Genetic Diseases

The ability of an individual to perform various body functions are encoded in a chemical language in the genes of ells. A gene is a physically defined segment of DNA which constitutes the genetic material. A gene performs a specific function. Each individual begins with a single fertilized egg cell. Each fertilized egg has a cell with a set of genes contributed by father and another identical set of genes contributed by mother. There are about 35,000 genes in each somatic cell.

A defect in any one of the genes results in a genetic disease. This change in the gene is called mutation. The genetic disease, therefore, results from an intrinsic defect in the ability to perform a certain function. As against this, an infectious disease results from the entry of infecting microbes in the body of an individual.

There are three major reasons why genetic diseases have come into lime light now.

The diagnostic tools and procedures have got more refined with the technical advances. Gas chromatograph in conjunction with a mass spectrometer can identify each component peak on the basis of its mass. This has enabled the diagnosis of a variety of genetic diseases hitherto unknown.
Infectious diseases which lead to early death have been brought under control with the development of powerful antibiotics. This has led to the increase in the average lifespan from 28-30 years in 1950 to 70-72 years in 2011. Increase in the life span gives a chance for genetic diseases to clinically manifest.
With increased awareness about the genetic entity in the disease process and with the ability to carry out prenatal diagnostic procedures, more and more people have started approaching genetic centers for diagnosis and management.

There are various approaches available for the diagnosis of genetic diseases.

If the patient suffers from a gross physical and mental abnormality, it is likely to be due to the chromosomal aberration. This could be numerical or structural. These diseases, therefore, can be diagnosed by karyotyping or chromosomal analysis.
One can directly look for the function which is affected or is being performed with reduced efficiency. This involves doing the quantitative estimation of the biocatalyst, the enzyme, which is the product of the gene.
Biochemical reactions follow a certain temporal sequence. If the sequence of reaction is A B C Product, each step requires an enzyme to do the conversion from the previous step to the next. If one of these enzymes is defective, the chemical (metabolite) on which it acts accumulates. For example, if the B cannot be converted to C because of the defect in the enzyme converting B to C, the chemical B will accumulate in the body leading to the non-formation of C. If this chemical B happens to be toxic the person will suffer from the disease. A classical example of such a disease is diabetes where extra glucose from blood does not get converted into the storage product, glycogen, in the liver. The disease can also be diagnosed by the assay of the missing product C.
One can now directly look at the genetic material, the DNA, and identify the defective gene. This is done by comparing the DNA pattern of a normal individual with the patient. DNA patterns are generated by cutting the genetic material into small fragments using specific enzymes known as DNA restriction endonucleases. The fragment carrying the gene involved in the disease is identified with the help of the gene probe. This approach is, however, still restricted to a limited number of genetic diseases such as sickle cell anemia.
A selected segment of the gene can be amplified several thousand times in a few hours by using a method called Polymerase Chain Reaction or PCR. One can compare the defective gene segment and normal gene segment by electrophoretic analysis. The DNA for this purpose can be obtained from white blood cells.
Prenatal diagnosis of the genetic disease can be done by using amniotic fluid or amniotic fluid cells or chorion villus sample. The accumulated product such as mucopolysaccarides or argininosuccinic acid can be assayed in the amniotic fluid. Amniotic cells can be grown in the tissue culture medium and the grown cells can be used for the estimation of the enzyme. Chorionic villus sample can also be used for measuring the enzyme directly. DNA from all these sources can be used for amplification and diagnosis.
Prenatal diagnosis is an important aspect of management. Some genetic diseases can be managed from this stage onwards. The unmanageable diseases can be prevented by forestalling the birth of the affected fetus.

As it is mentioned before, there are about 35,000 genes in any somatic cell. Therefore, theoretically any one of the genes going bad will result in a genetic disease. However, things are not that bad. We harbor a pair of each individual gene. If one of two genes in pair is defective the other good gene takes over and carries out the function normally. These individuals are known as carries of the disease. Such gene mutations are as recessive mutations. There are certain other gene mutations which show up and causes even if one of the pair of genes is normal. Such mutations are called dominant mutations.

In human beings there are twenty two pairs of identical chromosomes in both males and females. They are called autosomes. There is twenty third pair of chromosomes which differs in males from females. This pair is known as sex chromosomes. It consists of two identical X Chromosomes in females and X and Y chromosomes in males. The appearance of disease arising due to a gene mutation on a sex chromosome therefore differs. Having got two X chromosomes, in females, recessive gene mutations on the X-chromosomes never shown-up. A defective gene on X chromosome however, is manifested in males. A classical example of sex-linked mutation showing-up in males and not in females is Hemophilia.

The incidence of gene influenced disease is quite high, and it is to be groups have a much higher than average incidence of certain diseases. Genetic diseases account for 5-8% of pediatric hospital admissions and about 9% of pediatric deaths. Several of these metabolic diseases are manageable. Early diagnosis followed by effective treatment often prevents the severe consequences of the disease and allows normal physical and mental development. In other words diseases antenatal diagnosis and genetic counseling with the option of abortion of the affected fetuses are of increasing importance when there is no adequate treatment and affected individual are severely handicapped or suffer distress and early death

The average frequency for any one single gene is, one in 10,000 to one in 1, 00,000 live births. This depends on the size of the gene and several other factors. Consanguineous marriages increase this frequency several fold.

There are about 7000 genetic diseases known as today, out of which about 3000 are manageable. Diabetes is a genetic disease. Once the patient has diabetes, he has to observe diet restrictions in addition to taking medications to control his blood sugar level. The patient is, therefore, best describe as being managed rather than treated as he has to take medicines throughout his life. This is where a genetic disease strikingly differs from an infectious disease.

Out of the remaining 3500 diseases about 1000 to 1500 diseases can be prenatally diagnosed. Prenatal diagnosis enables the family to prevent the recurrence of the disease in the next child in the same family.

Recently, however, a success story is being described in treating the disease ADA-deficiency (adenosine deaminase deficiency). In this disease there is a deficiency of immunoglobulin and cell-mediated immunity. Clinically the patient suffers from the immunodeficiency triad of persistent diarrhea, progressive pulmonary disease and extensive moniliasis. Development of skeletal abnormalities is also common in this disease.

Bone-marrow transplantation from a healthy donor has been successful in patient with this disease. Recent attempts in gene therapy in animal models have also met with great success.

There are five different approaches that one can consider in the management of a genetic disease.

Surgical approach- Structural deformities such as cleft-lip, squint, bony deformities can be corrected by taking recourse to the surgery. This treatment is of course possible after birth. There are a few limited instances where surgery for correction has been used in utero.
Metabolic approach- As it was said before, metabolic derangement due to defective gene in a biochemical pathway results in the depletion of the enzyme acts. The approach here is, to reduce the source of the basic compound in the diet which results in the accumulation. The second supplementary approach to this problem is to give large quantities of cofactors, such as vitamins, required by the enzyme structure is corrected by the cofactor and the accumulation of the substrate on which this enzyme acts is prevented. Concomitantly, the depletion of the product following the enzyme catalysis is also corrected. A rather novel approach to reduce the amount of a toxic metabolite is to bind the metabolite into a non-toxic and readily excreted conjugate. This approach is necessary when the accumulation of the toxic metabolite cannot be controlled by dietary therapy or when the requirement for effective control would be so stringent as to threaten normal growth and development.
Tissue transplantation approach- Transplantation as a form of therapy for genetic disease serves primarily either to replace or supplement abnormal cells with their equivalent or to act as a source of the gene product. This approach to therapy is well established for certain disorders and holds great promise for others. Bone marrow transplantation for the treatment of lysosomal storage diseases has proved efficacious. There is no reason to be optimistic, but at the same time cautions. More diseases are being included for the treatment using tissue transplantation. Several centers are involved in this endeavor. The time has come to do a prospective and comparative analysis so that more specific recommendations can be provided in the future.
Enzyme replacement therapy approach- Enzyme replacement therapy (ERT) for lysosomal storage diseases received considerable attention during 1970’s. the success of ERT in treating adenosine deaminase deficiency and Gaucher’s disease have to stimulate renewed interest in this therapeutic strategy. The problems that discouraged clinical investigation from pursuing this approach have, for the most part, been identified. Some have been solved, and most appear solvable in the light of our increasing understanding of endocytic processes and their determinants. New technologies can provide sufficiently large quantities of enzymes for extended trials. Finally, there are recent data from trials in patients indicating therapeutic effectiveness which makes ERT look much more promising now than it did 20 years ago.
Gene therapy approach- The process of somatic gene therapy involves the addition of the normal gene into a genetically defective cell. Genes can be transferred into germline or into somatic cells. The latter therapy is limited to only the patient with the disease. The former approach results in the correction of the disease is prevented even in future generations.
Several strategies are used to introduce a foreign DNA into the cell. The gene therapy approach in the treatment of genetic diseases certainly show promise especially with the success of this approach in animal models.

We are passing through an exciting and extraordinary period of development in the biological sciences. As the modern techniques of cell and molecular biology are applied to the medical field, we shall undoubtedly solve many of the remaining mysteries of human pathology. Medical science are now in the most productive phase of their evolution.

Cytogenetics is the study of chromosomes structure, functions, behavior and pathology. In each cell of our body, there are 23 pairs of chromosomes of which 22 pairs are called autosomes, which are responsible mainly for structure, and function of the body systems and one pair is called sex chromosomes, which is principally responsible for structure and functions of reproductive systems. However, a small number of genes located on autosomes have influence on reproductive function just as those on the sex chromosome may have some part in control of other bodily functions. Majority of the autosomal and a few sex chromosomal aberrations (X-linked MR) hamper mental development and may in some cases, alter physical development as well.

Cytogenetics is an exciting, dynamic field of study which analyzes the number and structure of human and animal chromosomes. Changes that affect the number and/or structure of the chromosomes can cause problems with growth, development, and how the body functions. Chromosomal abnormalities can happen when egg and sperm cells are being made, during early fetal development, or after birth in any cell in the body. Changes to chromosome structure can disrupt genes, causing the proteins made from disrupted genes to be missing or faulty. Depending on size, location, and timing, structural changes in chromosomes can lead to birth defects, syndromes or even cancer. However, some chromosomal changes may have no effect on a person’s health.

The incidence of chromosomal aberrations is observed more commonly than it is thought. About 7.5% of all conceptions are affected by chromosomal disorders. 60% of early spontaneous miscarriages have chromosomal abnormality and are lost in the first trimester. 5% of late spontaneous abortion and 6.5% of stillbirth have chromosomal abnormalities. Thus, the frequency of chromosomal defects seen in live births is 6%.

Most of the manifestations of autosomal abnormalities present at birth but sex chromosomal abnormalities may not present until puberty. Individuals with balanced chromosomal rearrangement are diagnosed only when couple karyotype is done in view of their history of replaced abortion or birth defects in their progeny.

It is often thought that cytogenetic studies are dead-end studies with no possible treatment. Though this is a fact, cytogenetic studies can be successfully used in the management of the affected, recurrence risk estimation and in offering various reproductive options to couples.

Etiological Studies.
Assessment of morbidity and mortality in the affected.
Genotype-Phenotype Correlation.
Recurrent risk and reproductive fitness studies.
Breakpoint studies in structural rearrangements.

In the 1980s, advances were made in molecular cytogenetics. While radioisotope-labeled probes had been hybridized with DNA since 1969, the movement was now made in using fluorescent-labeled probes. Hybridizing them to chromosomal preparations using existing techniques came to be known as fluorescence in situ hybridization (FISH). This change significantly increased the usage of probing techniques as fluorescent-labeled probes are safer. Further advances in micromanipulation and examination of chromosomes led to the technique of chromosome microdissection whereby aberrations in chromosomal structure could be isolated, cloned and studied in ever greater detail.

Those who have

Delayed development
Mental retardation
Physical malformations
Disordered sexual development
Recurrent abortions and
Cancers, especially of the blood ( leukaemia)
Prenatal diagnosis (in pregnancy) of Down syndrome and several other chromosomal abnormalities. The indications for cytogenetic analysis in pregnancy are

Advanced maternal age ( above 35 years)
Abnormalities in the unborn baby detected by ultrasonography / triple screening
if there are other children in the family with chromosomal abnormalities

Detection of chromosomal abnormalities has an important role in the diagnosis and management of many genetic diseases and cancers, especially leukemia and other diseases of the bone marrow. In these conditions, the chromosomal analysis provides information about outcome and recurrence risk to patients and their families and helps to plan specific treatment.