CLINICAL Question on Glucose 6 phosphate deficiency

This document describes how glucose 6 phosphate deficiency manifests clinically

1. Question 3 PRESENTED BY KAWALYA STEVEN, NOURLDIN ABDALLA, KATUSIIME JULIAN

2. 3. A 23-year-old male developed fever about two weeks back. He had bouts of shivering, temperature of 40.4°C and was delirious . The family physician suspected malaria and started treatment with primaquine after identification of the parasites in a blood smear. The fever subsided the next day, but the patient continued to feel weak and listless. By the next day these symptoms aggravated and he felt fatigue, dizziness, breathlessness on slightest exertion, headache, insomnia and paresthesia of the fingers and toes. Three days later, the patient noticed dark (black) coloured urine.

3. Clinical Examination and lab findings On examination, he showed pallor of the skin and the mucus membrane. Oedema feet, jaundice, tachycardia (heart rate 110/min), and systolic murmurs were the other prominent examination findings. His sclera was yellow and the spleen was marginally enlarged. The red cells, on microscopic examination, were found to contain small inclusion bodies (Heinz bodies). Since the above tests were suggestive of acute haemolytic crisis, further tests were done, including estimation of the RBC enzymes . Activity of glucose 6-phosphate dehydrogenase was found deficient, i.e. less than 10% of the normal.

4. Q.1. State the biochemical basis of development of haemolytic disease in this patient. Q.2. What is glutathione and what is its role in body? How does glutathione fail to perform its function following administration of primaquine in this patient? Q.3. Does the disorder affect other tissues of the body as well? Explain. Q.4. Comment on the following observations: (i) The dark coloured urine (ii) Presence of Heinz bodies in red cells. Q.5. Does the disorder in this patient offer any advantage as well? If yes, explain how. 3.Write short notes on; i. Sorbital intolerance ii. Wernicke- Korsakoff syndrome. iii. Refsum’s Disease

5. Glucose-6-phosphate dehydrogenase deficiency X linked disorder Reduced activity of G6PD Inability to remove H2O2 Accumulated H2O2 leads to oxidation of hemoglobin with precipitation of globin chains Heinz bodies Red cells with heinz bodies destroyed in spleen(extravascular hemolysis)

6. Measurement of methemoglobin levels is appropriate when methemoglobinemia is suspected, such as when hypoxia does not improve with supplemental oxygen therapy or when there has been exposure to a potential oxidative stressor (e.g., benzene).

7. glucose-6-phosphate dehydrogenase (G6PD) deficiency. This disorder is characterized by hemolysis due to intracellular generation and accumulation of free oxygen radicals and peroxides generated by certain oxidant drugs (e.g., nitrofurantoin , aspirin, and antimalarials ). Acute hemolytic episodes and premature red cell destruction may also be induced by infection, diabetic ketoacidosis, and exposure to certain chemicals (e.g., benzene, naphthalene) and fava beans diet. Hemoglobin typically precipitates into Heinz bodies, that damage to the red blood cell membrane.

8. Pathways that lead to the hemoglobin damage :   NADPH deficiency can cause a dysfunction in glutathione peroxidase which is an enzyme that converts hydrogen peroxide, a reactive oxygen species, into water.   G6PD (glucose-6-phosphate dehydrogenase) deficiency exacerbated by administration of oxidant drugs (e.g., primaquine , dapsone , quinidine) can also result in Heinz bodies.   G6PD deficient red cells in combination with high levels of oxidants causes a cross-linking of sulfhydryl groups on globin chains which causes a denaturing and formation of Heinz bodies.  

9. The excess beta globin chains aggregate to form HbH , which has decreased solubility and precipitates in the red blood cell cytoplasm, due to a perturbation in the quaternary structure of hemoglobin.   The presence of Heinz bodies may also be a feature of hyposplenism / asplenia , when a damaged or absent spleen cannot remove these damaged cells from circulation.  

10. What is Wernicke- Korsakoff syndrome ? is a neurological disorder caused by the lack of thiamine (vitamin B1). One cause of elevated lactate is thiamine deficiency . Thiamine is an essential cofactor in the tricyclic acid (TCA) cycle, aiding in the conversion of pyruvate to acetyl CoA as thiamine The disorder's main features are problems in acquiring new information or establishing new memories, and in retrieving previous memories. Causes; Alcohol abuse; Dietary deficiencies, Prolonged vomiting, Eating disorders, Effects of chemotherapy B1 deficiency causes damage to the brain's thalamus and hypothalamus. Symptoms include : Mental confusion -Vision problems Coma -Hypothermia Low blood pressure -Lack of muscle coordination (ataxia)

11. Sorbitol intolerance Sorbitol is the sugar alcohol of fructose. Due to its sweet taste, it is often used as a substitute for sugar or for many diet products. However , sorbitol has a laxative effect, meaning that products sweetened with sorbitol also have to come with an appropriate warning. In such a sorbitol intolerance, the small intestine is unable to utilise the sorbitol absorbed through food . It continues into the large intestine where it is broken down by bacteria. This fermentation process releases gases that have a negative impact on digestion. This results in stomach pain, bloating, headaches, tiredness, diarrhoea

12. Adult Refsum’s Disease Biochemical defect Defect in enzyme Phytanoyl CoA H ydroxylase (Phytanic acid oxidase) Autosomal recessive disorder in mutation of PHYH gene Phytanic acid accumulates in brain and other nervous tissues lab Findings Plasma Level of phytanic acid > 200µmol/L Normal< 30µmol/L

13. Phytanic acid is oxidized by Phytanic acid α oxidase (α- hydroxylase enzyme ) T o yield CO 2 and odd chain fa tty acid Pristanic acid that can be subsequently oxidized by beta oxidation . 36

14. Molecular Toxicology of Refsum’s Disease PA is directly toxic to ciliary ganglion cells and induces calcium – driven apoptosis in purkinji cells Recent studies has found that PA has a Rotenone like action in inhibiting complex –I and enhancing production of reactive oxygen species ROS, inducing apoptosis . This is the reason why neuronal cells and retina rich in mitochondria are prime tissue affected in Refsum’s disease

15. / Phytanic Acid

16. Refsum’s Disease Clinical manifestations Severe neurological symptoms such as ., Polyneuropathy, Retinitis pigmentosa (associated with night blindness) Nerve deafness Cerebellar ataxia Patients should avoid intake of diet such as green vegetables and milk.