This document summarizes many metabolic disorders organized by the affected enzyme, pathway, or type of disorder. Some key disorders mentioned include: - Sickle cell anemia caused by a mutation replacing glutamate with valine on the beta globin chain. - Various thalassemias caused by defects in alpha or beta globin chain production leading to anemia. - Phenylketonuria caused by a defect in phenylalanine hydroxylase leading to intellectual disability if untreated. - Glycogen storage diseases caused by defects in glycogen breakdown enzymes leading to hypoglycemia. - Urea cycle disorders caused by enzyme defects preventing ammonia detoxification leading to hyperammone

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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
THALASSEMIAS
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
HbH 3 defective Accumulation of β4 tetramers in newborns, severe anemia
Β-thalassemia: major Deletion of both betas Both β chains defective, fatal HEINZ bodies, inability of HbF HbA, manifests around 8 mos old.
Minor Deletion of 1 beta chain Only 1 β chain defective, not fatal
COLLAGEN DISEASES
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
Alport’s Affect glomerular basement membrane, hearing loss, ocular defects
Goodpasture’s Antibodies destroy basement membrane of pulmonary and glomerular capillaries
Menke’s Lysyl oxidase/Cu2+
Deficient cross linking secondary to functional copper deficiency; depigmented
(steely) hair, arterial tortuosity and rupture, cerebral degeneration, anemia, osteoporosis.
ETC INHIBITORS
Electron transport blockers Complex1 NADH dehydrogenase Amobarbital, rotenone
Complex III cytochrome reductase Antimycin A
Complex IV cytochrome oxidase CO,CN
Complex V (ATP synthase) Oligomycin
TCA CYCLE
Fluoroacetate Aconitase Inhibited
Malonate Succinate dehydrogenase Inhibited
Arsenite Α-ketogluconate dehydrogenase Inhibited
HEREDITARY MITOCHONDRIAL DISEASES
Leber’s hereditary optic neuropathy Complex 1 (NADH
dehydrogenase)
Degeneration of optic nerve, blindness in early adult
Kearns-Sayre Ragged red fibers, heart block, retinal pigmentation

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MELAS Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like episodes
MERRF Myoclonus epilepsy with ragged red fibers; ataxia, sensorineural deafness
GLUCOSE & PYRUVATE METABOLISM
Pyruvate dehydrogenase deficiency Pyruvate dehydrogenase Lactic acidosis, neurologic defects (Wernicke-Korsakoff)
Pyruvate DH complex deficiency Pyruvate DH complex Pyuvate to lactate, neonatal death, infancy death, episodic ataxia after meal
Arsenic poisoning G3PDH Lost NADH, pyruvate accumulates
Pyruvate kinase deficiency Pyruvate kinase Most common enzyme deficiency in glycolytic pathway; hemolytic anemia, jaundice
GALACTOSE METABOLISM
Classical galactosemia GALT Cirrhosis, mental retardation, cataracts, galactosuria
Galactokinase deficiency Galactokinase Cataracts, galactosemia, 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, renal disease, hypophosphatemia, gout
Essential fructosuria Fructokinase Benign condition, fructosuria
HMP PATHWAY/NADPH RELATED DISORDERS
Hemolytic Anemia G6PD X linked, hemolytic anemia often induced by infections, oxidant drugs & fava beans; inadequate NADPH
production results in reduction in antioxidant activity of glutathione in mature RBC’s
Class I: chronic nonspherocytin anemia, most severe
Class II: Mediterranean, normal stability, scarce activity in RBCs
Class III: A-, oldest RBCs removed
Amyotrophic Lateral Sclerosis Superoxide dismutase Degenerated motor neurons in CNS
Chronic granulomatosis NADPH oxidase Persistant chronic pyogenic infections; deficiency of enzyme located in leukocyte membrane
GLYCOGEN STORAGE DISEASES
Type 0 Glycogen synthase Hypoglycemia, death, hyperketonia
VON Gierke’s (Type 1) Glucose 6-phosphate Hepatosplenomegaly, severe fasting hypoglycemia
Pompe’s (Type II) α-1-4 glucosidase
(acid maltase)
Infants: mental retardation, cardiomegaly, death by 2 yrs; juvenile myopathy
Adult: gradual skeletal myopathy
Cori’s (Type III) α-1-6 glucosidase Mild hypoglycemia, hepatomegaly
Andersen’s (Type IV) Glucosyl-4-6-transferase Hepatosplenomegaly, liver failure, death by 2 yrs
McArdle’s (Type V) Muscle glycogen phosphorylase Muscle cramping, fatigue, no increase in lactic acid after exercise
Hers’ (Type VI) Liver glycogen phosphorylase Mild hypoglycemia
Mucopolysaccharidoses
Hurler’s α-L-iduronidase Corneal clouding, MR, coarse facial features, early death
Hunter’s Iduronate sulfatase X-linked, physical deformity, MR

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Sanfilippo’s Types A-D Type-Aheparan sulfate
Type BN-
acetylglucosaminidase
Type CN-acetyltransferase
Type D N-acetylglucosamine
Severe nervous system disorders; mental retardation
Scheie’s α-L-iduronidase Like Hurler’s but normal life span
Sly’s β-glucronidase Hepatosplenomegaly, physical deformity
Synthesis of glycoproteins
I-cell disease Lysosomal hydrolytic enzymes Deficiency in ability to phosphorylated mannose residuesof potential lysosomal enzymes;
results in incorrect targeting of glycoproteins; death by 8 yrs; elevated N-linked glycoproteins in urine.
Metabolism of Dietary Lipids
Congenital A-beta-lipoproteinemia Apo B-48 Accum of chylomicrons in enterocytes
Type 1 hyperlipidemia (familial hyperchylomicronemia) Apo C-II, Capillary lipoprotein
lipase
Accumulation of chylomicrons in plasma; high plasma TAGs and eruptive xanthomas (TAG deposits in skin) and
pancreatitis.
Type II hyperlipidemia Genetic defect in synthesis, processing or functioning of LDL receptor; elevated LDL levels
Familial hypercholesterolemia
Type III hyperlipidemia (familial dysbetalipoproteinemia) Apolipoprotein E Accumulation of chylomicron remnants in plasma
Type IV hyperlipidemia Inc. VLDL due to obesity, alcohol, diabeties
Type V hyperlilidemia Inc. chylomicrons, TAGs, VLDL, pancreatitis
Wolman disease Cannot hydrolyze lysosomal cholesteryl esters
Familial LCAT deficiency Complete absence of LCAT, 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, destroyed myelin
Mobilization of Stored Fats & [FA]
Carnitine deficiency inability to use long chain FA as fuel, causes: congenital, liver disease
CAT-1 def Liver cannot synthesize glucose during fast, hypoglycemia, coma, death
CAT-2 def Cardiomyopathy, muscle weakness following exercise
Medium chain Fattyacyl CoA dehydrogenase deficiency Medium chain fatty acyl CoA Decreased FA oxidation, severe hypoglycemia; cause of 10% SIDS cases, Reyes syndrome; treat with
high carb diet
Paroxysomal Nocturnal Hemoglobinuria GPI synthase In hematopoietic cells
Refsum disease Fatty acid alpha-hydroxylase AR, increased phytanic acid, neurologic symptoms

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Vit B12 def Methylmalonic academia and aciduria, metabolic acidosis
Phospholipid metabolism
Niemann-Pick Type A Sphingomyelinase Cherry red macula, hepatosplenomegaly, severe mental retardation, death in early childhood
Type B Chronic lung damage, death in early adulthood
Type C Sphingomyelinase Cannot transport unesterified cholesterol out of lysosomes
SPHINGOLIPIDOSES
Tay-Sachs β-hexoaminidase A Cherry-red macula inc. GM2, blindness, MR, early death
Gaucher’s β-glucosidase Sphingolipidosis, inc. glucocerebrosides, hepatosplenomegaly, MR, frequently fatal
Metachromatic leukodystrophy Arylsuldatase A MR, demyelination, fatal in 1st
decade
Krabbe’s β-galactosidase Inc. galactocerebrosides, MR, almost total absence of myelin, fatal
GM1 gangliosidosis β-galactosidase GM1 accumulation, MR, skeletal deformities, death
Sandhoff’s disease Β-hexosaminidase A & B Inc. globosides; same symptoms as Tay-Sachs with rapid progression.
Fabry’s α-galactosidase Inc. globosides; X linked, kidney & heart failure, redish purple skin rash
Farber’s Ceraminidase Inc. ceramide, painful and progressively deformed joints; granulomas, fatal early in life
Cholesterol & steroid metabolism CAH Congenital Adrenal Hyperplasia
Smith-Lemli-Opitz Syndrome 7-hydrocholesterol-7-reductase AR, double bond migration (Lanosterol to Cholesterol)
Fatty Liver Imbalanced TG synthesis and
VLDL secretion
Causes: obesity, diabetes mellitus, alcoholism
Cholelithiasis Cholesterol gallstones Malabsorption, obstructed biliary tract, hepatic dysfunction; treat: laparoscopic cholecystectomy
3-β-hydroxysteroid dehydrogenase def 3-β-hydroxysteroid dehydrogenase Inc. pregnenolone, No glucocorticoids, mineralocorticoids, androgens, or estrogen; early death
17-α -hydroxylase deficiency 17-α -hydroxylase Sex hormones & cortisol not produced inc. production of aldosterone gives HTN, phenotypically female
but unable to mature
21-α -hydroxylase deficiency 21-α -hydroxylase Most common CAH; ACTH levels inc. gives inc. sex hormones & masculinization
11-β-hydroxylase deficiency 11-β -hydroxylase Dec. cortisol & aldesterone; masculization
AMINO ACID METABOLISM
Classic PKU Phenylalanine hydroxylase MR, dec. melanin synthesis; fair skin, mousy odor, congenital pyloric stenosis, screen after 1st exposure
to phenylalanine in breat milk, restrict phenylalanine intake, increase tyrosine
Malignant PKU Dihydrobiopterin reductase/
synthase
Similar to classic PKU, melatonin and serotonin synthesis also compromised., restrict phenylalanine,
add tyrosine, L-dopa, 5-hydroxytryptophan

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Maternal PKU Mother with either classic or
malignant
Developmental abnormalities, microcephaly, MR, mother didn’t stay within dietary restrictions during
pregnancy
Alcaptonuria Homogentisate oxidase Benign; homogentisate accumulation forms polymers which darkens standing urine. Ochronosis;
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; high mortality rate;
neurologic problems
Propionyl CoA Carboxylase Deficiency Propionyl CoA Carboxylase Elevated propionate in blood; accumulation of odd chain FA in liver; developmental problems
Cystathioninuria Cystathionase Accumulation of cystathionine and metabolites, no clinical symptoms
Homocystinuria Cystathionine synthetase Accumulation of homocysteine in urine, elevated methionine & metabolites in blood, MR, osteoporosis
Histidinemia Histidase Elevated histadine in blood and urine, 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, inc. glycine in blood.
UREA CYCLE
Type I Hyperammonemia Carbamoylphosphate synthetase I Within 24-48 hrs after birth infant becomes increasingly lethargic, needs stimulation to feed, vomiting,
hypothermia, & hyperventilation; without appropriate intervention death occurs; treat with arginine which
activates N-acetylglutamate synthetase
N-acetylglutamate synthetase deficiency N-acetylglutamate synthetase Severe/mild hyperammonemia associated wuth deep coma, acidosis, recurrent diarrhea, ataxia, hypoglycemia,
hyperornithinemia; treatment includes administration of carbamoyl glutamate which activates CPS I
Type 2 hyperammonemia Ornithine transcarbmoylase Most commonly occurring UCD, only X linked, increased ammonia and aa in serum, increased serum
orotic acid due to mitochondrial carbamoylphosphate entering cytosoland incorporating in pyrimidine
nucleotides leading to excess productin and excess catabolic products; treat with high carb, low protein diet,
and sodium phenylacetate/benzoate for ammonia detox
Classic Citrullinemia Argininosuccunate synthetase Episodic hyperammonemia, vomiting, lethargy, ataxia, seizures, coma; treat with arginine to increase
citruline excertion and sodium benzoate to detox ammonia
Argininosuccinate Aciduria Argininosuccinate lyase
(argininosuccinase)
Episodic symptoms similar to classic citrullinemia, elevated plasma and CSF argininosuccunate;
treat with argentine and sodium benzoate.
Hyperargininemia Arginase Rare UCD progressive spastic quadriplegia and MR high ammonia & arginine in CSF & serum, high arginine,
lysine, and ornithine in urine; treat with low protein diet including essential AA but no arginine
HEME BIOSYNTHESIS/DEGREDATION
Acute Intermittent porphyria Uroporphyrinogen synthase Autosomal dominant, inc. porphobilinogen & ALA in urine, attacks precipitated by drugs that induce
cytochrome P450 in liver
Congenital erythropoietic porphyria Uroporphyeinogen III synthase Inc. uroporphyrinogen I & uroporphyninI
Prophyria Cutanea Tarda Uroporphyrinogen decarboxylase Inc. uroporphyrinogen III which converts to uroporphyrinogen I & coproporphyrinogen I
Hereditary Coproporphyria Coproporphyrinogen oxidase Inc. coproporphyrinogen III
Varigate Porphyria Protoporphyrin oxidase Accumulation of protoporphyrinogen IX

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Erythropoietic Protoporphyria Ferrochelatase Accumulation of protoporphyrin IX
Sideroblastic Anemia ALA synthase X-linked
Crigler-Najjar syndrome Bilirubin glucuronyl transferase In newborns: newborn jaundice, treat with blue light
Lead poisoning ferrochelatase/ ALA
dehydratase
Inc. ALA and protoporphyrin XI, DEC. heme
CONGENITAL ADRENAL HYPERPLASIA
3-β-hydroxysteroid DH def. No glucocorticoids, mineralocorticoids, androgens/estrogens, hyponatremia, feminine genitalia,
early death
17-α-hydroxylase def. No sex hormones, cortisol, inc. mineralocorticoids, hypernatremia, HTN, feminine genitalia,
early death
21-α-hydroxylase def. Greater than 90% CAH, no mineralo/glucocorticoids, inc. androgens, masculinization
11-β-hydroxylase def. Dec. cortisol, aldesterone, and corticosterone, inc. deoxycorticosterone; fluid retention, HTN,
masculinization
LETTER NAME COENZYME/
ACTIVE FORM
DEFICIENCY
B1 Thiamine TPP Beri-beri; Wernicke-Korsakoff
B2 Riboflavin FAD, FMN Dermatitis, cheilosis, glossitis
B3 Niacin NAD, NADP Pellagra; 3 D’s,
B6 Biotin Biotin Adivin; dermatitis, glossitis, anorexia, nausea
B6 Pantothenic acid CoA Not significant
B Folic Acid THF Megaloblastic anemia, neural tube defects, PABA analogues, dihydrofolate inhibitors
B12 Cobalamin 5’deoxyadenosyl cobalamin,
methylcobalamin
Pernicious anemia, CNS symotoms, folate trap
B6 Pyridoxine, pyridoxal Pyridoxal PO4 Rare, isoniazid can induce deficiency
C Ascorbic acid Ascorbic acid Scurvey
A Retinol Retinol in vision, retinoic acid in epithelial
cells
Blindness, sterility, skin problems
D Cholecalciferol 1,25-diOH D3 Children: rickets, adults: osteomalacia
K Phyllo/menaquinones Same Hypothrombinemia
E Tocopherols α-tocopherol Abnormal cell membranes

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Vitamin Functions Deficiency disease
A
Retinol, carotene
Visual pigments in the retina; regulation of gene expression and cell
differentiation ( -carotene is an antioxidant)
Night blindness, xerophthalmia; keratinization of skin
D Calciferol Maintenance of calcium balance; enhances intestinal absorption of Ca2+
and mobilizes bone mineral; regulation of gene expression and cell
differentiation
Rickets = poor mineralization of bone; osteomalacia = bone demineralization
E Tocopherols, tocotrienols Antioxidant, especially in cell membranes; roles in cell signaling Extremely rare—serious neurologic dysfunction
K Phylloquinone: menaquinones
Coenzyme in formation of -carboxyglutamate in enzymes of blood
clotting and bone matrix
Impaired blood clotting, hemorrhagic disease
B1 Thiamin
Coenzyme in pyruvate and -ketoglutarate dehydrogenases, and
transketolase; regulates Cl–
channel in nerve conduction
Peripheral nerve damage (beriberi) or central nervous system lesions (Wernicke-Korsakoff syndrome
B2 Riboflavin Coenzyme in oxidation and reduction reactions; prosthetic group of
flavoproteins
Lesions of corner of mouth, lips, and tongue, seborrheic dermatitis
Niacin Nicotinic acid, nicotinamide Coenzyme in oxidation and reduction reactions, functional part of NAD
and NADP; role in intracellular calcium regulation and cell signaling
Pellagra—photosensitive dermatitis, depressive psychosis
B6 Pyridoxine, pyridoxal,
pyridoxamine
Coenzyme in transamination and decarboxylation of amino acids and
glycogen phosphorylase; modulation of steroid hormone action
Disorders of amino acid metabolism, convulsions
Folic acid Coenzyme in transfer of one-carbon fragments Megaloblastic anemia
B12 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; role in regulation of cell cycle
Impaired fat and carbohydrate metabolism, dermatitis
C Ascorbic acid Coenzyme in hydroxylation of proline and lysine in collagen synthesis;
antioxidant; enhances absorption of iron
Scurvy—impaired wound healing, loss of dental cement, subcutaneous hemorrhage