Congenital Malformations , Aging

jamesmayur · #1 03-03-2008, 11:37 PM

CONGENITAL MALFORMATIONS

The science that studies the causes of structural, behavioral, functional, and metabolic disorders present at birth is called teratology (Gr. teratos, monster). Congenital malformations, congenital anomalies, and birth defects are synonymous terms. Major structural anomalies occur in 2-3% of liveborn infants, and an additional 2-3% are recognized in children by age 5 years for a total of 4-6%.

Birth defects are the leading cause of infant mortality, accounting for approximately 21 % of all infant deaths. In 40-60% of all birth defects, the cause is unknown. Genetic factors, such as chromosome abnormalities and mutant genes, account for approximately 15%; environmental factors produce approximately 10%; a combination of genetic and environmental influences produces 20-25%; and twinning causes 0.5-1%.

Minor anomalies such as microtia (small ears), pigmented spots occur in approximately 15% of newborns. These are not detrimental to the health of the individual but in some cases are associated with major defects.
There are several types of anomalies:
 Malformations
 Disruptions
 Deformations and
 Syndrome
Malformations occur during formation of structures, e.g., during organogenesis. Most malformations have their origin during the 3rd to 5th weeks of gestation. They may result in complete or partial absence of a structure or in alterations of its normal configuration.

Disruptions result in morphological alterations of structures after their formation and are due to destructive processes, for example, vascular accidents leading to bowel atresias.

Deformations are due to mechanical forces that mold a part of the fetus over a prolonged period of time. Clubfeet, due to compression in the amniotic cavity, are an example. Deformations often involve the musculoskeletal system and may be reversible postnatally.

Syndrome refers to a group of anomalies occurring together that have a specific, common etiology. In contrast, association refers to the nonrandom appearance of two or more anomalies that occur together more frequently than by chance alone but for which the etiology has not been determined.

ENVIRONMENTAL FACTORS

It was generally assumed that congenital defects were caused primarily by hereditary factors. When it is found that German measles affecting a mother during early pregnancy caused abnormalities in the embryo, it suddenly became evident that congenital malformations in humans could also be caused by environmental factors. Furthermore, linking limb defects to the sedative thalidomide, made it clear that drugs could cross the placenta and produce birth defects. Since that time, many agents have been identified as teratogens (factors that cause anomalies).

INFECTIOUS AGENTS

Rubella or German Measles
Cytomegalovirus
Herpes Simplex Virus
Varicella (Chickenpox)
Human Immunodeficiency Virus (HIV)
Toxoplasmosis
Syphilis

RADIATION
The teratogenic effect of ionizing radiation has been known for many years. The abnormalities include microcephaly, skull defects, spina bifida, blindness, cleft palate, and defects of the extremities. Radiation mainly results from treating pregnant women with large doses of x-rays or radium.

CHEMICAL AGENTS
One example is thalidomide, an antinauseant and sleeping pill that causes amelia and meromelia (total or partial absence of the extremities). Other chemical agents that belong to this category include, amninopterin, that is used as an antineoplastic agent. Hormones, progesterone and diethylstilbesterol (estrogen) used to prevent abortion, oral contraceptives, maternal diseases (diabetes and phenylketonuria), nutritional deficiencies (cretinism is related to mother’s iodine deficiency), hypoxia and environmental chemicals such as mercury, lead and pesticides (agent orange) also cause congenital abnormalities.

DIZYGOTIC TWINS
These are twins that develop from two separate ova which were fertilized at the same time. They do not necessarily have come from the same ovary. They are no more similar to each other than to other members of the family. Non-identical twins never share the same amnion, chorion or placenta. There may be, however, fusion of separate placentae.

MONOZYGOTIC TWINS

These are twins that develop from the same ovum. They are always of the same sex and have the same arrangement of genes and chromosomes. They are usually alike in physical and mental character.

AGING

Genetic theories of aging

Genetic theories of aging suggest that aging is due to

1. Problems with stability of DNA over time and
2. Problems with the transcription of information from the chromosomal DNA to RNA.

Genetic theories of aging

a) Aging Programme

It is suggested that in an organism there is an aging program: This aging program targets various organs and systems and carries the organism through the aging process, from young to old and finally death.

b) Error buildup: Another theory suggests that aging is the result of cumulative errors in gene expression and cellular metabolism, intrinsic to the system or caused by environmental insults.

c) Mutation Accumulation Theory

In a population, the mutations and errors that occur after the reproductive age are not selected against, resulting in pathogenesis and senescence. Example: The genetic mutation in Huntington’s disease (HD), a severe late-onset neurodegenerative disorder, is nonetheless maintained in the human population.

d) Gene Regulation Theory

In humans, siblings of centenarians live longer than the control population. A genetic linkage to chromosome 4 has been found with this phenomenon. Thus it is suggested that genetic factors may play a role in normal life span of organism.

e) Cell Senescence or Telomere Theory

Senescence occurs as a result of a limitation in the number of cell divisions (i.e., limit in replicative capacity). Replicative senescence is caused by the shortening of the telomeres, Telomeres consists of repeated DNA sequences found at the ends of the chromosomes.
Supporting Evidence:
Telomerase is an enzyme that adds telomere repeat sequences to the 3' end of DNA strands. By lengthening this strand DNA polymerase is able to complete the synthesis of the "incomplete ends" of the opposite strand.
Telomerase over-expression immortalizes primary human cell cultures.
All cancer cells and normal stem and germ cells maintain telomere length through multiple cell division.

Contradictory Evidence:

Telomerase-deficient mice do not show accelerated aging.

Cellular Senescence: Secondary Effects

Senescent cells may promote aging and cancer through upregluating the proinflammatory cytokines such as IL-1a and EGF-like growth factors.

Non-genetic theories of aging

The immunological theory proposes that alterations in the immune system contribute to the changes associated with old age. With increasing age, the immune system is thought to become less efficient, with reduced capacity to deal with infection. Immune System protects the body against bacteria, virus, fungus/ multicellular parasites, cancer and toxins. Aged individuals have increased incidence of infections, increased incidence of autoimmune disease and increased cancer incidence

The connective tissue theory relates aging to changes in the collagen, elastin and the ground substance of connective tissue. As collagen comprises 25% of body protein, any changes in it will have marked effects. Aging changes in the skin. Aging decreases the wound healing, immunity, tanning, elasticity, clearance of foreign substances, thickness and increases blisters, infection, roughness, dryness, cancer, fragility, insensitivity. Ultraviolet radiation decreases collagen in the skin. Substances like antioxidants and retinoids (vitamin A metabolites and analogs) are used as treatment for skin disorders. However, it should be noted that retinoid is teratogenic substance.

The free-radical theory suggests that aging is due to the damage caused by free-radicals. Our body is equipped with certain mechanisms that fight the free radical damage. However, in certain cases this damage can be extensive. Free radicals cause peroxidation of fats that damages membranes in the body.

All living organisms generate reactive oxygen species (ROS) containing free radicals by leaking intermediate through the electron transport chain in mitochodria. These free radicals cause a cumulative damage in proteins, DNA and lipids with age.

Following are the supporting evidences for the role of oxidants and anti-oxidants in aging.
1. All aerobic organisms express superoxide dismutase (SOD), an enzyme that exclusively scavenges superoxide anions.
2. Elevated levels of such damaged molecules have been demonstrated in aged organisms.
3. Drosophila and C. elegans strains selected for long lifespan have elevated levels of SOD and/or catalase and increased resistance to oxidative stress.
4. Anti-oxidant compounds that mimic catalase and SOD delay aging in worms.

Contradictory evidence:

Dietary antioxidants reduce accumulation of oxidized molecules in mice but do not extend their lifespan. However, ubiquitous overexpression of SOD in rodents does not extend lifespan.

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