Genetic and Congenital Disorders

List and explain current methods utilized for postnatal diagnosis.

1. Newborn screening tests. (testing done on all newborns such as PKU, and thyroid problems.: 2. Diagnostic testing at any stage in life.

Sex-Linked Inheritance

A particularly important category of genetic linkage has to do with the X and Y sex chromosomes. These not only carry the genes that determine male and female traits but also those for some other characteristics as well.

Autosomal Inheritance

A pattern of inheritance in which the transmission of traits depends on the presence or absence of certain alleles on the autosomes. The pattern may be dominant or recessive, and males and females are usually affected with equal frequency.

Autosomal Dominant Disorders

A single mutant allele from an affected parent is transmitted to an offspring regardless of the sex. The affected parent has a 50% chance of transmitting the disorder to each offspring. The unaffected relatives of the parent or unaffected siblings of the offspring do not transmit disorder. In many conditions, the age of onset is delayed, and the signs and symptoms of the disorder do not appear until later in life. Examples- 1. Marfan Syndrome-am autosomal dominant disorder of connective tissue, which gives shape and structure to other tissues in the body and holds them in place. 2. Neurofibromatosis-A condition that causes tumors to develop from schwann cells of the neurological system. Other examples-achondroplasia, osteogenesis imperfecta.

Fragile X syndrome

A single-gene disorder that causes intellectual disability. Mutation occurs at the Xq287 on the fragile site and is characterized by amplification of CGG repeat. This idorder affects approx 1 in 1250 males and 1 in 2500 females. Affects boys more often than girls.

Define Teratogen

An agent that is able to cause abnormalities in a developing fetus. A teratogenic agent can be chemical, physical, or biologic agent that produces abnormalities during embryonic or fetal development. Maternal disease or altered metabolic state also can affect the development of the embryo or fetus.

What are chromosomal Defects? What causes chromosomal defects?

Chromosomal disorders form a major category of genetic diseases, accounting for a large proportion of reproductive wastage (early gestational abortions), congenital malformations, and intellectual disability. Cytogenetics is the term given to chromosome disorders. Structural changes in chromosomes usually result from breakage in one or more of the chromosomes followed by a rearrangement or deletion of the chromosome parts.

Congenital Disorders

Congenital Defects, sometimes called birth defects are abnormalities of body structure, function, or metabolism that are present at birth. May be caused by genetic factors or environmental factors that are active during embryonic development.

List and explain current methods of prenatal screening.

Current methods for prenatal diagnostic testing include: 1. Ultrasound, 2. Maternal blood screening tests, 3. amniocentesis, 4. chronic villus sampling, 5. and percutaneous umbilical fetal blood sampling.

What sorts of disease conditions are associated with mitochondrial inheritance?

Deafness, chronic progressive external opthalmoplegia-progressive weakness of extraocular muscles, Kearns-Sayre syndrome-Progressive weakness of the extraocular muscles of early onset with heart block, retinal pigmentation, bone marrow failure, diabetes, encephalopathies, myopathies...etc..

What is a single gene? What do single gene disorders usually result in?

Disorders caused by a defective or mutant allele at a single gene locus and follow mendelian patterns of inheritance. They are characterized by their patterns of transmission, which usually are obtained through a family genetic history. Virtually all single gene disorders lead to formation of an abnormal protein or decreased production of gene product. The disorder can result in a defective enzyme or decreased amounts of enzyme, defects in receptor proteins, and their function, alterations in nonenzyme proteins, or mutations resulting in unusual reactions to drugs.

Describe some examples of defects involving autosomal and sex chromosomes.

Down syndrome is a autosomal Defect. Causes a combo of birth defects including some degree of intellectual disability, characteristic facial features, and other health problems. 95% of cases of down syndrome are caused by nondisjunction or an error is cell division during meosis in a trisomy chromosome. Turner syndrome is a disorder involving sex chromosomes. Turner syndrome describes an absence of all (45,X) or part of the X chromosome. Characteristically, the girl with Turner Syndrome is short, but body proportions are normal. These females lose majority of oocytes by 2 years of age. Can range with no abnormalities to cardiac abnormalities, problems with hearing/vision, small mandible and horseshoe kidney with webbed neck. Klinefelter Syndrome is an example in males where testicular dygenesis accompanied by the presence of one or more extra X chromosomes in excess of the normal male XY complement.

What are factors that may affect the severity of the birth defects associated with teratogen exposure?

Exposure of fetus to drugs can cause:miscarriage, stillbirth, premature labor and brain damage. Exposure of fetus to radiation can cause: small head, spina bifida, blindness, cleft lip/palate, and otherdefects. Exposure of fetus to infectious agents can cause: miscarriage, stillbirth, premature labor, and birth defects. Deficiencies of nutrients and vitamins also may be a factor.

Trisomy

Extra single chromosome in a pair resulting in 47 total chromosomes. Trisomy 18 (edwards syndrome), Trisomy 13 (patau Syndrome) and trisomy 21 (Down syndrome)

Describe examples of disorders that are caused by teratogenic agents.

Fetal Alcohol Syndrome (FAS)-refers to a group of physical, behavioral, and cognitive fetal abnormalities that oocur secondary to drinking alcohol while pregnant. This can cause prenatal or postnatal retardation; CNS involvement including development delays, behavioral dysfunction, intellectual impairment, and brain and skull malformation. Criteria s for this dx includes three things: 1. Three facial abnormalities, 2. Growth Deficits, 3. CNS abnormalities. Folic Acid Deficiency has been implicated in the development of neural tube defects (NTDs that include spina bifida, anaencephaly, and encephalocele).

Genetic Disorders

Genetic disorders can be described as a discrete event that affects gene expression in a group of cells related to each other by gene linkage. Most genetic disorders are caused by changes in the DNA sequence that alters the synthesis of a single gene product. Make their appearance later in life.

Aneuploidy

Having an abnormal number of chromosomes is referred to as this.

Monosomy

Missing chromosome in a pair resulting in 45 chromosomes.The defects associated with monosomy of the autosomes are severe and usually cause abortion. Monosomy of the X chromosome, or tuner syndrome, causes less severe effects.

Mosaicism

Mitotic errors in early development give rise to two or more cell lines characterized by distinctive karotypes. Can result from mitotic errors during cleavage of the fertilized ovum or in somatic cells. Sometimes this consists of an abnormal karyotype and a normal one, in which case the physical deformities caused by abnormal cell line usually are less severe.

In-born errors of metabolism refer to what?

Most single-gene disorders result in "in-born errors of metabolism" an error in a single gene >> faulty protein >> protein may be involved in a metabolic pathway.

What is mitochondrial DNA inheritance?

Mothers transmit mitochondrial DNA to both sons and daughters, and is only passed down through mothers. This can be explained by the fact that the ova contain numerous mitochondria in their abundant cytoplasm, whereas spermatozoa only contain a few, if any mitochondria, thus the mtDNA in the zygote is derived solely from the mother. The mitochondria contain their own DNA, which is distinct from nuclear DNA. Thus DNA, which is inherited maternally is subject to mutations at a higher rate than nuclear DNA, and it has no repair mechanisms.

What us Mulitfactorial Inheritance? Name an example of a multifactorial inheritance disorder.

Multifactorial inheritance disorders are caused by multiple genes, and in many cases environmental factors. These exact number of genes contributing to mutifactorial traits is not known, and these traits do not follow the same clear cut pattern of of inheritance as do single-gene disorders. These disorders can be expressed during fetal life and be present at birth, or they may be expressed later in life. These disorders can include: Cleft lip or palate, club foot, congenital dislocation of the hip, congenital heart disease, pyloric stenosis, and urinary tract malformation.

What is meant by genomic imprinting? Can you name some examples?

Occurs when only one of two copies of gene is active. Some genes are active only when they are inherited from the father and vise versa with mother. Then the copy from the other parent is imprinted and so is silenced also from expression. Prader WIlli Syndrome is an example. The set of genes on chromosome 15 is inactivated on paternal chromosome. There is an imprinting of the maternal chromosome which is silenced. Angelman Syndrome is also an example where the set of genes on chromosome 15 are inactivated on maternal chromosome, there is an imprinting of the paternal chromosome which is silenced.

Elevated AFP (alpha-fetoprotein) levels are associated with what?

Ordinarily, only a small amount of AFP gains access to the amniotic fluid and crosses the placenta to the mother's blood. However, when there is a neural tube defect in the fetus, from failure of part of the embryologic neural tube to close, then there is a means for escape of more AFP into the amniotic fluid. omphalocele and gastroschisis (both are defects in the fetal abdominal wall), the AFP from the fetus will end up in maternal blood in higher amounts.

X-Linked Recessive Disorders

Sex-linked disorders are almost always associated with the X, or female chromosome, and the inheritance pattern is predominately recessive. Because of the presence of a normal paired gene, female heterozygotes rarely experience effects of a defective gene, whereas males who receive the gene are typically affected. A mom that carries a normal and a mutant allele on X chromosome has a 50% chance of transmitting the defective gene to her sons and her daughters have a 50% chance of being carriers of the mutant gene. Examples-Hemophilia A, and duchenne MS.

Non-disjunction

The failure of of the chromosomes to separate during oogenesis or spermatogeneis. this can occur in either autosomes or the sex chromosomes and is call non-disjunction. Nondijunction gives rise to germ cells that have an even number of chromosomes.

List and explain current methods of prenatal diagnostic testing.

The purpose of prenatal screening and diagnosis is not just to detect fetal abnormalities, but also to allay anxiety and provide assistance to prepare for a child with a specific disability. Prenatal screening cannot be used to rule out all possible fetal abnormalities.

What is the most vulnerable time during fetal development?

The time interval, which is often referred to as the period of organogensis, extends from day 15 to day 60 after conception. Environmental influences during the first 2 weeks after fertilization may interfere with implantation and result in abortion or early resorption of the products of conception.

Autosomal Recessive Disorders

These disorders are only manifested when both members of the gene pair are affected. In this case both parents may be unaffected but carriers of the defective gene. These disorders affect both sexes. The age of onset is frequently early in life. Auto Recessive disorders include almost all inborn errors of metabolism. Examples- 1. Phenylkentoniuria- a rare recessive metabolic disorder. Cause by the deficiency of the liver enzyme phenylalanine hydroxylase, which allows toxic levels of amino acid, phenylalanine to accumulate in tissues of the blood. 2. Tay-Sachs Disease-A variant of ca class of lysosomal storage diseases, known as the gangliodisoses, in which there is failure to break down the GM2 ganglionsides of cell membranes. Other Examples-cystic fibrosis, sickle cell disease.