Genetic Disorders

Diseases caused by mutations in the mitochondrial genes

There are 37 mitochondrial genes Inheritance of mitochondrial DNA differs from that of nuclear DNA in that the mitochondrial type is associated with maternal inheritance resulting from the fact that the ova contain mitochondria within their abundant cytoplasm, whereas the spermatozoa contain few if any.

Mothers transmit mitochondrial genes to all of their offspring (males & females). However, daughters (not sons) transmit these genes further to their progeny.

Because mt DNA encodes enzymes involved in oxidative phosphorylation, mutations affecting these genes exert their deleterious effects primarily on the organs most depend on this process, like CNS, skeletal muscles, cardiac muscles, liver and kidneys. A minimum number of mutant mt DNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease. This is called "threshold effect".

Diseases associated with mitochondrial inheritance are rare and many of them affect the neuro-muscular system. An example is Leber hereditary optic neuropathy.

Genomic imprinting

All humans inherit two copies of each gene (maternal & paternal). In many genes there is no difference between the two. However, functional differences exist in some genes. These differences arise from an epigenetic process called genomic imprinting, where certain genes are differentially inactivated during gametogenesis.

Maternal imprinting implies that the maternal allele is inactivated, whereas the paternal imprinting refers to transcriptional inactivation of the paternal allele. Imprinting occurs in ovum or sperm Examples: Prader-Willi syndrome (maternal imprinting) Angelman syndrome (paternal imprinting). Both disorders arise from deletion in chromosome 15, but have different clinical features.

Gonadal Mosaicism

With every autosomal dominant disorder some patients do not have affected parents due to new mutations in either sperm or egg. Such patient's siblings are neither affected nor at increased risk of developing the disease. In some autosomal dominant disorders, exemplified by osteogenesis imperfecta, phenotypically normal parents have more than one affected child. This clearly violates the laws of mendelian inheritance. Studies indicate that gonadal mosaicism may be responsible for such unusual pedigrees

Gonadal mosaicism may be responsible for this which is due to mutation that occurs postzygotically during early embryonal development. If the mutation affects only cells destined to form gonads, the gametes carry the mutation, but the somatic cells are completely normal. Such an individual is said to exhibit gonadal mosaicism. A phenotypically normal parent who has germ line mosaicism can transmit the disease-causing mutation to the offspring's through the mutant gamete, and there is a definite possibility that more than one child of such a parent would be affected.

Aim of study of genetic diseases

Disease diagnosis Gene therapy

Diagnostic application

DNA probes can be powerful tools for the diagnosis of human disease, both genetic and acquired, which include: Detection of inherited mutations that underlie the development of genetic diseases either prenatally or at birth. Detection of acquired mutations that underlie the development of neoplasms. Accurate diagnosis and classification of neoplasms, especially of hematopoietic system. Diagnosis of infectious diseases. Determination the relatedness and identity in transplantation, paternity testing and forensic medicine.

Diagnosis of genetic diseases

Diagnosis of genetic diseases requires examination of genetic material (chromosomes and genes) Cytogenetic analysis (Chromosomal abnormalities) (karyotypic) Molecular analysis (Gene abnormalities)

Prenatal chromosome analysis should be offered to all patients who are at risk of cytogenetically abnormal progeny. It can be performed on cells obtained by: 1. Pre-implantation Diagnosis 2. Maternal Blood Test (14-20 weeks) 3. Amniocentesis (15-17 weeks) 4. Chorionic Villus Test (8-11 weeks) 5. Fetal blood (umbilical cord blood)

Some important indications are

Advanced maternal age (more than 34 years), because of greater risk of trisomies. A parent who is a carrier of structurally abnormal chromosome. A parent with a previous child with a chromosomal abnormality. A parent who is a carrier of an X-linked genetic disorder (to determine the fetal sex).

Postnatal chromosome analysis is usually performed on peripheral blood lymphocytes Multiple congenital anomalies. Unexplained mental or physical retardation. Suspected aneuploidy (Down syndrome). Suspected sex chromosome abnormality (turner syndrome). Suspected fragile X-syndrome. Infertility, to rule out sex chromosome abnormality. Multiple spontaneous abortions.



Molecular analysis
To detect subtle changes in individual genes by using recombinant DNA technology. Prenatally, amniotic fluid or biopsy of chorionic villi is used as early as the first trimester. Postnatally, tiny amount of whole blood or even dried blood can supply sufficient DNA for PCR amplification.

Methods used for diagnosis Techniques used Hybridization PCR Microarray Others

Gene therapy
The goal of treating genetic diseases by transfer of somatic cells transfected with the normal gene. Problems include Designing appropriate vectors to carry the gene Unexpected complications resulting from random insertion of the normal gene in the host genome. E.g.; gene therapy in patients with X-linked severe combined immunodeficiency.

Therapeutic Applications

There are 2 areas of application: Production of human biologically ultra-pure active agents in virtually unlimited quantities by inserting the requisite gene into bacteria or other suitable cells in tissue culture. Some examples include; A. Soluble TNF receptor for blocking TNF in treatment of rheumatoid disease. B. Tissue plasminogen activator for treatment of thrombotic states.


C. Growth hormone for treatment of deficiency states. D. Erythropoietin to reverse several types of anemias. E. Myeloid growth and differentiation factors to enhance production of monocytes and neutrophils in states of poor marrow function.

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