Page 217 - Concise Pathology for Exam Preparation ( PDFDrive )

202 SECTION I General Pathology

proteins affected are collagen (osteogenesis imperfecta), dystrophin (muscular dystrophy),
spectrin (spherocytosis), etc.

Mutations Leading to Aberrant Drug Reactions
Prototypical example is drug induced injury seen in glucose-6-phosphate deficiency. No
haemolysis is seen in these patients under normal circumstances, however, administration
of certain drugs like primaquine can result in severe haemolysis.

Q. Write briefly on enzyme defects and their consequences.
Ans. Disorders associated with defects in enzymes include the following:
1. Phenylketonuria (PKU)
• PKU is characterized by deficiency of phenylalanine hydroxylase, which converts
phenylalanine to tyrosine.
• Infants are normal at birth but they develop increased phenylalanine levels within a
few weeks.
• Rising phenylalanine levels impair development of the brain, leading to severe men-
tal retardation.
• Other clinical features are seizures, decreased pigmentation of the hair and skin,
eczema and strong mousy or musty odour of sweat and urine (due to accumulation
of minor pathway products).
2. Galactosaemia
• Galactose comes from the metabolism of lactose (glucose 1 galactose). In galactosae-
mia, there is a total lack of galactose-1-phosphate uridylyltransferase (GALT)
leading to accumulation of glucose-1-phosphate and galactose.
• Galactose-1-phosphate is toxic and damages tissue resulting in neonatal cholestasis
(may progress to cirrhosis), CNS damage (mental retardation), renal damage (ami-
noaciduria) and Escherichia coli sepsis. Excess galactose may be converted into
polyol (alcohol sugar), which causes osmotic damage to the lens, nerve
tissue, liver and CNS.
3. Homocystinuria
Homocystinuria is due to deficiency of cystathionine synthetase. It resembles Marfan
syndrome (shares arachnodactyly and a dislocated lens). Differentiating features from
Marfan syndrome include mental retardation, thromboembolic episodes (homocysteine
damages endothelial cells) and osteoporosis.
4. Alkaptonuria
• Alkaptonuria (ochronosis) is secondary to a lack of homogentisic oxidase required
for the metabolism of phenylalanine.
• There is an increase in homogentisic acid in urine, which is colourless at first but
turns black after oxidation, upon exposure to light.
• Homogentisic acid binds to collagen in connective tissue, tendons and
cartilage (causing a crippling joint disease), and imparts a black colour to all
these tissues.
5. Lysosomal storage diseases (See question on “Lysosomal storage diseases”).
6. Glycogen storage diseases (See question on “Glycogen storage diseases”).

Q. Write briefly on lysosomal storage diseases.

Ans. Lysosomes contain a variety of hydrolytic enzymes that are involved in degradation
of complex substrates, eg, sphingolipids and mucopolysaccharides, into soluble end
products. Due to a lack of a lysosomal enzyme, catabolism of a substrate remains
incomplete leading to accumulation of the partially degraded insoluble metabolites within
the lysosomes.
• Approximately 40 lysosomal storage diseases have been identified.
• Lysosomal storage diseases have an AR transmission and commonly affect infants and
children.

mebooksfree.com