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Inborn Errors in Metabolism

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Inborn Errors in Metabolism Tishk International University Faculty of Science Department of Medical Analysis Advanced Clnical Biochemistry Inborn errors in metabolism Grade 4-Spring 2020-2021 Dr. Rundk A. Hwaiz Inborn errors of Carbohydrate Metabolism 1. Hemolytic anemia’s caused by deficiencies of- a) Hexokinase b) B. Pyruvate kinase c) Glucose-6-(P)-dehydrogenase 2. Pyruvate dehydrogenase deficiency. 3. Carbohydrate intolerance disorders- a) A. Lactose intolerance. b) B. Fructose intolerance. 4. Fructosuria 5. Galactosemia 6. Glycogen storage disorders. 1. Hemolytic anemia caused by different enzyme deficiencies A. Hexokinase deficiency: This is very rare among all the hemolytic disorders. Glycolysis in the RBC is linked with (2,3- Bisphosphoglyceric acid) production, essential for the oxygen transport. In the deficiency of the hexokinase, the synthesis and concentration of 2,3-BPG are low in RBC, so the oxygen unload to the tissues decreased, condition leads to Hemolysis. B. Pyruvate kinase deficiency: It is an autosomal recessive disorder and most common red cell enzymopathy after G-6-PD deficiency. PK catalyses the conversion of phosphoenolpyruvate to pyruvate with the generation of ATP. Inadequate ATP generation leads to premature red blood cell death (Prickle cells). C. Glucose-6-phosphate dehydrogenase deficiency : G-6-PD deficiency is a X-linked recessive disorder. Frequency is 1 in 5,000 births. The deficiency occur in all the cells of affected individuals. But it is more severe in RBCs. RBCs depend only on HMP shunt for their NADPH requirement. G-6PD deficiency leads impaired NADPH production, so oxidized glutathione is not converted to its reduced form. Low NADPH concentration also results the accumulation of methemoglobin and peroxides in RBC, causes loss of RBC membrane integrity. It is mostly asymptomatic, but when the enzyme deficient subjects exposed to severe infection, administered oxidant drugs such as – Anti-malarial (Primaquine) – Anti-biotic (Sulfamethoxazole) – Antipyretic (Acetanilide) Favism :- Ingestion of FAVA beans, Leads to Hemolytic anemia. 2. Pyruvate dehydrogenase deficiency Frequency is 1 in 250,000 births. Main symptom is lactic acidosis. Neuronal loss in brain. Muscular hypotonia. 3. Carbohydrate intolerance disorders A. Hereditary Lactose intolerance It is a rare disorder, due to the deficiency of Lactase (β- Galactosidase) enzyme. Symptoms - Diarrhea, inadequate nutrition and fluid & electrolyte disturbances. Prominent feature is Lactosuria (Lactose in urine). Milk is not digested in the individuals B. Hereditary Fructose intolerance It is an autosomal recessive disorder. Incidence is 1 in 20,000. The defect is Adolase-B (fructose-1-(P) aldolase) Fructose -1(P) cannot be metabolized. Fructose-1(P) X Glyceraldehyde + DHAP. It leads to accumulation of fructose-1-(P) severe hypoglycemia, vomiting, hepatic failure and jaundice. Treatment :- Early detection and intake of diet free from fructose and sucrose, are advised to overcome fructose intolerance 4. Essential fructosuria Due to the deficiency of fructokinase, fructose is not converted to fructose-1-(P). Fructose X Fructose-1-(P). This is an asymptomatic condition with excretion of fructose in urine. 5. Galactosemia It is a serious serious autosomal recessive disorder resulting from the deficiency of galactose-1-(P) uridyltransferase, leads to accumulation of Galactose- 1-(P) in the liver and becomes toxic. Incidence is one in 35,000 births. Galactose -1-(P) X UDP Galactose Symptoms: The build up of galactose and the other chemicals can cause serious health problems like Swollen and inflamed liver, Kidney failure, Stunted physical and mental growth Cataracts in the eyes. If the condition is not treated there is a 70% chance that the child could die. Treatment :- Galactose free diet is preferred i.e. milk will be avoided. 6. Glycogen storage diseases The metabolic defects concerned with the glycogen synthesis and degradation are collectively called as GSD All Glycogen storage disorders are Autosomal recessive disorders I. (Von Gierkes disease) is rare disorder is due to glucose-6- phosphatase deficiency causing ineffective glycogenolysis, hypoglycemia during fasting states, growth retardation, ketosis, lactic acidosis, pronounced hepatomegaly due to accumulation of glycogen in liver. II. Pomp’s disease Acid alpha-glucosidase deficiency Hypertrophic cardiomyopathy in infants Skeletal and respiratory muscle weakness CK value are elevated III. Cori’s disease Is an autosomal recessive metabolic disorder. inborn error of metabolism characterized by a deficiency in glycogen de- branching enzymes This disease principally affects the liver slowing of growth, low blood sugar levels and, sometimes, seizures. Muscle weakness may develop later in life IV. Anderson’s disease Brancher enzyme deficiency Extremely rare hereditary metabolic disorder produced by absence of the enzyme amylo-1:4,1:6- transglucosidase, which is an essential mediator of the synthesis of glycogen. An abnormal form of glycogen, amylopectin, is produced and accumulates in body tissues, particularly in the liver and heart V. Mc Ardle’s Disease Is a metabolic disease affecting skeletal muscle. Severe rhabdomyolysis may lead to acute kidney injury. Potential hyperuricaemia; overproduction of adenosine monophosphate (AMP), with accelerated liberation of hypoxanthine and xanthine into the blood, possibly leading to hyperuricaemia People with McArdle's disease develop severe muscle cramps and fatigue in the first few minutes of activity VI. Her’s Disease is a type of glycogen storage disease •Caused by a deficiency in liver glycogen phosphorylase No specific symptoms are associated with Hers disease (glycogen storage disease, type VI). Hepatomegaly may be present; Growth retardation is possible. The liver isoform of phosphorylase is deficient VII. Tauri’s disease It is caused by deficient activity of the enzyme phosphofructokinase This disease is one of the metabolic muscle disorders that interferes with the processing of food (in this case, carbohydrates) for energy production Newborn presents with hyperglycemia, liver Presentation dysfunction, jaundice, coagulopathy, E-coli sepsis and cataracts Deficiency in the enzyme Galactose and galactose- galactose-1-phosphate Galactosemia 1-phosphate uridyltransferase (GALT) Diagnosis reducing substances in urine Diagnosis GALT enzyme activity and blood galactose-1-phosphate values Treatment Elimination of galactose from diet for life Newborn infant presents with hypoglycemia, lactic Presentation acidosis, hyperurecemia, hyperlidimia, hepatomeagly with elevated liver enzyme, doll like face and thin extremities. Von Gierke deficient in glucose-6- Inability to release disease phospahatase enzyme free glucose • Glucagon administration produces no hyperglycemic Diagnosis response • Genetic testing For children, uncooked cornstarch will sustain blood glucose for 4-6 h. For young children, continuous Treatment nasogastric tube of glucose to sustain normal blood glucose level especially at night Presentation Strenuous exercise muscle cramps • High CPK Diagnosis • Myoglobinuria Myophosphorylase Mc Ardele disease deficiency • Avoid strenous exercise to prevent rhabdomyolysis Treatment • Oral fructose/glucose intake can improve exercise tolerance Deficiency of fructose 1,6- biphosphate aldolase • Autosomal recessive Fructose intolerance • Age 4-6 months Reducing substance in urine Infant is healthy until fructose or sucrose is ingested e.g. Avoid all source of fructose juice or sweetened cereal and sucrose Jaundice, vomiting, lethargy, seizures and irritability .
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