Disorder of glycolysis Pyruvate kinase deficiency Pyruvate kinase

Disorder of glycolysis • Pyruvate kinase deficiency – Pyruvate kinase is a key enzyme in glycolysis, catalyzes the final step with formation of ATP – Genetic deficiency of pyruvate kinase in the erythrocyte leads to haemolytic anaemia due to excessive erythrocyte destruction – The normal mature erythrocyte lacks mitochondria and is completely dependent on glycolysis for its energy in the form ATP – Decreased ATP production affects the cation pump in the cell membrane. Ca+ enters cells, while K+ and H 2 O leave the cell and cells became dehydrated and phagocytosed by cells in the spleen – The premature death and lysis of the red blood cells result in haemolytic anaemia

Disorder of glycolysis (cont’d) • Hexokinase defficiency – Genetic defect in the hexokinase of erythrocyte reduces the amount of oxygen that is available for the tissues. Because hexokinase is the first enzyme in glycolysis, the red blood cells of these patients contain low concentration of 1, 3 -BPG which normally allows haemoglobin to release oxygen in tissue – Consequently due to low level of 1, 3 -BPG less oxygen is available for the tissue – This defect will also result in anaemia

Glycogen storage diseases (GSDs) • There a group of genetic diseases that result from a defect in an enzyme required for glycogen synthesis or degradation • Results in – Formation of abnormal structure of glycogen – Accumulation of excessive amounts of normal glycogen in specific tissues as a result of impaired degradation. • A particular enzyme may be defective in a single tissues, such as the liver, muscle kidney, intestine, myocardium • The severity of the GSDs range from fatal in infancy to mild disorders that are life threatening

Glycogen storage diseases (cont’d) • Von Gierke’s disease – Deficiency of G-6 -Pase in liver or kidney results in hypoglycemia, lactic acidemia, hyperlipemia ketosis and hyperuricemia • Pompe’s disease – Deficiency of lysosomal α-1, 4 and α-1, 6 glucosidase all organs with lysosomes results in infantile form, early death, cardiac failure, accumulation of glycogen in lysosomes

Glycogen storage diseases (cont’d) • Mc-Ardle syndrome – Absence of muscle glycogen phosphorylase in skeletal muscle results in excessive induced muscular pain, cramp, decrease serum lactate after exercise

Disorder of Pentose Phosphate Pathway • Deficiency of glucose-6 -phosphate dehydrogenase – Several types of X-linked inherited deficiency of the enzyme G-6 -p D have been recognised – Deficiency is caused by over 400 different mutations in the gene coding of G 6 PD. Only some of the mutations cause clinical symptoms – Enzyme deficient cells have a lower rate of NADPH production, resulting in a deficiency of reduced glutathione (GSH), which is essential to maintain the integrity of the erythrocyte membrane and for keeping Hb in the ferrous state

Disorder of Pentose Phosphate Pathway (cont’d) – The reduced form of glutathione serves as a sulfhydryl buffer that maintains the cysteine residues of Hb and other red blood cell proteins in the reduced state – In the absence of enzyme, the sulfhydryl group of haemoglobin can no longer be maintained in the reduced form and haemoglobin molecules then cross link with one another to form aggregates of heinz bodies on the cell membranes and that leads to lysis of RBC

Disorder of Pentose Phosphate Pathway (cont’d) • Most individuals who have inherited on of the many G 6 PD mutations are asymptomatic. • However, some individuals with G 6 PD deficiency develop haemolytic anaemia if they are exposed to, – Certain oxidant drugs – Certain types of infections

Disorders of fructose metabolism • Essential fructosuria – Essential fructosuria is a rare and benign genetic disorder caused by a deficiency of the enzyme fructokinase – In this order fructose can not be converted to fructose -1 -P – This is bengin because no toxic metabolites of fructose accumulate in the liver and the patient remains nearly asymptomatic – There is no renal threshold for fructose, so that the appearance of fructose in urine does not require a high fructose concentration in the blood

Disorders of fructose metabolism (cont’d) • Hereditary fructose intolerance = fructosemia – It is due to deficiency of the enzyme Aldolase-B – Fructose-1 -phosphate cannot be converted to DHAP and GA and therefore fructose-1 - P accumulates in the blood – This results in the inhibition of fructokinase and an impaired clearance of fructose from the blood

Disorders of fructose metabolism (cont’d) • Clinical findings – Accumulation of fructose -1 - P leads to liver and kidney damage – Hypoglycemia due to inhibition of glycogenolysis and gluconeogenesis • Treatment – Elimination of fructose containing foods from the diet.

Disorders of galactose metabolism • Galactosemia It is an inborn error of metabolism caused by enzyme deficiencies in the galactose pathway. Three defects have been described due to deficiency of: • Galactokinase • Galactose-1 -phosphate uridyl transferase • UDP-galactose-4 -epimerase They all interfere with the normal metabolism of galactose, causing a rise in plasma and urine galactose.

Disorders of galactose metabolism (cont’d) • The commonest and most sever enzymatic defect is due to galactose-1 -phosphate uridyl transferase deficiency which prevents conversion of galactose to glucose and leads to: – accumulation of galactose-1 -P – depletes liver inorganic phosphate – liver failure and mental retardation.

Disorders of galactose metabolism (cont’d) • Clinical findings – Galactose which increases in concentration in blood, is reduced by aldose reductase in the eye to galactitol, which accumulates causing cataract – Galactosemia usually manifests itself in the neonatal period or early infancy. Such infants may show symptoms such as: • Failure to thrive • Vomiting, diarrhoea • If untreated go on to develop liver disease, mental retardation, renal tubular damage due to deposition of galactose-1 - P in tubular cells