Pathophysiology- Genetic and Cogenital Disorders

What are the 3 ways in which teratogenic agents can can birth defects

1. direct exposure of the pregnant woman and embryo to the agent 2. Through exposure of the soon to be pregnant woman to an agent that has a slow clearance rate. 3. As a result of mutagenic effects of an environmental agent that occur before pregnancy, causing permanent damage to a woman or mans reproductive cells.

What is the prevalence of Marfan Syndrome?

1 per 5000; 70%-80% are familial and the remainder are sporatic.

Three Causes of Congenital Defects

1. Genetic 2. Environmental Factors 3. Intrauterine Factors

What are two common examples of Autosomal Dominant Disorders

1. Marfan Syndrome 2. Neurofibromatosis

What are two diseases associated with Autosomal Recessive Disorders?

1. Phenylketonuria 2. Tay-sachs Disease

What are the 4 factors that influence a drugs affect on the fetus?

1. The rate in which the drug crosses the placenta 2. The duration of exposure 3. The stage of placental and fetal development at the time of exposure. 4. The molecular weight of a drug. Drugs with a weight of less than 500 can cross the placenta easily. Drugs weighing more than 1000 can cross poorly.

What are the occurrence risks for Autosomal Recessive Disorders?

-25% risk for an affected child -50% risk for carrier child -25% chance for a normal child

What are the main physical features of Down Syndromes?

-Growth failure; and small square head -Flat facial profile -small low set ears

What are examples of the Skeletal System abnormalities in Marfan Syndrome.

-Long thin body -Long extremities -Hyper-extensible Joints -Spinal deformalities -Pectus Excavatum or pigeon chest

What are examples of Cardiovascular abnormalities associated with Marfan Syndrome?

-Mitral valve prolapse -Progressive dilation of the aortic valve ring -Weakness of the aorta and other arteries -Rupture of the aorta may lead to premature death -Pregnancy increased the risk of aortic dissection

What are examples of ocular abnormalities associated with Marfan syndrome

-Myopia -Retinal Detachments

What drugs have been identifies as leading to fetal malformations

-Thalidomide -Antimetabolites: used in cancer treatments -Anticoagulant drug: warfarin -Several anticonvulsant drugs -Ethyl Alcohol -cocain

Folic Acid deficiency

-deficiencies in vitamins and nutrients -neural tube defects -spina bifida

What are symptoms associated with NF-2?

-headaches -Hearing loss -Tinnitus

What effects can cocaine have on fetal development?

-interrupts uteroplacental blood flow -maternal hypertension -stimulation of uterine contractions -fetal vasoconstriction

What are characteristic features of FAS?

-small palpebral fissures -thin upper lip -elongated and flattened mid face and philthrum

Type 2 Neurofibromatosis is asymptomatic through the first _______ years of life.

15 years

All women of the child bearing age should receive _______ of folic acid daily

400 mcg

How would a male with trisomy 21 be designated on paper?

47, XY, +21 -The total number of chromosomes, followed by the sex, and then the description of the abnormality.

A parent that is effected by an autosomal dominant disorder has a ______ chance of transmitting their disorder to each offspring

50%

Fetal Alcohol Sydrome

A constellation of physical, behavioral, and cognitive abnormalities, resulting from maternal alcohol consumption.

At what age does Tay-Sachs generally manifest itself?

6-10 months

Klinefelter Syndrome

A condition found only in males, where there is 1 or more extra X chromosome present. It is considered one of the most common genetic abnormalities. Many men live their lives without being aware that they have an additional chromosome. Major Characteristics include: Enlarges breasts, sparse facial hair, small testes, testes do not respond to stimulation from gonadotrophins during puberty which results in male with tall stature with abnormal proportions.

What is Neurofibromatosis?

A disorder involving benign neurogenic tumors that arise from Schwann cells and other elements of the peripheral nervous system. Results from a defect in a tumor repressor gene that regulates cell differentiation and growth.

What are X linked disorders?

A sex linked disorder.

What are the 5 categories of drug risks.

A: least dangerous B, C, D: increasingly more dangerous X: contraindicated during pregnancy

What type of disorder is Neurofibromatosis?

Autosomal Dominant Disorder

Why type of genetic disorder is Marfan Syndrome?

Autosomal Dominant Disorder

What is Von Willebrand disease, and what type of genetic disorder is it?

Autosomal Dominant Disorder Bleeding Disorder

What is Osteogenesis imperfecta, and what type of genetic disorder is it?

Autosomal Dominant Disorder Brittle Bone Disease due to defects in collagen synthesis

What is Adult Polycystic Kidney disease, and what type of genetic disorder is it?

Autosomal Dominant Disorder Chronic Kidney Disease

What is Spherocytosis, and what type of genetic disorder is it?

Autosomal Dominant Disorder Disorder of the red blood cells

What is Huntington Chorea, and what type of genetic disorder is it?

Autosomal Dominant Disorder Neurodegenerative Disorder

What is Familial Hypercholesterolemia, and what type of genetic disorder is it?

Autosomal Dominant Disorder Premature Atherosclerosis

What is Achondroplasia and what type of genetic disorder is it?

Autosomal Dominant Disorder Short-Limb Dwarfism

What is Tay-Sachs disease and what type of genetic disorder is it associated with?

Autosomal Recessive A lysosomal storage disease called gangliosidosis, where the cells are unable to breakdown GM2 gangliosides of cell membrane.

What is Phenylketonuria and what type of genetic disorder is associated with it?

Autosomal Recessive A rare metabolic disorder caused by a deficiency in the liver enzyme phenylalanine hydroxylase. Because there is a lack of the enzyme, toxic levels of phenylalanine build up in the system. When untreated mental retardation and other signs of neurologic development impairments may develop.

What is Cystic Fibrosis, and what type of genetic disorder is it?

Autosomal Recessive Disorder of membrane transport of chloride ions in exocrine glands causing lung and pancreatic disease.

What is Glycogen Storage Disease, and what type of genetic disorder is it?

Autosomal Recessive Excessive accumulation of glycogen in the liver and hypoglycemia; glycogen accumulation in striated muscle in myopathic forms.

What is Oculocutaneous Albinism, and what type of genetic disorder is it?

Autosomal Recessive Hypo-pigmentation of skin, hair, and eyes as a result of inability to synthesize melanin

What is sickle cell disease, and what type of genetic disorder is it?

Autosomal Recessive Red blood cell defect

Autosomal Recessive diseases occur only when ________ members of the gene pair are effected.

Both

List Some X-Linked dissorders

Bruton-type hypogammaglobulinemia (immuno deficiency) Hemophilia A (Bleeding Disorder) Duchenne Dystrophy ( Muscular Dystrophy)

What is the most common cause of genetic disorder?

Changes in the DNA sequence that alter the synthesis of a single gene product

What is Down Syndrome, and What type of genetic disorder is it associated with?

Chromosomal Disorder A disorder that is caused by nondisjunction of the cells that results in trisomy of the 21st chromosome. The most common birth defect is mental retardation.

__________ form a major category of genetic diseases, accounting for a large proportion of reproductive wastage (early gestational abortions), congenital malformations, and mental retardation.

Chromosomal Disorders

What factors may lead to breakage of chromosomes?

Exposure to radiation, influence by certain chemicals, extreme changes in the cellular environment, and viral infections.

What is the most common birth defect?

Cleft palate or lip

What is the difference between congenital and genetic disorders?

Congenital disorders are present at birth, but genetic disorders may manifest themselves later in life.

What greatly increases the chances of developing a child with an autosomal recessive disorder?

Consanguineous Mating: mating of two related individuals

When it comes to autosomal dominant disorders, onset is always __________.

Delayed. The signs and symptoms do not appear until later in life.

What is considered to be the most common chromosomal disorder.

Down Syndrome

________ are caused by multiple genes and environmental factors.

Multifactorial Inheritance Disorders

Which population of people is most at risk for developing tay-sachs?

Eastern European Ashkenazi Jews

A developing embryo may be influenced by the __________ that it shares with the mother.

Environmental factors

nondisjunction

Failure of the chromosomes to separate during oogenesis or spermatogenesis. Leads to germ cells with uneven numbers of chromosomes

True or false: Multifactorial Inheritance Disorders follow a clear cut pattern of inheritance.

False. They can be expressed early in life, present at birth, or may be expressed later in life.

Intrauterine Factors of Congenital Defects

Fetal crowding, positioning or entanglement of fetal parts

Thalidomide

Gives rise to full range of malformations, including short, flipper like appendages of all 4 extremities

Aneuploidy

Having an abnormal number of chromosomes

What is Turner Syndrome?

In females only, the absence of all or part of the X chromosome that leads to the absence of ovaries and no signs of secondary characteristics. The female is usually short in stature, but body parts are normal. These females have a normal intelligence, but may have spacial orientation and ADD issues.

What may increase a woman's risk of having a child with down syndrome?

Increased Age. As a woman ages, there is a greater chance of a woman having been exposed to damaging environmental agents (drugs, chemicals, radiation)

_________ drugs tend to cross the placenta more rapidly and enter the fetal circulation.

Lipid soluble

Environmental Factors of Congenital Defects

Maternal disease, infection or drugs taken during pregnancy

Some of the best documented teratogens are ___________ which causes neurologic deficits and blindness; located in some fish and water.

Mercury

What is unique about mitochondrial DNA

Mitochondria contain their own DNA which is unique from DNA located in the cell nucleus.

A cleft lip/ palate is an example of what type of disorder?

Multifactorial Inheritance Disorder

What organ systems are affected by Marfan Syndrome?

Ocular system, Cardiovascular System, and Skeletal System -An individual may have abnormalities in one or up to all three of the systems

A routine test in newborns that screens for serum phenylalanine levels is testing for which disease?

Phenylketonuria

____________ can cause microcephaly, skeletal malformations and mental retardation.

Radiation

Genetic Factors of Congenital Defects

Single or multi-factorial inheritance or chromosomal aberrations

Unlike DNA, there are no __________ available to fix rearrangements or mutations.

repair mechanisms

What does Torch stand for?

T- Taxoplasmosis O- Other R- Rubella C- Cytomegalovirus H-Herpes

Which cells are effected by Tay-Sacs?

The disease may be present in all cells, but is primarily found in brain neurons and retinal cells. The brain neurons are destructed and the retina is a cherry red spot on the macula. This leads to rapid mental and motor deterioration (including seizures) and visual impairments.

Genetic Anticipation

The increased occurrence of the disorder in successive generations

What prenatal screening can be done for Down Syndrome?

The only way to determine the presence of down syndrome in the fetus is through chromosome analysis via chronic villus sampling, amniocentesis, or percutanesous umbilical blood sampling.

Polysomy

The presence of more than 2 chromosomes to a set. Occurs when a germ cell containing more than 23 chromosomes is involved in conception.

Monosomy

The presence of only one member of a chromosome pair. This is a sever defect and generally causes spontaneous abortion

Variable expressivity

They can be expressed differently among individuals

What are the most common problems seen in children with cleft palate/lip?

They have problems with feeding and speech.

What type of development does Propylthiouracil impair?

Thyroid

What type of neurofibromatosis is associated with cafe au lait spots?

Type 1

What type of neurofibromatosis is associated with pigmented nodules of the iris?

Type 1

Which type of neurofirbomatosis is associated with learning disabilities, ADD, and abnormal speech?

Type 1

What are Subcutaneous lesions and what type of Neurofibromatosis are they associated with?

Type 1 growths just below the skin

what are plexiform neurofibromas, and what type of neurofibromatosis are they associated with?

Type 1 involving larger peripheral nerves; tend to form large tumors that cause severe disfiguration of the face or skeletal deformities.

What are cutaneous neurofibromas and what what type of neurofibromatosis are they associated with?

Type 1 lesions that project from the body. -They vary in number -The greatest number is found on the trunk

Which type of Neurofibromatosis is the most common and most visible?

Type 1 NF

What are the two forms of Neurofibromatosis?

Type 1 NF (NF-1) and Type 2 bilateral acoustic NF (NF-3)

What type of neurofibromatosis is associated with disorientation while diving or swimming under water?

Type 2

Which type of neurofibromatosis is associated with tumors of the acoustic nerve?

Type 2

Reduced Penetrance

When a person inherits a dominant mutant gene but fails to express it.

Sex linked disorders are almost always associated with the ___ chromosome and the inheritance pattern is predominantly _______.

X Recessive: Therefore males are typically more effected than females

What is Fragile X Syndrome and what type of genetic disorder is it?

X-linked Disorder Affects males and females In Males, characterized by mental retardation and a shared physical phenotype: -long face, everted ears, hyper extended joints, high arched palate, mitral valve prolapse, MOST DISTINCTIVE FEATURE: large testes. In females, there is relatively normal cognitive ability, but they tend to have premature ovarian failure, where they begin menopause early. Caused by a repeating sequence of 3 nucleotides with fragile X gene.

Organogenesis

a period extending from gestational day 15 to 60 when organs are being developed . This is the period when embryos are most easily disturbed by environmental influences.

Multifactorial Inheritance Disorders involve a __________ or _____________________.

a single organ or tissue developed from the same embryonic field

All single gene dosorders lead to formation of _________ or ________ production of gene product.

abnormal protein decreased

Environmental factors are thought to play a greater role in disorders of multifactorial inheritance that develop in ________ life

adult life. diabetes, cancer, hypertension, psychiatric disorders.

Congenital Defects

aka: birth defects abnormalities of a body structure, function or metabolism that are present at birth

Teratogenic Agents

chemical, physical or biological agent that produces abnormalities during embryonic development.

Vitamin A causes what defects?

cleft palate, heart defects, retinal and optic nerve abnormalities, and CNS malformations

When is the typical age of onset for autosomal recessive disorders.

early in life

____________ can cross the placenta and cause damage to the developing embryo and fetus.

environmental chemicals and drugs

Disorders of the mDNA are inherited on the _______ line.

maternal

What type of development does Tetracycline impair?

mineralization phase of tooth development

Disorders with the sex chromosomes are (choose 1: more common/ less common) than with the autosomes

more common. They are also much better tolerated than those with the autosomes.

mDNA mutations often effect the ______ system.

musculoskeletal

Mutations of mDNA generally effect tissue that are dependent on....

oxidative phosphorylation to meet their high needs for metabolic energy.

Single-gene disorders are primarily found in what age group?

pediatric

In Autosomal Dominant Disorder is a ________ mutant allele from an affected parent is transmitted to an offspring.

single

Single-Gene Disorders are caused by defective or mutant alleles at a ________ gene locus and follow mendelian patterns of inheritance.

single

Torch screening test examines the infants serum for __________.

the presence of antibodies or the agents.

The amount of alcohol that can be safely consumed during pregnancy is ________.

unknown.