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 4 tetramers in newborns, HYDROPS FATALIS

HbH

3 defective

Accumulation of 4 tetramers in newborns, severe anemia

Deletion of both betas

Both chains defective, fatal HEINZ bodies, inability of HbF HbA, manifests around 8 mos old.

Deletion of 1 beta chain

Only 1 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

1- anti-trypsin deficiency

Inherited defect in alpha 1 anti-trypsin resulting in emphysema

THALASSEMIAS
-thalassemia: Silent Carrier
Mild Symptoms

-thalassemia: major
Minor
COLLAGEN DISEASES

Alports

Affect glomerular basement membrane, hearing loss, ocular defects

Goodpastures

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

-ketogluconate dehydrogenase

Inhibited

Complex 1 (NADH
dehydrogenase)

Degeneration of optic nerve, blindness in early adult

Menkes
ETC INHIBITORS
Electron transport blockers

TCA CYCLE

HEREDITARY MITOCHONDRIAL DISEASES

Lebers hereditary optic neuropathy
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

Classical galactosemia

GALT

Cirrhosis, mental retardation, cataracts, galactosuria

Galactokinase deficiency

Galactokinase

Cataracts, galactosemia, 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, renal disease, hypophosphatemia, gout

Essential fructosuria

Fructokinase

Benign condition, fructosuria

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 RBCs
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

Type 0

Glycogen synthase

Hypoglycemia, death, hyperketonia

VON Gierkes (Type 1)

Glucose 6-phosphate

Hepatosplenomegaly, severe fasting hypoglycemia

Pompes (Type II)

-1-4 glucosidase
(acid maltase)

Infants: mental retardation, cardiomegaly, death by 2 yrs; juvenile myopathy

Adult: gradual skeletal myopathy

Coris (Type III)

-1-6 glucosidase

Mild hypoglycemia, hepatomegaly

Andersens (Type IV)

Glucosyl-4-6-transferase

Hepatosplenomegaly, liver failure, death by 2 yrs

McArdles (Type V)

Muscle glycogen phosphorylase

Muscle cramping, fatigue, no increase in lactic acid after exercise

Hers (Type VI)

Liver glycogen phosphorylase

Mild hypoglycemia

Hurlers

-L-iduronidase

Corneal clouding, MR, coarse facial features, early death

Hunters

Iduronate sulfatase

X-linked, physical deformity, MR

HMP PATHWAY/NADPH RELATED DISORDERS

GLYCOGEN STORAGE DISEASES

Mucopolysaccharidoses

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Sanfilippos Types A-D

Type-Aheparan sulfate
Type BNacetylglucosaminidase
Type CN-acetyltransferase
Type D N-acetylglucosamine

Severe nervous system disorders; mental retardation

Scheies

-L-iduronidase

Like Hurlers but normal life span

Slys

-glucronidase

Hepatosplenomegaly, physical deformity

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.

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.

Synthesis of glycoproteins
I-cell disease
Metabolism of Dietary Lipids

Type II hyperlipidemia
Type III hyperlipidemia (familial dysbetalipoproteinemia)

Genetic defect in synthesis, processing or functioning of LDL receptor; elevated LDL levels
Familial hypercholesterolemia
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

Type B
Type C

Cherry red macula, hepatosplenomegaly, severe mental retardation, death in early childhood
Chronic lung damage, death in early adulthood

Sphingomyelinase

Cannot transport unesterified cholesterol out of lysosomes

Tay-Sachs

-hexoaminidase A

Cherry-red macula inc. GM2, blindness, MR, early death

Gauchers

-glucosidase

Sphingolipidosis, inc. glucocerebrosides, hepatosplenomegaly, MR, frequently fatal

Metachromatic leukodystrophy

Arylsuldatase A

MR, demyelination, fatal in 1st decade

Krabbes

-galactosidase

Inc. galactocerebrosides, MR, almost total absence of myelin, fatal

GM1 gangliosidosis

-galactosidase

GM1 accumulation, MR, skeletal deformities, death

Sandhoffs disease

-hexosaminidase A & B

Inc. globosides; same symptoms as Tay-Sachs with rapid progression.

Fabrys

-galactosidase

Inc. globosides; X linked, kidney & heart failure, redish purple skin rash

Farbers

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--hydroxysteroid dehydrogenase def

3--hydroxysteroid dehydrogenase

Inc. pregnenolone, No glucocorticoids, mineralocorticoids, androgens, or estrogen; early death

17- -hydroxylase deficiency

17- -hydroxylase

Sex hormones & cortisol not produced inc. production of aldosterone gives HTN, phenotypically female
but unable to mature

21- -hydroxylase deficiency

21- -hydroxylase

Most common CAH; ACTH levels inc. gives inc. sex hormones & masculinization

11--hydroxylase deficiency

11- -hydroxylase

Dec. cortisol & aldesterone; masculization

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

SPHINGOLIPIDOSES

AMINO ACID METABOLISM

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Maternal PKU

Mother with either classic or

malignant

Developmental abnormalities, microcephaly, MR, mother didnt 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 -ketoacid

dehydrogenase

Elevated levels of amino acids and their 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.

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

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

UREA CYCLE

HEME BIOSYNTHESIS/DEGREDATION

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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/
dehydratase

Inc. ALA and protoporphyrin XI, DEC. heme

ALA

CONGENITAL ADRENAL HYPERPLASIA

3--hydroxysteroid DH def.

No glucocorticoids, mineralocorticoids, androgens/estrogens, hyponatremia, feminine genitalia,

early death

17--hydroxylase def.

No sex hormones, cortisol, inc. mineralocorticoids, hypernatremia, HTN, feminine genitalia,

early death

21--hydroxylase def.

Greater than 90% CAH, no mineralo/glucocorticoids, inc. androgens, masculinization

11--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 Ds,

B6

Biotin

Biotin

Adivin; dermatitis, glossitis, anorexia, nausea

B6

Pantothenic acid

CoA

Not significant

Folic Acid

THF

Megaloblastic anemia, neural tube defects, PABA analogues, dihydrofolate inhibitors

B12

Cobalamin

5deoxyadenosyl cobalamin,
methylcobalamin

Pernicious anemia, CNS symotoms, folate trap

B6

Pyridoxine, pyridoxal

Pyridoxal PO4

Rare, isoniazid can induce deficiency

Ascorbic acid

Ascorbic acid

Scurvey

Retinol

Retinol in vision, retinoic acid in epithelial

cells

Blindness, sterility, skin problems

Cholecalciferol

1,25-diOH D3

Children: rickets, adults: osteomalacia

Phyllo/menaquinones

Same

Hypothrombinemia

Tocopherols

-tocopherol

Abnormal cell membranes

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Vitamin

Functions

Deficiency disease

Visual pigments in the retina; regulation of gene expression and cell

Night blindness, xerophthalmia; keratinization of skin

Retinol,

carotene
differentiation (

-carotene is an antioxidant)

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

Tocopherols, tocotrienols

Antioxidant, especially in cell membranes; roles in cell signaling

Extremely rareserious neurologic dysfunction

Phylloquinone: menaquinones

Impaired blood clotting, 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, and
transketolase; regulates Cl channel in nerve conduction

B2

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

Pellagraphotosensitive 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

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")

Biotin

Coenzyme in carboxylation reactions in gluconeogenesis and fatty acid

synthesis; role in regulation of cell cycle

Impaired fat and carbohydrate metabolism, dermatitis

Ascorbic acid

Coenzyme in hydroxylation of proline and lysine in collagen synthesis;

antioxidant; enhances absorption of iron

Scurvyimpaired wound healing, loss of dental cement, subcutaneous hemorrhage

B12

Riboflavin