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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.

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]
Psychomotor Retardation
  • Abstract 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]

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.

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]
  • It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice .[uniprot.org]
  • .- Prenatal Detection and Treatment.- P.[books.google.de]
  • Form a definitive diagnosis and create the best treatment plans possible with comprehensive coverage of all pediatric cancers, including less-common tumors, as well as all hematologic disorders, including newly recognized ones.[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

  • 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]
  • 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]

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]
  • Balances summaries of relevant pathophysiology with clear, practical clinical guidance to help you thoroughly understand the underlying science of diseases.[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]

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]
  • Pre-incubation for 10 min with 1 μg poly(dI-dC) (Roche Diagnostics, Mannheim, Germany) prevented non-specific binding.[haematologica.org]
  • Cannot synthesize the enzyme phosphorylase (due to a gene mutation) Inability to break down muscle glycogen Prevents lactate production (blood lactate levels do not rise during high- intensity exercise) Patients complain of exercise intolerance and muscle[quizlet.com]
  • Clinical Management The accurate diagnosis and family studies are important to prevent numerous unnecessary diagnostic and therapeutic manipulations.[web.archive.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: 2018-06-22 01:28