In this article we will discuss about the Genetic Diseases:- 1. Major Classes of Genetic Diseases 2. Pathologic Consequences 3. Early Diagnosis of Certain Inborn Errors to Avoid Permanent Damage 4. Successful Treatment.
Major Classes of Genetic Diseases:
Genetic diseases can be divided into three classes:
i. Chromosomal Disorders.
ii. Monogenic (Classic Mendelian) Disorders.
iii. Multifactorial Disorders.
i. Chromosomal Disorder:
These are the conditions in which there is an excess or loss of chromosomes, deletion of part of a chromosome, or a translocation. The best known condition is Down syndrome. They can be known by analysis of the karyotype (chromosomal pattern) of an individual. Chromosomal translocations are important in a activating oncogenes.
ii. Monogenic Disorders:
They are classified as:
(a) Autosomal dominant
(b) Autosomal recessive
(c) X-linked.
Dominant is used to mean that the mutation will be clinically evident even if only one chromosome is affected. Recessive denotes that both chromosomes must be affected (homozygous) X- linked indicates that the mutation is present on the X-chromosome.
As females have two chromosomes, they may be either homozygous or heterozygous for the affected gene. Thus X-linked inheritance in females can be dominant or recessive. Males have only one X-chromosome, so that they will be affected if they inherit the mutant gene.
iii. Multifactorial Disorders:
Multifactorial disorders involve the action of a number of genes. The pattern of inheritance of these conditions does not follow classical Mendelian genetics. Less is known about this class, but importance is more because common adult diseases such as ischemic heart disease and hypertension are members of this group.
Pathologic Consequences by Genetic Diseases:
In case, an enzyme is affected by mutation, an inborn error of metabolism may result.
An inborn error of metabolism is a genetic disorder in which a specific enzyme is affected, producing a metabolic block, which leads to pathologic consequences as shown below:
Where E = mutant enzyme and X, Y = alternative products of the metabolism of S. A block has three results.
i. Decreased formation of the product P.
ii. Accumulation of the substrate S behind the block.
iii. Increased formation of metabolites (X, Y) of the substrate S, resulting from its accumulation.
Any one of these three results may have pathologic effects.
In the case of phenylketonuria (PKU), the mutant enzyme is phenylalanine hydroxylase, resulting in the following condition:
So, patients with PKU synthesize less tyrosine, have increased phenylalanine levels in plasma, and also show increased amounts of phenyl-pyruvate and other metabolites of phenylalanine in their body fluids and urine.
This causes decreased availability of tyrosine for protein and neurotransmitter synthesis in the brain and also the inhibitory effects of high level of phenylalanine on the transport of other amino-acids into the brain.
Both decreased formation of product and accumulation of substrate or other metabolites behind a block as well as change of feedback regulation alter the flux through metabolic pathway leading to pathologic effects.
Some inborn errors of metabolism are harmless. These are usually blocked in peripheral areas of metabolism, where neither low formation of product nor accumulation of its precursor perturbs the cell.(e.g., pentosuria).
In many cases, if a structural gene for a non-catalytic protein is affected by a mutation, a mutant protein is synthesized. The mutant protein may not function properly (certain mutant hemoglobin’s), may aggregate (Hbs) or may move very slowly through the cell (e.g., α1,-antitrypsin).
Early Diagnosis of Certain Inborn Errors to Avoid Permanent Damage:
Treatment must be commenced immediately in certain inborn errors, otherwise the victimized will be permanently damaged (e.g., PKU and galactosemia).
A number of useful clues are given below:
The sources of material that can be analysed and the major tests used in investigating patients or fetuses suspected of having genetic diseases are listed below. Chorionic villus sampling and amniocentesis apply only to investigation of the fetus.
Measurement of activity of enzyme in red cells, white cells, or tissue biopsy.
Electrophoresis (e.g., for Hbs).
Analyses by Southern blotting of restriction fragment length polymorphisms (RFLPs) and other features of DNA structure linked to or causing specific diseases (e.g., Hbs, Huntington’s chorea, DNA, etc.)
Identification of novel metabolite in urine of plasma by GLC-Ms.
Successful Treatment for Some Genetic Diseases:
One of the four following applications is employed in general for the treatment of genetic diseases:
i. Attempts to correct the metabolic consequences of the disease by administration of the missing product or limiting the availability of substrate.
ii. Attempts to replace the absent enzyme or protein or to increase its activity.
iii. Attempts to remove excess of a stored compound.
iv. Attempts to correct the basic genetic abnormality.
Enzyme replacement therapy has so far obtained mostly limited success. Problems arise in obtaining good sources of human enzymes (placentae have been useful in some instances), targeting enzymes in sufficient amounts to the suitable organ, and maintaining their activities in tissues if they are rapidly degraded.
This is specially difficult in the case of brain, where administered enzymes must be made to cross the blood-brain barrier. Liposomes have been tried to use to deliver enzymes to target organs, but success has not been obtained.
Gene therapy could involve:
(i) Gene replacement
(ii) Correction, or
(iii) Augmentation.
In (i) the mutant gene would be removed and replaced with a normal gene. In (ii) only the mutated area of the affected gene would be corrected, the remainder being left unchanged. Augmentation involves introduction of foreign genetic material into a cell to compensate for the defective product of the mutant gene. It is already possible to introduce a normal gene into affected cells (e.g., by transfusion).
Such cells contain both the mutant and the foreign gene. The foreign gene is introduced at random sites on chromosomes, may interrupt the expression of certain host genes and is not subject to normal regulatory mechanisms. Gene therapy is a key area in medical research.
