ORPHA: 90031;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q22.1 | Hemolytic anemia due to hexokinase deficiency | 235700 | Autosomal recessive | 3 | HK1 | 142600 |
A number sign (#) is used with this entry because nonspherocytic hemolytic anemia due to hexokinase deficiency is caused by homozygous or compound heterozygous mutation in the HK1 gene (142600) on chromosome 10q22.
Hexokinase deficiency is an autosomal recessive disorder characterized by early-onset severe hemolytic anemia (summary by van Wijk et al., 2003).
Valentine et al. (1967) described a child with anemia present from birth and deficiency of red cell hexokinase. The father and one sib had low levels. The mother's level was also low but within the range of normal. The deficiency apparently did not involve leukocytes and platelets and was different from the hexokinase deficiency identified in Fanconi pancytopenia (227650). Necheles et al. (1970) found, however, associated deficiency of leukocyte hexokinase.
Rijksen and Staal (1978) studied a patient with hemolytic anemia due to hexokinase deficiency and showed that the mutant enzyme had abnormal electrophoretic properties and abnormal behavior with respect to its regulation by glucose-1,6-diphosphate and inorganic phosphate. They proposed that there are two different hexokinases type I in red cells, only one of which was mutant in this case.
Rijksen et al. (1983) reported a girl, born of consanguineous parents, with neonatal jaundice and transfusion-dependent hemolytic anemia. Residual HK1 activity in the patient's red cells and platelets was about 25% of normal, consistent with hexokinase deficiency. In lymphocytes, HK activity was normal; HK1 was low but the deficiency was compensated by HK3 (142570). The parents and 3 sibs were apparent heterozygotes, as demonstrated by 50 to 67% residual activity in their red cells, but they had no clinical signs of hexokinase deficiency. The patient's mutant enzyme showed a 2-fold decrease in affinity for Mg-ATP2 and a markedly decreased affinity for the inhibitor glucose-1,6-diphosphate.
Paglia et al. (1981) found a low activity isozyme of red cell hexokinase in a Chinese boy with chronic hemolytic anemia. Because of subtle differences between the hexokinases of the parents, it was proposed that the proband might be a compound heterozygote.
The transmission pattern of hemolytic anemia due to hexokinase deficiency in the families reported by Rijksen et al. (1983) and later by van Wijk et al. (2003) was consistent with autosomal recessive inheritance.
Bianchi and Magnani (1995) reported the molecular characterization of the defect in HK1 in a patient with hemolytic anemia due to hexokinase deficiency. PCR amplification and sequence of the cDNA revealed compound heterozygosity for a deletion and a single nucleotide substitution. The 96-bp deletion (142600.0001) involved nucleotides 577 to 672 of their cDNA sequence and was found in the cDNA of none of 14 unrelated normal subjects. The sequence of the HK1 allele without deletion showed a T-to-C transition of nucleotide 1677, which caused the amino acid change leu529-to-ser (142600.0002). The substitution was not found in 10 normal controls. Bianchi and Magnani (1995) stated that to their knowledge only 14 cases had been described, 2 of which had been studied in their laboratory: HK-Melzo and HK-Napoli. It was in HK-Melzo in which the molecular defect was demonstrated. They showed that in the HK-Melzo variant, the HK deficiency was expressed not only in erythrocytes but also in platelets, lymphocytes, and fibroblasts. All these types of cells contain HK type 1 as the predominant glucose phosphorylating enzyme and, in particular, platelets and erythrocytes share a strict dependence upon glucose utilization for their physiologic
In a girl with severe nonspherocytic hemolytic anemia due to hexokinase deficiency previously reported by Rijksen et al. (1983), van Wijk et al. (2003) identified a homozygous mutation in the HK1 gene (T680S; 142600.0004). The mutation segregated with the disorder in the family and was not found in 50 controls.
Altay, C., Alper, C. A., Nathan, D. G. Normal and variant isoenzymes of human blood cell hexokinase and the isoenzyme patterns in hemolytic disease. Blood 36: 219-227, 1970. [PubMed: 5427456]
Bianchi, M., Magnani, M. Hexokinase mutations that produce nonspherocytic hemolytic anemia. Blood Cells Mol. Dis. 21: 2-8, 1995. [PubMed: 7655856] [Full Text: https://doi.org/10.1006/bcmd.1995.0002]
Board, P. G., Trueworthy, R., Smith, J. E., Moore, K. Congenital nonspherocytic hemolytic anemia with an unstable hexokinase variant. Blood 51: 111-118, 1978. [PubMed: 618553]
Gelsanz, F., Meyer, E., Paglia, D. E., Valentine, W. N. Congenital hemolytic anemia due to hexokinase deficiency. Am. J. Dis. Child. 132: 636-637, 1978. [PubMed: 655151] [Full Text: https://doi.org/10.1001/archpedi.1978.02120310100023]
Keitt, A. S. Hemolytic anemia with impaired hexokinase activity. J. Clin. Invest. 48: 1997-2007, 1969. [PubMed: 4980929] [Full Text: https://doi.org/10.1172/JCI106165]
Magnani, M., Stocchi, V., Canestrari, F., Dacha, M., Balestri, P., Farnetani, M. A., Giorgi, D., Fois, A., Fornaini, G. Human erythrocyte hexokinase deficiency: a new variant with abnormal kinetic properties. Brit. J. Haemat. 61: 41-50, 1985. [PubMed: 4052330] [Full Text: https://doi.org/10.1111/j.1365-2141.1985.tb04058.x]
Magnani, M., Stocchi, V., Cucchiarini, L., Novelli, G., Lodi, S., Isa, L., Fornaini, G. Hereditary nonspherocytic hemolytic anemia due to a new hexokinase variant with reduced stability. Blood 66: 690-697, 1985. [PubMed: 4027385]
Necheles, T. F., Rai, U. S., Cameron, D. Congenital nonspherocytic hemolytic anemia associated with an unusual erythrocyte hexokinase abnormality. J. Lab. Clin. Med. 76: 593-602, 1970. [PubMed: 5458022]
Paglia, D. E., Shende, A., Lanzkowsky, P., Valentine, W. N. Hexokinase 'New Hyde Park': a low activity erythrocyte isozyme in a Chinese kindred. Am. J. Hemat. 10: 107-117, 1981. [PubMed: 7234862] [Full Text: https://doi.org/10.1002/ajh.2830100202]
Rijksen, G., Akkerman, J. W. N., van den Wall Bake, A. W. L., Hofstede, D. P., Staal, G. E. J. Generalized hexokinase deficiency in the blood cells of a patient with nonspherocytic hemolytic anemia. Blood 61: 12-18, 1983. [PubMed: 6848140]
Rijksen, G., Staal, G. E. J. Human erythrocyte hexokinase deficiency: characterization of a mutant enzyme with abnormal regulatory properties. J. Clin. Invest. 62: 294-301, 1978. [PubMed: 27532] [Full Text: https://doi.org/10.1172/JCI109129]
Siimes, M. A., Rahiala, E. L., Leisti, J. Hexokinase deficiency in erythrocytes: a new variant in 5 members of a Finnish family. Scand. J. Haemat. 22: 214-218, 1979. [PubMed: 451452] [Full Text: https://doi.org/10.1111/j.1600-0609.1979.tb02799.x]
Valentine, W. N., Oski, F. A., Paglia, D. E., Baughan, M. A., Schneider, A. S., Naiman, J. L. Hereditary hemolytic anemia with hexokinase deficiency. Role of hexokinase in erythrocyte aging. New Eng. J. Med. 276: 1-11, 1967. [PubMed: 6015552] [Full Text: https://doi.org/10.1056/NEJM196701052760101]
van Wijk, R., Rijksen, G., Huizinga, E. G., Nieuwenhuis, H. K., van Solinge, W. W. HK Utrecht: missense mutation in the active site of human hexokinase associated with hexokinase deficiency and severe nonspherocytic hemolytic anemia. Blood 101: 345-347, 2003. [PubMed: 12393545] [Full Text: https://doi.org/10.1182/blood-2002-06-1851]