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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


NADH cytochrome b5

Diminished oxygen-carring capacity of ferric Hb (metHb) headache, lightheadedness, dyspenea and chocolate

Α-thalassemia: Silent Carrier

1 defective

No symptoms

Mild Symptoms

2 defective

2 alpha chains missing

Hb B

4 defective

Accumulation of γ4 tetramers in newborns, HYDROPS FATALIS


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


Proly/lysyl hydroxylase

Vit C def. no hydroxylation


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


α1- anti-trypsin deficiency

Inherited defect in alpha 1 anti-trypsin resulting in emphysema

Β-thalassemia: major


Affect glomerular basement membrane, hearing loss, ocular defects


Antibodies destroy basement membrane of pulmonary and glomerular capillaries

Electron transport blockers

Lysyl oxidase/Cu

Deficient cross linking secondary to functional copper deficiency; depigmented
(steely) hair, arterial tortuosity and rupture, cerebral degeneration, anemia, osteoporosis.

Complex1 NADH

Amobarbital, rotenone

Complex III cytochrome

Antimycin A

Complex IV cytochrome


Complex V (ATP






retinal pigmentation MELAS Mitochondrial myopathy. sensorineural deafness GLUCOSE & PYRUVATE METABOLISM Pyruvate dehydrogenase deficiency Pyruvate dehydrogenase Lactic acidosis. oldest RBCs removed Amyotrophic Lateral Sclerosis Superoxide dismutase Degenerated motor neurons in CNS Chronic granulomatosis NADPH oxidase Persistant chronic pyogenic infections. galactosemia. deficiency of enzyme located in leukocyte membrane Glycogen synthase Hypoglycemia. gout Essential fructosuria Fructokinase Benign condition. hemolytic anemia. ataxia. episodic ataxia after meal Arsenic poisoning G3PDH Lost NADH. lactic acidosis. heart block. blindness in early adult HEREDITARY MITOCHONDRIAL DISEASES Leber’s hereditary optic neuropathy Kearns-Sayre Ragged red fibers. pyruvate accumulates Pyruvate kinase deficiency Pyruvate kinase Most common enzyme deficiency in glycolytic pathway. galactosuria Galactokinase deficiency Galactokinase Cataracts. infancy death. hemolytic anemia often induced by infections. neonatal death. inadequate NADPH production results in reduction in antioxidant activity of glutathione in mature RBC’s Class I: chronic nonspherocytin anemia. oxidant drugs & fava beans. death. neurologic defects (Wernicke-Korsakoff) Pyruvate DH complex deficiency Pyruvate DH complex Pyuvate to lactate. normal stability. mental retardation. cataracts. renal disease. galactosuria 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. scarce activity in RBCs Class III: A-. most severe Class II: Mediterranean. encephalomyopathy. jaundice GALACTOSE METABOLISM Classical galactosemia GALT Cirrhosis. hyperketonia GLYCOGEN STORAGE DISEASES Type 0 2 . fructosuria HMP PATHWAY/NADPH RELATED DISORDERS Hemolytic Anemia G6PD X linked. stroke-like episodes MERRF Myoclonus epilepsy with ragged red fibers. hypophosphatemia.Malonate Succinate dehydrogenase Inhibited Arsenite Α-ketogluconate dehydrogenase Inhibited Complex 1 (NADH dehydrogenase) Degeneration of optic nerve.

physical deformity Lysosomal hydrolytic enzymes Deficiency in ability to phosphorylated mannose residuesof potential lysosomal enzymes. MR. high plasma TAGs and eruptive xanthomas (TAG deposits in skin) and pancreatitis. coarse facial features. TAGs. elevated N-linked glycoproteins in urine. early death Hunter’s Iduronate sulfatase X-linked. diabeties Type V hyperlilidemia Inc. elevated LDL levels Familial hypercholesterolemia Apolipoprotein E Accumulation of chylomicron remnants in plasma Type IV hyperlipidemia Inc. severe fasting hypoglycemia Pompe’s (Type II) α-1-4 glucosidase (acid maltase) Infants: mental retardation. results in incorrect targeting of glycoproteins. hepatomegaly Andersen’s (Type IV) Glucosyl-4-6-transferase Hepatosplenomegaly. fatigue. physical deformity. VLDL. no increase in lactic acid after exercise Hers’ (Type VI) Liver glycogen phosphorylase Mild hypoglycemia Hurler’s α-L-iduronidase Corneal clouding. liver failure. Mucopolysaccharidoses Synthesis of glycoproteins I-cell disease Metabolism of Dietary Lipids Type II hyperlipidemia Type III hyperlipidemia (familial dysbetalipoproteinemia) Genetic defect in synthesis. MR Sanfilippo’s Types A-D Type-Aheparan sulfate Type BNacetylglucosaminidase Type CNacetyltransferase Type D Nacetylglucosamine Severe nervous system disorders. Congenital A-beta-lipoproteinemia Apo B-48 Accum of chylomicrons in enterocytes Type 1 hyperlipidemia (familial hyperchylomicronemia) Apo C-II. alcohol. chylomicrons. cardiomegaly. death by 2 yrs. VLDL due to obesity. death by 8 yrs. juvenile myopathy Adult: gradual skeletal myopathy Cori’s (Type III) α-1-6 glucosidase Mild hypoglycemia. processing or functioning of LDL receptor. death by 2 yrs McArdle’s (Type V) Muscle glycogen phosphorylase Muscle cramping. mental retardation Scheie’s α-L-iduronidase Like Hurler’s but normal life span Sly’s β-glucronidase Hepatosplenomegaly.VON Gierke’s (Type 1) Glucose 6-phosphate Hepatosplenomegaly. pancreatitis 3 . Capillary lipoprotein lipase Accumulation of chylomicrons in plasma.

MR. liver disease CAT-1 def Liver cannot synthesize glucose during fast. fatal in 1st decade Krabbe’s β-galactosidase Inc. cause of 10% SIDS cases. metabolic acidosis Phospholipid metabolism Niemann-Pick Type A Sphingomyelinase Type B Type C Cherry red macula. globosides. glucocerebrosides. hypoglycemia. fatal early in life Cholesterol & steroid metabolism CAH Congenital Adrenal Hyperplasia SPHINGOLIPIDOSES 4 . skeletal deformities. redish purple skin rash Farber’s Ceraminidase Inc. MR. muscle weakness following exercise Medium chain Fattyacyl CoA dehydrogenase deficiency Medium chain fatty acyl CoA Decreased FA oxidation. ceramide. increased phytanic acid. fatal GM1 gangliosidosis β-galactosidase GM1 accumulation. neurologic symptoms Vit B12 def Methylmalonic academia and aciduria. same symptoms as Tay-Sachs with rapid progression. Fabry’s α-galactosidase Inc. granulomas. death in early adulthood Sphingomyelinase Cannot transport unesterified cholesterol out of lysosomes Tay-Sachs β-hexoaminidase A Cherry-red macula inc. low HDL Fish Eye Disease Partial LCAT absense Zellweger syndrome Defective peroxisomal biogenesis.Wolman disease Cannot hydrolyze lysosomal cholesteryl esters Familial LCAT deficiency Complete absence of LCAT. destroyed myelin Mobilization of Stored Fats & [FA] Carnitine deficiency inability to use long chain FA as fuel. kidney & heart failure. death Sandhoff’s disease Β-hexosaminidase A & B Inc. accumulated VLCFAs in blood X-linked Leukodystrophy Defective peroxisomal activation of VLCFAs. painful and progressively deformed joints. inc. GM2. death CAT-2 def Cardiomyopathy. MR. demyelination. hepatosplenomegaly. blindness. almost total absence of myelin. Reyes syndrome. galactocerebrosides. MR. frequently fatal Metachromatic leukodystrophy Arylsuldatase A MR. early death Gaucher’s β-glucosidase Sphingolipidosis. hepatosplenomegaly. globosides. severe hypoglycemia. severe mental retardation. X linked. causes: congenital. treat with high carb diet Paroxysomal Nocturnal Hemoglobinuria GPI synthase In hematopoietic cells Refsum disease Fatty acid alphahydroxylase AR. coma. death in early childhood Chronic lung damage.

needs stimulation to feed. hypothermia. gives inc. alcoholism Cholelithiasis Cholesterol gallstones Malabsorption. androgens. no clinical symptoms UREA CYCLE Type I Hyperammonemia 5 . No glucocorticoids. neurologic problems Propionyl CoA Carboxylase Deficiency Elevated propionate in blood. or estrogen. early death 17-α -hydroxylase deficiency 17-α -hydroxylase Sex hormones & cortisol not produced inc. mother didn’t stay within dietary restrictions during pregnancy Alcaptonuria Homogentisate oxidase Benign. glycine in blood. without appropriate intervention death occurs. increase tyrosine Malignant PKU Dihydrobiopterin reductase/ synthase Similar to classic PKU. 5-hydroxytryptophan Maternal PKU Mother with either classic or malignant Developmental abnormalities. homogentisate accumulation forms polymers which darkens standing urine. masculization Classic PKU Phenylalanine hydroxylase MR. dec. melanin synthesis. microcephaly. melatonin and serotonin synthesis also compromised. sex hormones & masculinization 11-β-hydroxylase deficiency 11-β -hydroxylase Dec. accumulation of odd chain FA in liver. L-dopa. Carbamoylphosphate synthetase I Within 24-48 hrs after birth infant becomes increasingly lethargic. hepatic dysfunction. vomiting. treat with arginine which AMINO ACID METABOLISM Accumulation of cystathionine and metabolites. mineralocorticoids. mousy odor.Smith-Lemli-Opitz Syndrome 7-hydrocholesterol-7reductase AR. double bond migration (Lanosterol to Cholesterol) Fatty Liver Imbalanced TG synthesis and VLDL secretion Causes: obesity. screen after 1st exposure to phenylalanine in breat milk. & hyperventilation. pregnenolone. MR. production of aldosterone gives HTN. elevated methionine & metabolites in blood. developmental problems Cystathioninuria Propionyl CoA Carboxylase Cystathionase Homocystinuria Cystathionine synthetase Accumulation of homocysteine in urine. cortisol & aldesterone. phenotypically female but unable to mature 21-α -hydroxylase deficiency 21-α -hydroxylase Most common CAH. add tyrosine. ACTH levels inc. restrict phenylalanine. MR. inc. diabetes mellitus. restrict phenylalanine intake. Ochronosis. 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.. fair skin. treat: laparoscopic cholecystectomy 3-β-hydroxysteroid dehydrogenase def 3-β-hydroxysteroid dehydrogenase Inc. obstructed biliary tract. high mortality rate. 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. congenital pyloric stenosis.

masculinization 11-β-hydroxylase def. inc. seizures. early death 17-α-hydroxylase def. androgens/estrogens. elevated plasma and CSF argininosuccunate. and corticosterone. Hyperargininemia Arginase Rare UCD progressive spastic quadriplegia and MR high ammonia & arginine in CSF & serum. high arginine. cortisol. early death 21-α-hydroxylase def. aldesterone. No glucocorticoids. acidosis. hypernatremia. only X linked. ALA and protoporphyrin XI. treat with blue light Lead poisoning ferrochelatase/ ALA dehydratase Inc. treatment includes administration of carbamoyl glutamate which activates CPS I Type 2 hyperammonemia Ornithine transcarbmoylase Most commonly occurring UCD. HTN. ataxia. uroporphyrinogen III which converts to uroporphyrinogen I & coproporphyrinogen I Hereditary Coproporphyria Coproporphyrinogen oxidase Inc. inc. feminine genitalia. treat with high carb. vomiting. treat with low protein diet including essential AA but no arginine Acute Intermittent porphyria Uroporphyrinogen synthase Autosomal dominant. ataxia. androgens. fluid retention. recurrent diarrhea. and ornithine in urine. uroporphyrinogen I & uroporphyninI Prophyria Cutanea Tarda Uroporphyrinogen decarboxylase Inc. porphobilinogen & ALA in urine. deoxycorticosterone. heme HEME BIOSYNTHESIS/DEGREDATION CONGENITAL ADRENAL HYPERPLASIA 3-β-hydroxysteroid DH def. lethargy. Greater than 90% CAH. Dec. DEC. feminine genitalia. hyperornithinemia. no mineralo/glucocorticoids. 6 . coproporphyrinogen III Varigate Porphyria Protoporphyrin oxidase Accumulation of protoporphyrinogen IX Erythropoietic Protoporphyria Ferrochelatase Accumulation of protoporphyrin IX Sideroblastic Anemia ALA synthase X-linked Crigler-Najjar syndrome Bilirubin glucuronyl transferase In newborns: newborn jaundice. inc. increased serum orotic acid due to mitochondrial carbamoylphosphate entering cytosoland incorporating in pyrimidine nucleotides leading to excess productin and excess catabolic products. treat with arginine to increase citruline excertion and sodium benzoate to detox ammonia Argininosuccinate Aciduria Argininosuccinate lyase (argininosuccinase) Episodic symptoms similar to classic citrullinemia. inc. treat with argentine and sodium benzoate. coma. cortisol. and sodium phenylacetate/benzoate for ammonia detox Classic Citrullinemia Argininosuccunate synthetase Episodic hyperammonemia. hypoglycemia. hyponatremia. lysine.activates N-acetylglutamate synthetase N-acetylglutamate synthetase deficiency N-acetylglutamate synthetase Severe/mild hyperammonemia associated wuth deep coma. mineralocorticoids. mineralocorticoids. attacks precipitated by drugs that induce cytochrome P450 in liver Congenital erythropoietic porphyria Uroporphyeinogen III synthase Inc. low protein diet. increased ammonia and aa in serum. HTN. No sex hormones.

25-diOH D3 Children: rickets. PABA analogues. dihydrofolate inhibitors Purine & thymine síntesis.masculinization LETTER NAME COENZYME/ ACTIVE FORM DEFICIENCY REACTIONS TYPE B1 Thiamine TPP Beri-beri. methylcobalamin Pernicious anemia. pyruvate carboxylase Carboxylation B6 Pantothenic acid CoA Not significant Citrate & FA synthase Acyl carrier B Folic Acid THF Megaloblastic anemia. Gly. glossitis. adults: osteomalacia Calcium levels in plasma K Phyllo/menaquinones Same Hypothrombinemia Formation of gcarboxyglutamate E Tocopherols α-tocopherol Abnormal cell membranes Redox Carboxylation of certain Glu residues Anti-oxidant 7 . B6 Biotin Biotin Adivin.propionyl carboxulase. NADP Pellagra. folate trap Synth of Met & isomerization of methylmalonyl CoA succinyl CoA B6 Pyridoxine. sterility. isoniazid can induce deficiency AST. decaeboxyl ation. transfer of α-ketols B2 Riboflavin FAD. PDC and α-KG Dehydrogenase Oxidative. Wernicke-Korsakoff Transketolase. CNS symotoms. anorexia. cheilosis.ALT Transamination. skin problems Visual cycle D Cholecalciferol 1. pyridoxal Pyridoxal PO4 Rare. Met. neural tube defects. nausea Acetyl carboxylase. Ser. hydrox of Praline & lysine A Retinol Retinol in vision. retinoic acid in epithelial cells Blindness. deamination C Ascorbic acid Ascorbic acid Scurvey Hydroxylation of praline in collagen Antioxidant. FMN Dermatitis. glossitis Succinate DH Redox B3 Niacin NAD. Cys 1 C metabolism B12 Cobalamin 5’deoxyadenosyl cobalamin. 3 D’s. dermatitis.