Page 216 - Concise Pathology for Exam Preparation ( PDFDrive )

8 Genetic and Paediatric Disorders 201

Q. Write briefly on gene polymorphism.
Ans. Gene polymorphism is an occurrence in a population of two or more genotypes in
frequencies that cannot be accounted for by recurrent mutation. Genetic variations occurring
in more than 1% of a population would be considered useful polymorphisms for genetic
linkage analysis. Such occurrences are generally long term. Genetic polymorphism may be
balanced (such that allele frequencies are in equilibrium with one another at a given locus) or
transient (such that a mutation is spreading through the population in a constant direction).

Q. What are SNP genotyping arrays?

Ans. Single nucleotide polymorphism (SNP) genotyping arrays are newer genomic arrays
based on identification of SNPs sites genome wide. SNPs are the most common DNA
polymorphisms which occur after every thousand nucleotides throughout the
genome. SNP arrays are used to find copy number abnormalities when the karyotype is
normal but a structural abnormality is suspected.

Q. Write briefly on the biochemical consequences of single gene
Mendelian disorders.
Ans. The following mechanisms are involved in single-gene disorders:
1. Enzyme defects.
2. Defects in membrane receptors.
3. Abnormalities in the quantity, structure and function of nonenzymatic proteins.
4. Mutations leading to aberrant drug reactions.

Enzyme Defects

Mutations may result in the synthesis of a defective enzyme or synthesis of reduced quan-
tity of a normal enzyme. The biochemical consequences of an enzyme defect in such a
reaction may lead to three major consequences:
1. Defect in an enzyme in a major pathway may result in accumulation of the substrate or
one or more intermediates. An increased level of one of the intermediates stimulates the
minor pathway leading to an excess of other metabolites. Excess quantity of the sub-
strate or the intermediates may lead to tissue injury, particularly if they are toxic in
nature. For example, in galactosaemia, the deficiency of galactose-l-phosphate uridyl-
transferase leads to the accumulation of galactose and consequent tissue damage.
2. An enzyme defect can block a major pathway and lead to decreased amount of end
product that may be necessary for normal function. For example, a deficiency of mela-
nin may result from lack of tyrosinase, which is necessary for biosynthesis of melanin
from its precursor, tyrosine leading to a clinical condition called albinism.
3. Failure to inactivate a tissue-damaging substrate, eg, a1-antitrypsin (a1-AT) deficiency.
Patients who have an inherited deficiency of serum a1-AT are unable to inactivate
neutrophil elastase in their lungs. This leads to destruction of elastin in the alveolar
walls, resulting eventually in pulmonary emphysema.

Defects in Membrane Receptors

Defective receptor mediated transport as seen in familial hypercholesterolemia (decreased
number or defective function of LDL receptors leads to impaired transport of LDL into
cells and excessive cholesterol synthesis).

Abnormalities in the Quantity, Structure and Function of
Nonenzymatic Proteins

Examples of genetic disorders with abnormalities in the quantity, structure and function
of nonenzymatic proteins include haemoglobinopathies like sickle cell anemia. Other

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