Dr.G.Bhanu Prakash – www.gims-org.com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits DISORDER ENZYME HEMOGLOBINOPATHIES Sickle Cell anemia (Hemoglobin S disease) Glutamate (HbA) replaced with valine (HbS) on beta chain; anemia, pain, dec. circulation, infections Hemoglobin C disease Glutamate (HbA) replaced with lysine (HbC) , mild anemia Hemoglobin SC disease Hbs + HbC, undiagnosed until childbirth / surgery, can be fatal Methemoglobinemia NADH cytochrome b5 reductase Diminished oxygen-carring capacity of ferric Hb (metHb) headache, lightheadedness, dyspenea and chocolate cyanosis 1 defective No symptoms 2 defective 2 alpha chains missing Hb B 4 defective Accumulation of γ4 tetramers in newborns, HYDROPS FATALIS HbH 3 defective Accumulation of β4 tetramers in newborns, severe anemia Deletion of both betas Both β chains defective, fatal HEINZ bodies, inability of HbF HbA, manifests around 8 mos old. Deletion of 1 beta chain Only 1 β chain defective, not fatal Scurvy Proly/lysyl hydroxylase Vit C def. no hydroxylation Ehlers-Danlos Lysyl hydroxylase Stretchy skin, loose joints, aortic aneurysm, ruptured colon, Osteogenesis Imperfecta Collagen Type 1 defect Brittle bones in babies, blue sclera, multiple fractures, slowed healing Type 1: heterozygous, postnatal, can survive Type 2: homozygous, perinatal, death in utero Emphysema α1- anti-trypsin deficiency Inherited defect in alpha 1 anti-trypsin resulting in emphysema THALASSEMIAS Α-thalassemia: Silent Carrier Mild Symptoms Β-thalassemia: major Minor COLLAGEN DISEASES Alport’s Affect glomerular basement membrane, hearing loss, ocular defects Goodpasture’s Antibodies destroy basement membrane of pulmonary and glomerular capillaries Lysyl oxidase/Cu2+ Deficient cross linking secondary to functional copper deficiency; depigmented (steely) hair, arterial tortuosity and rupture, cerebral degeneration, anemia, osteoporosis. Complex1 NADH dehydrogenase Amobarbital, rotenone Complex III cytochrome reductase Antimycin A Complex IV cytochrome oxidase CO,CN Complex V (ATP synthase) Oligomycin Fluoroacetate Aconitase Inhibited Malonate Succinate dehydrogenase Inhibited Arsenite Α-ketogluconate dehydrogenase Inhibited Complex 1 (NADH dehydrogenase) Degeneration of optic nerve, blindness in early adult Menke’s ETC INHIBITORS Electron transport blockers TCA CYCLE HEREDITARY MITOCHONDRIAL DISEASES Leber’s hereditary optic neuropathy Kearns-Sayre Ragged red fibers, heart block, retinal pigmentation 1 mental retardation. hepatomegaly Andersen’s (Type IV) Glucosyl-4-6-transferase Hepatosplenomegaly. liver failure. lactic acidosis. death. sensorineural deafness GLUCOSE & PYRUVATE METABOLISM Pyruvate dehydrogenase deficiency Pyruvate dehydrogenase Lactic acidosis. fatigue. episodic ataxia after meal Arsenic poisoning G3PDH Lost NADH. scarce activity in RBCs Class III: A-. fructosuria Hemolytic Anemia G6PD X linked. galactosuria GALACTOSE METABOLISM UDP galactose 4-epimerase deficiency Benign: affects RBCs and WBCs Malignant: similar to GALT def FRUCTOSE METABOLISM Hereditary fructose intolerance Aldolase B Toxic liver damage. neurologic defects (Wernicke-Korsakoff) Pyruvate DH complex deficiency Pyruvate DH complex Pyuvate to lactate. infancy death. inadequate NADPH production results in reduction in antioxidant activity of glutathione in mature RBC’s Class I: chronic nonspherocytin anemia. juvenile myopathy Adult: gradual skeletal myopathy Cori’s (Type III) α-1-6 glucosidase Mild hypoglycemia. encephalomyopathy. hemolytic anemia often induced by infections. severe fasting hypoglycemia Pompe’s (Type II) α-1-4 glucosidase (acid maltase) Infants: mental retardation. jaundice Classical galactosemia GALT Cirrhosis. normal stability. MR HMP PATHWAY/NADPH RELATED DISORDERS GLYCOGEN STORAGE DISEASES Mucopolysaccharidoses 2 . galactosemia. hemolytic anemia. cataracts. most severe Class II: Mediterranean. coarse facial features.G. oxidant drugs & fava beans. cardiomegaly. stroke-like episodes MERRF Myoclonus epilepsy with ragged red fibers. pyruvate accumulates Pyruvate kinase deficiency Pyruvate kinase Most common enzyme deficiency in glycolytic pathway. death by 2 yrs McArdle’s (Type V) Muscle glycogen phosphorylase Muscle cramping.Bhanu Prakash – www. renal disease. physical deformity. hypophosphatemia.Dr. early death Hunter’s Iduronate sulfatase X-linked. galactosuria Galactokinase deficiency Galactokinase Cataracts. MR. oldest RBCs removed Amyotrophic Lateral Sclerosis Superoxide dismutase Degenerated motor neurons in CNS Chronic granulomatosis NADPH oxidase Persistant chronic pyogenic infections. hyperketonia VON Gierke’s (Type 1) Glucose 6-phosphate Hepatosplenomegaly. deficiency of enzyme located in leukocyte membrane Type 0 Glycogen synthase Hypoglycemia.com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits MELAS Mitochondrial myopathy. death by 2 yrs. no increase in lactic acid after exercise Hers’ (Type VI) Liver glycogen phosphorylase Mild hypoglycemia Hurler’s α-L-iduronidase Corneal clouding.gims-org. ataxia. neonatal death. gout Essential fructosuria Fructokinase Benign condition. coma.gims-org.Bhanu Prakash – www. destroyed myelin Mobilization of Stored Fats & [FA] Carnitine deficiency inability to use long chain FA as fuel. Reyes syndrome. processing or functioning of LDL receptor. chylomicrons.com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits Sanfilippo’s Types A-D Type-Aheparan sulfate Type BNacetylglucosaminidase Type CN-acetyltransferase Type D N-acetylglucosamine Severe nervous system disorders. death by 8 yrs. neurologic symptoms 3 . pancreatitis Wolman disease Cannot hydrolyze lysosomal cholesteryl esters Familial LCAT deficiency Complete absence of LCAT. hypoglycemia. Synthesis of glycoproteins I-cell disease Metabolism of Dietary Lipids Type II hyperlipidemia Type III hyperlipidemia (familial dysbetalipoproteinemia) Genetic defect in synthesis. alcohol. causes: congenital. treat with high carb diet Paroxysomal Nocturnal Hemoglobinuria GPI synthase In hematopoietic cells Refsum disease Fatty acid alpha-hydroxylase AR. high plasma TAGs and eruptive xanthomas (TAG deposits in skin) and pancreatitis. death CAT-2 def Cardiomyopathy. physical deformity Lysosomal hydrolytic enzymes Deficiency in ability to phosphorylated mannose residuesof potential lysosomal enzymes. Congenital A-beta-lipoproteinemia Apo B-48 Accum of chylomicrons in enterocytes Type 1 hyperlipidemia (familial hyperchylomicronemia) Apo C-II. elevated N-linked glycoproteins in urine. VLDL due to obesity. cause of 10% SIDS cases. muscle weakness following exercise Medium chain Fattyacyl CoA dehydrogenase deficiency Medium chain fatty acyl CoA Decreased FA oxidation.G. liver disease CAT-1 def Liver cannot synthesize glucose during fast. elevated LDL levels Familial hypercholesterolemia Apolipoprotein E Accumulation of chylomicron remnants in plasma Type IV hyperlipidemia Inc. severe hypoglycemia. TAGs. diabeties Type V hyperlilidemia Inc. increased phytanic acid. VLDL. results in incorrect targeting of glycoproteins. mental retardation Scheie’s α-L-iduronidase Like Hurler’s but normal life span Sly’s β-glucronidase Hepatosplenomegaly. Capillary lipoprotein lipase Accumulation of chylomicrons in plasma.Dr. low HDL Fish Eye Disease Partial LCAT absense Zellweger syndrome Defective peroxisomal biogenesis. accumulated VLCFAs in blood X-linked Leukodystrophy Defective peroxisomal activation of VLCFAs. congenital pyloric stenosis. sex hormones & masculinization 11-β-hydroxylase deficiency 11-β -hydroxylase Dec. melanin synthesis. or estrogen. early death Gaucher’s β-glucosidase Sphingolipidosis. blindness. painful and progressively deformed joints. androgens. gives inc. fatal GM1 gangliosidosis β-galactosidase GM1 accumulation. early death 17-α -hydroxylase deficiency 17-α -hydroxylase Sex hormones & cortisol not produced inc. death Sandhoff’s disease Β-hexosaminidase A & B Inc. production of aldosterone gives HTN. ceramide. add tyrosine. hepatosplenomegaly. fatal early in life Cholesterol & steroid metabolism CAH Congenital Adrenal Hyperplasia Smith-Lemli-Opitz Syndrome 7-hydrocholesterol-7-reductase AR. MR. X linked. globosides. hepatosplenomegaly. double bond migration (Lanosterol to Cholesterol) Fatty Liver Imbalanced TG synthesis and VLDL secretion Causes: obesity. pregnenolone. dec.Bhanu Prakash – www. melatonin and serotonin synthesis also compromised. demyelination. hepatic dysfunction. death in early childhood Chronic lung damage. mineralocorticoids. same symptoms as Tay-Sachs with rapid progression. Fabry’s α-galactosidase Inc. MR. No glucocorticoids. GM2. masculization Classic PKU Phenylalanine hydroxylase MR. death in early adulthood Sphingomyelinase Cannot transport unesterified cholesterol out of lysosomes Tay-Sachs β-hexoaminidase A Cherry-red macula inc. alcoholism Cholelithiasis Cholesterol gallstones Malabsorption. phenotypically female but unable to mature 21-α -hydroxylase deficiency 21-α -hydroxylase Most common CAH. treat: laparoscopic cholecystectomy 3-β-hydroxysteroid dehydrogenase def 3-β-hydroxysteroid dehydrogenase Inc. obstructed biliary tract. fair skin. redish purple skin rash Farber’s Ceraminidase Inc. restrict phenylalanine intake.Dr. increase tyrosine Malignant PKU Dihydrobiopterin reductase/ synthase Similar to classic PKU. mousy odor. screen after 1st exposure to phenylalanine in breat milk. cortisol & aldesterone. granulomas. metabolic acidosis Phospholipid metabolism Niemann-Pick Type A Sphingomyelinase Type B Type C Cherry red macula. frequently fatal Metachromatic leukodystrophy Arylsuldatase A MR.G. ACTH levels inc. galactocerebrosides. severe mental retardation. restrict phenylalanine. L-dopa. 5-hydroxytryptophan SPHINGOLIPIDOSES AMINO ACID METABOLISM 4 . skeletal deformities. diabetes mellitus. glucocerebrosides. kidney & heart failure. inc.com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits Vit B12 def Methylmalonic academia and aciduria.. MR.gims-org. fatal in 1st decade Krabbe’s β-galactosidase Inc. almost total absence of myelin. globosides. MR. only X linked. ataxia. developmental problems Cystathioninuria Cystathionase Accumulation of cystathionine and metabolites. treat with high carb. acidosis. homogentisate accumulation forms polymers which darkens standing urine. inc.com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits Maternal PKU Mother with either classic or malignant Developmental abnormalities. low protein diet. porphobilinogen & ALA in urine. seizures. MR.G.gims-org. microcephaly. treat with arginine to increase citruline excertion and sodium benzoate to detox ammonia Argininosuccinate Aciduria Argininosuccinate lyase (argininosuccinase) Episodic symptoms similar to classic citrullinemia. lysine. treat with low protein diet including essential AA but no arginine Acute Intermittent porphyria Uroporphyrinogen synthase Autosomal dominant. coma. Hyperargininemia Arginase Rare UCD progressive spastic quadriplegia and MR high ammonia & arginine in CSF & serum. Ochronosis. uroporphyrinogen I & uroporphyninI Prophyria Cutanea Tarda Uroporphyrinogen decarboxylase Inc. high mortality rate.Bhanu Prakash – www.Dr. osteoporosis Histidinemia Histidase Elevated histadine in blood and urine. darkening of articular cartilage Maple Syrup Urine Disease Branched chain α -ketoacid dehydrogenase Elevated levels of α amino acids and their α –keto analogues in plasma and urine. uroporphyrinogen III which converts to uroporphyrinogen I & coproporphyrinogen I Hereditary Coproporphyria Coproporphyrinogen oxidase Inc. and sodium phenylacetate/benzoate for ammonia detox Classic Citrullinemia Argininosuccunate synthetase Episodic hyperammonemia. inc. elevated methionine & metabolites in blood. treat with arginine which activates N-acetylglutamate synthetase N-acetylglutamate synthetase deficiency N-acetylglutamate synthetase Severe/mild hyperammonemia associated wuth deep coma. coproporphyrinogen III Varigate Porphyria Protoporphyrin oxidase Accumulation of protoporphyrinogen IX UREA CYCLE HEME BIOSYNTHESIS/DEGREDATION 5 . increased ammonia and aa in serum. hyperornithinemia. Type I Hyperammonemia Carbamoylphosphate synthetase I Within 24-48 hrs after birth infant becomes increasingly lethargic. lethargy. & hyperventilation. needs stimulation to feed. attacks precipitated by drugs that induce cytochrome P450 in liver Congenital erythropoietic porphyria Uroporphyeinogen III synthase Inc. accumulation of odd chain FA in liver. and ornithine in urine. hypothermia. mother didn’t stay within dietary restrictions during pregnancy Alcaptonuria Homogentisate oxidase Benign. vomiting. sometimes MR Albinism Tyrosinase Inability to convert tyrosine to melanin Tyrosinosis Eumarylacetoacetate hydrolase Liver & kidney damage Nonketogenic hyperglycinemia Glycine cleavage complex Severe mental deficiencies & low survival rate past infancy. without appropriate intervention death occurs. hypoglycemia. increased serum orotic acid due to mitochondrial carbamoylphosphate entering cytosoland incorporating in pyrimidine nucleotides leading to excess productin and excess catabolic products. ataxia. high arginine. treat with argentine and sodium benzoate. vomiting. MR. recurrent diarrhea. neurologic problems Propionyl CoA Carboxylase Deficiency Propionyl CoA Carboxylase Elevated propionate in blood. no clinical symptoms Homocystinuria Cystathionine synthetase Accumulation of homocysteine in urine. elevated plasma and CSF argininosuccunate. treatment includes administration of carbamoyl glutamate which activates CPS I Type 2 hyperammonemia Ornithine transcarbmoylase Most commonly occurring UCD. glycine in blood. glossitis B3 Niacin NAD. HTN. feminine genitalia. methylcobalamin Pernicious anemia. retinoic acid in epithelial cells Blindness. DEC. isoniazid can induce deficiency C Ascorbic acid Ascorbic acid Scurvey A Retinol Retinol in vision. No glucocorticoids. cortisol.Bhanu Prakash – www. CNS symotoms. adults: osteomalacia K Phyllo/menaquinones Same Hypothrombinemia E Tocopherols α-tocopherol Abnormal cell membranes 6 . cortisol. glossitis. PABA analogues. Dec. dihydrofolate inhibitors B12 Cobalamin 5’deoxyadenosyl cobalamin. inc. NADP Pellagra. HTN. mineralocorticoids. dermatitis. No sex hormones. pyridoxal Pyridoxal PO4 Rare. FMN Dermatitis. Wernicke-Korsakoff B2 Riboflavin FAD. early death 21-α-hydroxylase def.gims-org. feminine genitalia. heme ALA CONGENITAL ADRENAL HYPERPLASIA 3-β-hydroxysteroid DH def. hypernatremia. B6 Biotin Biotin Adivin. 3 D’s. and corticosterone. cheilosis. inc. anorexia. fluid retention. hyponatremia. deoxycorticosterone. inc. no mineralo/glucocorticoids. nausea B6 Pantothenic acid CoA Not significant B Folic Acid THF Megaloblastic anemia. skin problems D Cholecalciferol 1. mineralocorticoids. androgens/estrogens. Greater than 90% CAH.25-diOH D3 Children: rickets. aldesterone. androgens.com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits Erythropoietic Protoporphyria Ferrochelatase Accumulation of protoporphyrin IX Sideroblastic Anemia ALA synthase X-linked Crigler-Najjar syndrome Bilirubin glucuronyl transferase In newborns: newborn jaundice. ALA and protoporphyrin XI. early death 17-α-hydroxylase def.G. masculinization 11-β-hydroxylase def. folate trap B6 Pyridoxine. neural tube defects. treat with blue light Lead poisoning ferrochelatase/ dehydratase Inc. sterility.Dr. masculinization LETTER NAME COENZYME/ ACTIVE FORM DEFICIENCY B1 Thiamine TPP Beri-beri. role in intracellular calcium regulation and cell signaling Pellagra—photosensitive dermatitis. dermatitis C Ascorbic acid Coenzyme in hydroxylation of proline and lysine in collagen synthesis. and tongue. convulsions Folic acid Coenzyme in transfer of one-carbon fragments Megaloblastic anemia Cobalamin Coenzyme in transfer of one-carbon fragments and metabolism of folic acid Pernicious anemia = megaloblastic anemia with degeneration of the spinal cord Pantothenic acid Functional part of CoA and acyl carrier protein: fatty acid synthesis and metabolism Peripheral nerve damage (nutritional melalgia or "burning foot syndrome") H Biotin Coenzyme in carboxylation reactions in gluconeogenesis and fatty acid synthesis.com @ Global institute of Medical sciences – The Medical Biochemistry Tit-Bits Vitamin Functions Deficiency disease A Visual pigments in the retina. osteomalacia = bone demineralization E Tocopherols.Bhanu Prakash – www. enhances intestinal absorption of Ca2+ and mobilizes bone mineral. modulation of steroid hormone action Disorders of amino acid metabolism. tocotrienols Antioxidant. antioxidant. depressive psychosis B6 Pyridoxine. seborrheic dermatitis Niacin Nicotinic acid. pyridoxal. regulates Cl– channel in nerve conduction B2 Coenzyme in oxidation and reduction reactions. lips. especially in cell membranes.gims-org. roles in cell signaling Extremely rare—serious neurologic dysfunction K Phylloquinone: menaquinones Impaired blood clotting. and transketolase.Dr. regulation of gene expression and cell differentiation Rickets = poor mineralization of bone. role in regulation of cell cycle Impaired fat and carbohydrate metabolism. functional part of NAD and NADP. loss of dental cement. prosthetic group of flavoproteins Lesions of corner of mouth. xerophthalmia. subcutaneous hemorrhage B12 Riboflavin 7 .G. regulation of gene expression and cell Night blindness. hemorrhagic disease Coenzyme in formation of clotting and bone matrix B1 -carboxyglutamate in enzymes of blood Thiamin Peripheral nerve damage (beriberi) or central nervous system lesions (Wernicke-Korsakoff syndrome Coenzyme in pyruvate and -ketoglutarate dehydrogenases. carotene differentiation ( -carotene is an antioxidant) D Calciferol Maintenance of calcium balance. nicotinamide Coenzyme in oxidation and reduction reactions. pyridoxamine Coenzyme in transamination and decarboxylation of amino acids and glycogen phosphorylase. enhances absorption of iron Scurvy—impaired wound healing. keratinization of skin Retinol.