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Hexokinase Deficiency

Hexokinase deficiency is an autosomal recessive genetic disease characterized by nonspherocytic hemolytic anemia. Jaundice, splenomegaly, pallor and constitutional symptoms such as lethargy and fatigue are main symptoms. A full laboratory workup, including genetic studies, are required to exclude more common causes of hemolytic anemia and confirm hexokinase deficiency as the underlying cause.


Presentation

Hexokinase deficiency (HKD) is a very rare occurrence in clinical practice, as only 17 families suffering from this condition have been described in literature by the beginning of the 20th century [1]. The only clinical sign of HKD is the appearance nonspherocytic hemolytic anemia [1] [2] [3], which can be accompanied by jaundice, lethargy, pallor, and fatigue. Severe neonatal jaundice may be seen as well, while splenomegaly and central nervous system symptoms such as mental retardation are also described in hemolytic anemias that arise due to glycolytic enzyme deficiencies [4]. The main reason for the red-blood-cell (RBC) related pathology lies in the fact that hexokinase 1 (HK1), expressed predominantly in erythrocytes, is affected by genetic mutations that render RBCs unable to produce energy from the glycolytic pathway, as HK is a pivotal enzyme for this process [1] [2] [3]. Earlier studies have associated latent diabetes and panmyelopathy with this condition [3], but because of a very low number of cases, these claims remain to be solidified. The clinical presentation of hexokinase deficiency is similar to the presentation of the pyruvate kinase deficiency; however, the anemia is more severe.

Splenomegaly
  • Jaundice, splenomegaly, pallor and constitutional symptoms such as lethargy and fatigue are main symptoms.[symptoma.com]
  • Abnormality of metabolism/homeostasis ; Autosomal recessive inheritance ; Cholecystitis ; Cholelithiasis ; Congenital onset ; Hyperbilirubinemia ; Jaundice ; Nonspherocytic hemolytic anemia ; Normochromic anemia ; Normocytic anemia ; Reticulocytosis ; Splenomegaly[mousephenotype.org]
  • Splenomegaly is present in many patients.[web.archive.org]
Pallor
  • Jaundice, splenomegaly, pallor and constitutional symptoms such as lethargy and fatigue are main symptoms.[symptoma.com]
  • Clinical Findings There is a history of weakness, fatigue, tachycardia, dyspnea, and pallor from anemia and tissue iron depletion. Physical findings include pallor, tachycardia, glossitis, koilonychia (spoon nails), and angular stomatitis.[web.archive.org]
Constitutional Symptom
  • Jaundice, splenomegaly, pallor and constitutional symptoms such as lethargy and fatigue are main symptoms.[symptoma.com]
Multiple Congenital Anomalies
  • Each had multiple congenital anomalies, panmyelopathy, and chromosomal aberrations characteristic of classic Fanconi's syndrome. Hexokinase deficiency has not been observed in other cases of Fanconi's syndrome.[jamanetwork.com]
Neonatal Jaundice
  • Severe neonatal jaundice may be seen as well, while splenomegaly and central nervous system symptoms such as mental retardation are also described in hemolytic anemias that arise due to glycolytic enzyme deficiencies.[symptoma.com]
  • The presenting features may vary from severe neonatal jaundice and anaemia (Figure 9.4), rarely even presenting with hydrops fetalis, severe CNSHA requiring repeated transfusions, moderate haemolysis with exacerbation during infections or pregnancy, to[europeanmedical.info]
Withdrawn
  • […] recessive inheritance ; Cholecystitis ; Cholelithiasis ; Congenital onset ; Hyperbilirubinemia ; Jaundice ; Nonspherocytic hemolytic anemia ; Normochromic anemia ; Normocytic anemia ; Reticulocytosis ; Splenomegaly Associated Genes HK1 Mouse Orthologs Hk1 (Withdrawn[mousephenotype.org]
  • The hemolysis may persist for weeks to months after the drug is withdrawn. Treatment with steroids may occasionally be required.[web.archive.org]
Abnormal Behavior
  • The mutant enzyme was characterized by normal kinetic parameters with respect to its substrates, glucose and MgATP2-, normal pH optimum, normal heat stability at 40 degrees C, but abnormal behavior with respect to its regulation by glucose-1,6-diphosphate[ncbi.nlm.nih.gov]
Psychomotor Retardation
  • A 14-month-old child who had a haemolytic episode when he was 5 years old, and with psychomotor retardation, was found to have decreased red cell hexokinase activity.[ncbi.nlm.nih.gov]
Dizziness
  • A low red blood cell count can lead to symptoms such as jaundice (yellowed skin), tiredness, dizziness, and pale skin. Treatment for NSHA includes blood transfusions in order to gain more healthy red blood cells into the body.[diseaseinfosearch.org]
  • Clinical Findings Patients present with headache, dizziness, vertigo, and visual disturbances. They may have a history of cerebrovascular accidents, myocardial infarction, angina, or venous thrombosis.[web.archive.org]
Lethargy
  • Jaundice, splenomegaly, pallor and constitutional symptoms such as lethargy and fatigue are main symptoms.[symptoma.com]
Vertigo
  • Clinical Findings Patients present with headache, dizziness, vertigo, and visual disturbances. They may have a history of cerebrovascular accidents, myocardial infarction, angina, or venous thrombosis.[web.archive.org]

Workup

The diagnosis of HK should be considered when all other causes of hemolytic anemia have been excluded. Firstly, a complete blood count (CBC) should be obtained, including levels of hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), as well as reticulocyte and platelet count [4]. If anemia without an identifiable cause is noted, a peripheral blood smear should be done, and hemolysis of RBCs, but in the absence of spherocytosis, is a diagnostic hallmark of HK deficiency. Furthermore, the direct coombs test; used to exclude autoimmune causes of hemolytic anemia like warm antibody hemolytic anemia (associated with the use of drugs, systemic lupus erythematosus or chronic lymphocytic leukemia), cold agglutinin disease and paroxysmal cold hemoglobinuria, should be performed as well [5]. In addition, bilirubin and lactate dehydrogenase (LDH) will be markedly elevated in hemolytic anemias, whereas reduced haptoglobin and detection of hemoglobin and hemosiderin in urine is frequently observed [6]. If enzymopathy remain the only diagnostic possibility for anemia, genetic tests to determine which enzyme is deficient and responsible for the symptoms must be conducted, especially in the presence of a positive family history, but very few laboratories possess the tools for such advanced diagnostic procedures [4]. Nevertheless, if valid clinical and laboratory criteria exist, genetic studies must be performed.

Normocytic Anemia
  • […] genetic, haematological Phenotypes Abnormality of metabolism/homeostasis ; Autosomal recessive inheritance ; Cholecystitis ; Cholelithiasis ; Congenital onset ; Hyperbilirubinemia ; Jaundice ; Nonspherocytic hemolytic anemia ; Normochromic anemia ; Normocytic[mousephenotype.org]
  • anemia 170 hemolytic anemia 170 Hemolytic Anemia, Nonspherocytic, due to Hexokinase Deficiency 1[rgd.mcw.edu]
  • Normocytic Anemia In normocytic anemias the mean corpuscular volume ranges between 80 and 94 and normochromic-normocytic cells are seen in the peripheral blood smear.[web.archive.org]
Erythroblast
  • The molecular effects of the novel splice site mutation c.876-2A G in intron 7 was studied on mRNA isolated from ex vivo cultured erythroblasts from the patient’s father, who was heterozygous for this mutation.[learningcenter.ehaweb.org]
  • Exons 2 and 3 were amplified from total RNA of ex vivo cultured erythroblasts of the patient, with primers spanning erythroid-specific exon 1 and exon 4 (S1).[haematologica.org]

Treatment

  • Which treatment must I follow if I have the disease? In cases of severe anaemia supportive measures and red cell transfusions are indicated.[enerca.org]
  • Treatment for NSHA includes blood transfusions in order to gain more healthy red blood cells into the body. If you or a family member has been diagnosed with NSHA, talk to your doctor about the most current treatment options.[diseaseinfosearch.org]
  • .- Prenatal Detection and Treatment.- P.[books.google.de]

Prognosis

  • In children, hypertransfusion improves the prognosis after neurologic complications. Chronic hypertransfusion might be considered in patients with severe disease.[web.archive.org]

Etiology

  • Therapy Determine and correct the underlying etiologic factors. Administer ferrous sulfate, 300 mg tid, for 4 to 6 months to replete body stores.[web.archive.org]
  • Etiology GSD I is caused by mutations in the G6PC gene resulting in lack of normal activity of the hepatic enzyme complex consisting of glucose-6-phosphate transporter (G6PT) and glucose-6-phosphatase-alpha, which catalyzes the final step in the production[online.epocrates.com]

Epidemiology

  • Methods Statistics Trigonometry Medical & Nursing Anatomy Anesthesiology Audiology Bacteriology Biochemistry Bioethics Biomedical Science Cardiology Cardiovascular Childbirth Chiropractic Dentistry Dermatology Diagnostic Imaging Drugs Endocrinology Epidemiology[brainscape.com]
Sex distribution
Age distribution

Pathophysiology

  • Nathan and Oski’s is the only comprehensive product on the market that relates pathophysiology in such depth to hematologic and oncologic diseases affecting children.[books.google.de]
  • Approximately 80 mutations in SLC37A4 (G6PT1) have been identified. [2] Pathophysiology GSD I results from lack of activity of the hepatic enzyme complex consisting of glucose-6-phosphate transporter (G6PT) and glucose-6-phosphatase-alpha, which is essential[online.epocrates.com]
  • Pathophysiology Thalassemias are autosomally dominant inherited disorders in which either alpha- or beta-globin chains are synthesized at a reduced rate, thereby reducing the production of hemoglobin A.[web.archive.org]
  • Chemical compound and disease context of HK1 Hexokinase II, one member of a family of structurally similar enzymes that catalyze the phosphorylation of glucose in the 6-position, has been suggested to play a role in the pathophysiology of noninsulin-dependent[wikigenes.org]

Prevention

  • […] associated with Describe the mutation in the DNA that causes sickle cell Position 6- Glutamic acid - valine What is the protein associated with sickle cell mutation How does HbS affect blood oxygen mutation affects shape of cells and oxygen affinity thus preventing[quizlet.com]
  • Prevention of pancreatic cancer induction in hamsters by metformin. ‎ Pagina 115 - Hemmings BA. Differential methylation and altered conformation of cytoplasmic and nuclear forms of protein phosphatase 2A during cell cycle progression. ‎[books.google.ro]
  • Indeed, the presence of growth-inhibiting compounds and conditions do not prevent its proliferation.[secure.megazyme.com]
  • Regulatory relationships of HK1 In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death [35] .[wikigenes.org]
  • Pre-incubation for 10 min with 1 μg poly(dI-dC) (Roche Diagnostics, Mannheim, Germany) prevented non-specific binding.[haematologica.org]

References

Article

  1. van Wijk R, Rijksen G, Huizinga EG, Nieuwenhuis HK, van Solinge WW. HK Utrecht: missense mutation in the active site of human hexokinase associated with hexokinase deficiency and severe nonspherocytic hemolytic anemia. Blood. 2003;101(1):345-347.
  2. Bianchi M, Crinelli R, Serafini G, Giammarini C, Magnani M. Molecular bases of hexokinase deficiency. Biochim Biophys Acta. 1997;1360(3):211-21.
  3. Rijksen G, Akkerman JW, van den Wall Bake AW, Hofstede DP, Staal GE. Generalized hexokinase deficiency in the blood cells of a patient with nonspherocytic hemolytic anemia. Blood. 1983;61(1):12-18.
  4. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
  5. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
  6. Aster JC, Abbas AK, Robbins SL, Kumar V. Robbins basic pathology. Ninth edition. Philadelphia, PA: Elsevier Saunders; 2013.

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Last updated: 2019-06-28 10:51