In this article we will discuss about the Genetic Bases of Disease:- 1. Major Classes of Genetic Disease 2. Genetic Diseases Produce their Pathologic Consequences 3. Early Diagnosis of Certain Inborn Errors is the most Essential 4. Successful Treatment 5. Gene Therapy in Clinical Trials is Feasible 6. Antisense or Triplex Therapy is Useful in the Treatment 7. Molecular Medicine is Advancing Rapidly.
Contents:
- Major Classes of Genetic Disease
- Genetic Diseases Produce their Pathologic Consequences
- Early Diagnosis of Certain Inborn Errors is the most Essential to Avoid Permanent Damage
- Successful Treatment is Available for Some Genetic Diseases
- Gene Therapy in Clinical Trials is Feasible, but its Efficacy must be Greatly Improved
- Antisense or Triplex Therapy is Useful in the Treatment of Genetic Diseases
- Molecular Medicine for Genetic Diseases is Advancing Rapidly
1. Major Classes of Genetic Disease:
a. Genetic diseases may be arranged into three major classes; chromosome disorders, monogenic disorders, and multifactorial disorders. Two additional classes are somatic disorders and mitochondrial disorders.
b. In chromosomal disorders, there is an excess or loss of chromosomes. The best- known such condition is Down syndrome. Chromosomal translocations are important in activating oncogenes.
c. The monogenic disorders involve single mutant genes. They are classified as autosomal dominant, autosomal recessive, or X-linked. The term “dominant”’ signifies that the mutation will be clinically evident if only one chromosome is affected (heterozygous); the term “recessive” denotes that both the chromoses must be affected (homozygous). “X-linked” disorders are those in which the mutation is present on the X-chromosome.
Females have two X-chromosomes, they may be either heterozygous or homozygous for the affected gene. So, 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.
d. Multifactorial disorders are associated with a number of genes and environmental factors. Less is known about this category of diseases, but it is gaining importance because of the common adult diseases such as ischemic heart disease and hypertension that are members of this group.
e. Mutations are highly involved in genetic disorders. Mutations of the mitochondrial genome have been demonstrated in a number of other neurologic diseases.
2. Genetic Diseases Produce their Pathologic Consequences:
a. If an enzyme (protein) is affected by mutation, an inborn error of metabolism may result. This produces a metabolic block which may have pathologic consequences.
where E = mutant enzyme, and X, Y = alternative products of the metabolism of S. A block has got three results (1) decreased formation of the product P, (2) accumulation of the substrate S, and (3) 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 phenyl-Ketonuria, the mutant enzyme is phenylalanine hydroxylase causing the following situation:
Therefore, patients with PKU have less tyrosine which is the main source for melanin formation. Hence, they are fair skinned. The plasma high levels of phenylalanine produces the inhibitory effects on the transport of other amino acids into brain. So the accumulation of substrate leads to pathologic effect.
b. Some inborn errors of metabolism are essentially harmless. These are usually due to blocks in peripheral areas of metabolism, where diminished formation of product or accumulation of its precursor perturbs the cell (e.g., pentosuria).
c. A mutant protein is synthesized if a structural gene for a non-catalytic protein is affected. Even a change of one amino acid can have serious pathologic consequences. The mutant protein does not function properly or move very slowly through the cell.
3. Early Diagnosis of Certain Inborn Errors is the most Essential to Avoid Permanent Damage:
In some cases, treatment must be started immediately for saving the infant from permanent damage (e.g., phenylketonuria, galactosemia). A number of cues are mentioned in Table 52.4.
The sources of material that can be analysed and the main tests used in investigating patients suspected of having genetic diseases are mentioned in table 52.5.
4. Successful Treatment is Available for Some Genetic Diseases:
a. One of the following points is taken into accounts for the treatment of genetic disease:
(i) Attempts to correct the metabolic consequences of a disease by administration of the missing product or by arranging 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 by gene therapy.
b. Some of these planning’s are undoubtedly effective for certain disorders, e.g., the dietary treatments of phenylketonuria and galactosemia, replacement therapy for hemophilia and agammaglobulinemia, and removal of iron by periodic bleeding in hemochromatosis. But attempts at enzyme therapy have limited success.
c. Enzyme therapy is difficult in the case of the brain, because administered enzymes must be made to cross the blood-brain barrier.
d. Because of the tremendous progress in the field of recombinant DNA technology, sufficient efforts are being devoted to gene therapy.
5. Gene Therapy in Clinical Trials is Feasible, but its Efficacy must be Greatly Improved:
a. Firstly, the major criteria should be satisfied to permit the use of gene therapy in humans (shown in table 52.7). Somatic gene therapy is only permissible in humans at present, because germ cell gene therapy transmits genetic alternations to offspring.
b. Gene therapy can involve gene replacement, correction, or augmentation. In replacement, the mutant gene should be removed and replaced with a normal gene. In correction, only the mutated area of the affected gene should be corrected and the remainder remains unchanged.
In augmentation there is the introduction of foreign genetic material into a cell to compensate for the defective product of the mutant gene and is the sole type of gene therapy available at present.
c. The foreign material can.be introduced into affected cells by any of the methods mentioned in table 52.8 for gene therapy in humans, the gene of interest is usually administered via a viral vector or via plasmid liposome complexes. The cells which take up the gene will contain both the mutant and the exogenously derived gene.
d. Various methods are being developed to target genes to specific sites in order to increase uptake and thus efficacy. Target cells have included bone marrow cells, fibroblasts, epithelial cells of the respiratory tract, hepatocytes and various tumor cells.
e. The three major routes by which genes have been introduced into humans are via retroviruses, adenoviruses, and plasmid— liposome complexes. In the case of retroviruses, the target cells must be actively growing, since cell division is required if the gene is to be integrated into the genome. For adenoviruses, their genome does not integrate with the host cell genome.
f. Attempts are created to develop in utero gene therapy for disorders such as a- thalassemia and adenosine deaminase deficiency. This can be accomplished by mixing fetal blood cells with a suitable retroviral vector carrying the gene requiring correction and re-transfusing the cells back into the fetus.
6. Antisense or Triplex Therapy is Useful in the Treatment of Genetic Diseases:
a. A triplex molecule is formed by the bending of oligonucleotides (about 20 bases long) through base-pairing to a specific mRNA or to double-stranded DNA.
b. Specific oligonucleotides is most essential to be synthesized. Such oligonucleotides can act as drugs (genetic medicine) inhibiting the synthesis of the protein products of specific genes involved in various diseases or inhibiting the genes themselves. One such oligonucleotide blocks the replication of HI V-I virus by combining with its gag gene and can thus prove useful in the treatment of AIDS. Other compounds are being investigated as treatments for autoimmune disorders or some type of cancer.
c. Some problems have been noted in the development of clinically useful antisense
compounds. Many oligonucleotides do not enter cells easily, and they may also be degraded inside cells by nucleuses. Therefore, chemists have synthesized modified oligonucleotides in which a critical oxygen atom in each nucleotide is replaced by a sulphur atom.
They have also an undesirable capacity to bind to various proteins producing unwanted side effects. In certain cases, control oligonucleotides have been found to produce effects similar to those observed with antisense compounds. It is hoped that antisense molecules will prove of therapeutic use in a variety of diseases.
7. Molecular Medicine for Genetic Diseases is Advancing Rapidly:
Some of the major advances (shown in table 52.9) have been made in the area of molecular medicine; all have been dependent upon the development of recombinant DNA technology.
