Pomeranian Medical University, 70-204 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2104-9386","authenticated-orcid":false,"given":"Weronika","family":"Pawlik","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Hemato-Oncology and Paediatric Gastroenterology, Pomeranian Medical University, 70-204 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Burzy\u0144ska","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 01-447 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad","family":"Wasilewski","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 01-447 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u017cbieta","family":"Kamie\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Hemato-Oncology and Paediatric Gastroenterology, Pomeranian Medical University, 70-204 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Urasi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Hemato-Oncology and Paediatric Gastroenterology, Pomeranian Medical University, 70-204 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,7]]},"reference":[{"key":"ref_1","unstructured":"Nelson, D.L., and Cox, M.M. (2017). Lehninger Principles of Biochemistry, W.H. Freeman. [7th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1242\/jeb.00241","article-title":"Isozymes of mammalian hexokinase: Structure, subcellular localization and metabolic function","volume":"206","author":"Wilson","year":"2003","journal-title":"J. Exp. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4034","DOI":"10.1182\/blood-2005-04-1622","article-title":"The energy-less red blood cell is lost: Erythrocyte enzyme abnormalities of glycolysis","volume":"106","year":"2005","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0167-4781(00)00147-0","article-title":"Structure of the 5\u2032 region of the human hexokinase type I (HKI) gene and identification of an additional testis-specific HKI mRNA","volume":"1493","author":"Andreoni","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1182\/blood-2002-06-1851","article-title":"HK Utrecht: Missense mutation in the active site of human hexokinase associated with hexokinase deficiency and severe nonspherocytic hemolytic anemia","volume":"101","author":"Rijksen","year":"2003","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Choi, Y., Sims, G.E., Murphy, S., Miller, J.R., and Chan, A.P. (2012). Predicting the functional effect of amino acid substitutions and indels. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046688"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1056\/NEJM196701052760101","article-title":"Hereditary hemolytic anemia with hexokinase deficiency. Role of hexokinase in erythrocyte aging","volume":"276","author":"Valentine","year":"1967","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1172\/JCI106165","article-title":"Hemolytic anemia with impaired hexokinase activity","volume":"48","author":"Keitt","year":"1969","journal-title":"J. Clin. Investig."},{"key":"ref_11","first-page":"1977","article-title":"Hexokinase deficiency in hemolytic anemia","volume":"46","author":"Moser","year":"1970","journal-title":"Die Med. Welt"},{"key":"ref_12","first-page":"593","article-title":"Congenital nonspherocytic hemolytic anemia associated with an unusual erythrocyte hexokinase abnormality","volume":"76","author":"Necheles","year":"1970","journal-title":"J. Lab. Clin. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1007\/BF01496345","article-title":"Hemolytic anemia and hexokinase deficiency associated with malformations","volume":"50","author":"Goebel","year":"1972","journal-title":"Klin. Wochenschr."},{"key":"ref_14","first-page":"628a","article-title":"Hexokinase Hamilton: An enzyme variant with abnormal Km for adenosine triphosphate (ATP) in non-spherocytic hemolytic anemia","volume":"23","author":"Semenuk","year":"1975","journal-title":"Clin. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1172\/JCI109129","article-title":"Human erythrocyte hexokinase deficiency: Characterization of a mutant enzyme with abnormal regulatory properties","volume":"62","author":"Rijksen","year":"1978","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1182\/blood.V51.1.111.111","article-title":"Congenital nonspherocytic hemolytic anemia with an unstable hexokinase variant","volume":"51","author":"Board","year":"1978","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1182\/blood.V51.5.935.935","article-title":"Hereditary nonspherocytic hemolytic anemia and hexokinase deficiency","volume":"51","author":"Beutler","year":"1978","journal-title":"Blood"},{"key":"ref_18","first-page":"636","article-title":"Congenital hemolytic anemia due to hexokinase deficiency","volume":"132","author":"Gilsanz","year":"1978","journal-title":"Am. J. Dis. Child."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/j.1600-0609.1979.tb02799.x","article-title":"Hexokinase deficiency in erythrocytes: A new variant in 5 members of a Finnish family","volume":"22","author":"Siimes","year":"1979","journal-title":"Scand. J. Haematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1111\/j.1365-2141.1980.tb06010.x","article-title":"Non-spherocytic haemolytic anaemia in mother and son associated with hexokinase deficiency","volume":"46","author":"Newman","year":"1980","journal-title":"Br. J. Haematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/ajh.2830100202","article-title":"Hexokinase \u2018New Hyde Park\u2019: A low activity erythrocyte isozyme in a Chinese kindred","volume":"10","author":"Paglia","year":"1981","journal-title":"Am. J. Hematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1182\/blood.V61.1.12.12","article-title":"Generalized hexokinase deficiency in the blood cells of a patient with nonspherocytic hemolytic anemia","volume":"61","author":"Rijksen","year":"1983","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1182\/blood.V66.3.690.690","article-title":"Hereditary nonspherocytic hemolytic anemia due to a new hexokinase variant with reduced stability","volume":"66","author":"Magnani","year":"1985","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1365-2141.1985.tb04058.x","article-title":"Human erythrocyte hexokinase deficiency: A new variant with abnormal kinetic properties","volume":"61","author":"Magnani","year":"1985","journal-title":"Br. J. Haematol."},{"key":"ref_25","first-page":"20","article-title":"Severe hexokinase deficiency as a cause of hemolytic anemia, periventricular leucomalacia and intrauterine death of the fetus","volume":"90","author":"Kanno","year":"1997","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.3324\/haematol.2008.002881","article-title":"First mutation in the red blood cell-specific promoter of hexokinase combined with a novel missense mutation causes hexokinase deficiency and mild chronic hemolysis","volume":"94","author":"Kersting","year":"2009","journal-title":"Haematologica"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1182\/blood-2016-03-702860","article-title":"Allogeneic bone marrow transplantation for treatment of severe hemolytic anemia attributable to hexokinase deficiency","volume":"128","author":"Khazal","year":"2016","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.bcmd.2016.04.002","article-title":"Molecular characterization of six new cases of red blood cell hexokinase deficiency yields four novel mutations in HK1","volume":"59","author":"Koralkova","year":"2016","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_29","first-page":"2478","article-title":"A Case Report of Congenital Non-spherocytic Hemolytic Anemia in a Patient from India","volume":"10","author":"Sonaye","year":"2018","journal-title":"Cureus"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/bjh.15981","article-title":"A nonsense variant in the Hexokinase 1 gene (HK1) causing severe non-spherocytic haemolytic anaemia: Genetic analysis exemplifies ambiguity due to multiple Isoforms","volume":"186","author":"Jamwal","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1136\/jclinpath-2020-206960","article-title":"Novel pathogenic variant c.2714C>A (p. Thr905Lys) in the HK1 gene causing severe haemolytic anaemia with developmental delay in an Indian family","volume":"74","author":"Dongerdiye","year":"2021","journal-title":"J. Clin. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/cge.14058","article-title":"HK1 haemolytic anaemia in association with a neurological phenotype and co-existing CEP290 Meckel-Gruber in a Romani family","volume":"101","author":"Sasaki","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1111\/bjh.19368","article-title":"Biallelic hexokinase 1 (HK1) variants causative of non-spherocytic haemolytic anaemia: A case series with emphasis on the HK1 promoter variant and literature review","volume":"204","author":"Ukonmaanaho","year":"2024","journal-title":"Br. J. Haematol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/12\/1576\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:49:23Z","timestamp":1760114963000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/12\/1576"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,7]]},"references-count":33,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["genes15121576"],"URL":"https:\/\/doi.org\/10.3390\/genes15121576","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,7]]}}}