Congenital and genetic diseases

Question 1

Define congenital

Answer 1

present at birth

Question 2

Define genetic

Answer 2

determined by genes

Question 3

Describe genetic abnormalities and the different kinds

Answer 3

morphologic defects present at birth. May or may not be a genetic basis for these defects. 3% of newborns. Most common cause of mortality in the 1st year of life.
- malformations
- deformations
- disruptions
- syndrome

Question 4

Describe malformations

Answer 4

result from an intrinsically abnormal development process. Examples: polydactyly (extra digit), spina bifida, congenital heart disease (malformation of the heart - missing part for example

Question 5

Describe deformations

Answer 5

result from mechanical forces - extrinsic cause for abnormality, localized or generalized (compression of a growing fetus by a biochemical force e.g. small uterus, large fetus, oligohydramnios- lack of amniotic fluid). Examples: positional abnormalities of the feet - club foot

Question 6

Describe disruptions

Answer 6

result from breakdown of a normal development process. Result from secondary destruction of an organ or body region. No intrinsic cause - usually extrinsic etiology. Example: limb/finger amputation due to amniotic band

Question 7

Describe syndromes

Answer 7

a syndrome is a characteristic association of several anomalies (deformation, disruption, and malformation). Caused by a single etiologic agent affecting several tissues. May or may not be sequential.

Question 8

What is Potter syndrome?

Answer 8

An example of both malformations and deformations. The basic defect is absent or abnormal kidney development, resulting in decreased amniotic fluid (oligohydramnios) and compression of the fetus. These lead to abnormal development of the lung (pulmonary hypoplasia) and death due to respiratory insufficiency. The fetal compression also produces abnormal facies (flattened face/ nose + low set ears) and abnormal positioning of the hands and feet - club feet.

Question 9

Define teratogens, give some examples

Answer 9

agents that produce congenital malformations, pathogenesis is complex and poorly understood.
1. Congenital infections (infectious organism)
2. Drugs and chemicals
3. Maternal disorder
4. Ionizing radiation

Question 10

Describe how congenital infections act as teratogens

Answer 10

• Mother is infected while pregnant
• Usually viruses
• examples: congenital rubella (german measles), CMV, herpes, varicella zoster (shingles and chicken pox), influenza, mumps, HIV.
• Maternal rubella occurring in the first trimester will cause fetal malformations. In a child or adult, rubella is a mild disease with fever and a transient skin rash. However, with a primary infection in a pregnant woman, there is hematogenous spread across the placenta to the fetus. The fetus is not capable of producing an immune response to the viral infection. The virus replicates in fetal cells, preventing their proper division resulting in growth retardation, cataracts, deafness and congenital heart disease. The risk is the highest if fetal infection occurs during the first 8 weeks. Other common congenital infections with teratogenic effects include cytomegalovirus, varicella zoster (chicken pox).

Question 11

Describe how drugs and chemicals act as teratogens

Answer 11

examples: thalidomide, alcohol, folate antagonists (cancer treatment), anti-convulsants (epilepsy and seizures) and 13-cis-retinoic acid (treat acne)
1. Thalidomide: was extensively used in some countries in the late 1950’s for symptomatic relief of nausea and vomiting of early pregnancy. In 1960, there was noted an increase in the number of infants born with limb defects. Astute observations by a German physician suggested that this was due to thalidomide. Subsequent studies confirmed this relationship, including reproduction of similar effects in experimental animals. Thalidomide affects the embryo between the third and fifth weeks post-conception by interfering with proper limb growth, producing phocomelia (‘seal limbs’).
2. Alcohol: excessive alcohol consumption during pregnancy causes prenatal and post-natal growth retardation, mental retardation, joint anomalies, heart defects and abnormal facies called fetal alcohol syndrome. This is the most common cause of mental retardation in the western world, affecting 1/300-1/2000 live births. There is an obvious dose-response effect but no safety line. The harmful effects of maternal alcohol ingestion are not restricted to a sensitive period of early pregnancy but extend throughout gestation.

Question 12

Describe how maternal disorders act as teratogens

Answer 12

example: diabetes mellitus
- The overall risk for major congenital malformations in diabetic pregnancies is 6%. The risk can be over 20% if diabetes is not appropriately controlled during the first trimester. Mothers with insulin-dependent diabetes have the highest risk. Malformations often involve kidneys, heart and brain. The severity of malformations is related to the degree of control of maternal diabetes during pregnancy.
- Maternal hyperglycemia - fetal hyperinsulinemia : large babies, cardiac anomalies, central nervous system malformations.

Question 13

Describe how ionizing radiation acts as a teratogen

Answer 13

Radiotherapy for treatment of cancer
Offspring of pregnant women exposed to the atomic bomb explosions in Hiroshima and Nagasaki, had an increased incidence of microcephaly and mental retardation.

Question 14

What are the different types of genetic diseases?

Answer 14

1. Chromosomal disorders
2. Single gene disorders
3. Multifactorial (polygenic) disorders

Question 15

What are numerical abnormalities?

Answer 15

• Chromosomal disorders
• aneuploidy (=abnormal number of chromosomes), disomic (normal, two sister chromosomes), trisomic (3 sister chromosomes - down syndrome = trisomy 21), monosomic (1 sister chromosome - turner syndrome = monosomy X)
• can be of autosomes or sex chromosomes

Question 16

Describe and list examples of numerical abnormalities of autosomes

Answer 16

example: down syndrome, trisomy 21. The chromosomal disorder affects approximately 1/800 live born infants. Malformations include abnormal facies (flat facial profile and epicanthic folds - inner part of eye has extra fold), palpebral fissure- palmar creases, congenital heart disease, duodenal stenosis or atresia and mental retardation/ intellectual disability, abundant neck skin and increased risk of acute leukemia (malignancy). There is a significant increased risk with advanced maternal age. With the maternal age 30 years, the incidence is about 1/900 whereas by 45 years the risk is 1/25. Parents have a normal karyotype. We do not know the pathogenesis.

Question 17

Describe and list examples of numerical abnormalities of sex chromosomes

Answer 17

examples:
1. turner syndrome (XO - absence of x chromosome), most common in females, phenotypically female, features: failure to develop secondary sex characteristics, normal mental status, short stature, primary amenorrhea (infertile) - don’t get menstrual period
2. Klinefelter syndrome (XXY - extra x chromosome), most common in males, features: elongated body (abnormal long legs), small atrophic testes, lack of secondary sex characteristics (like hair spread typically seen in masculinity), gynecomastia (breast development), and infertile.
- Abnormal numbers of sex chromosomes produce abnormalities less severe than with abnormal numbers of autosomes. However, these individuals fail to develop normal secondary sexual characteristics, are infertile and have skeletal abnormalities.
- More common than the autosomes
- Problems related to sexual development and fertility
- Difficult to diagnose at birth, first recognized at puberty

Question 18

What are structural abnormalities?

Answer 18

• chromosomal disorder
• result of chromosome breakage followed by loss or rearrangement of material. Include: deletions and balanced translocations
• example: cri-du-chat syndrome (partial deletion in the short arm of chromosome 5). Manifestations of this syndrome include cat-like cry in infancy, small head and facial abnormalities. -deletion, duplication, translocation, inversion (wolf-hirschhorn syndrome, jacobsen syndrome - deletions, certain types of cancer - translocations). Prader-willi syndrome

Question 19

What are single gene disorders?

Answer 19

• monogenic or mendelian disorders
• 80-85% are familial
• Mechanism of single gene disorders: usually affect a protein (enzyme, cell receptor, non-enzyme protein). Identifying the protein may aid in treatment.
• can be: autosomal or x-linked, and dominant or recessive

Question 20

Describe autosomal dominant

Answer 20

One parent has the disease, 50% risk to children. Both sexes are equally affected. Examples:
- Marfan syndrome
- familial hypercholesterolemia

Question 21

What is Marfan syndrome?

Answer 21

This is a disorder of connective tissue. Manifestations include long limbs (tall) and extremities, long tapering fingers and toes, and lax joints, dislocation of lens of eye and abnormal dilation of aorta (cardiovascular lesion -aortic dilatation, can kill the child). The gene is on chromosome 15. Defect in non-enzyme protein (fibrillin - extracellular glycoprotein which forms a matrix. Found in aorta, ligaments and the lens of the eye).
- No treatment to prevent condition
- autosomal dominant

Question 22

What is familial hypercholesterolemia?

Answer 22

this is one of the most common genetic diseases (most frequent mendelian disorder) and a leading cause of coronary heart disease. The basic defect is mutations in the gene encoding the low-density lipoprotein (LDL - binds low density lipoprotein, and transport and metabolism of LDL) receptor. Receptor is non-functioning resulting in an elevated plasma levels of LDL, causing loss of feedback control so there is increased synthesis of cholesterol. Increased cholesterol level in plasma and leads to deposition of cholesterol in arteries (vessel walls) - this leads to an increased risk of coronary heart disease and heart attacks. One of 500 persons carries the abnormal gene and may have coronary heart disease in early middle age. In homozygotes (1/1,000,000), the coronary heart disease is usually fatal in childhood. The gene is located in chromosome 19.
- Treatment: dietary restrictions, and try to lower the amount of cholesterol from medication.
- autosomal dominant

Question 23

Describe autosomal recessive

Answer 23

Both parents are normal but carriers, 25% risk to children. Both sexes are equally affected. Examples:
- Cystic fibrosis
- Phenylketonuria (PKU)

Question 24

What is Cystic fibrosis?

Answer 24

• This is the most common autosomal recessive disease in caucasian children with an incidence of 1/1600. Carrier frequency is about 1/20. The respiratory tree mucus is abnormal, causing repeated lung infection with the destruction of the lung tissue. The patients also have pancreatic insufficiency resulting in intestinal malabsorption. The gene (cystic fibrosis transmembrane regulator CFTR) is on chromosome 7. Involve epithelial transport protein (cystic fibrosis transmembrane regulator - CFTR) function: channel to allow movement of chloride.
• Affect fluid secretion. Produce an abnormal viscid mucus secretion. Affects the pancreas (intestinal malabsorption) and the lung. - often malnourished - excretion of enzymes to digest food from the pancreas are inhibited by this thick mucous.
• Can’t be treated by direct replacement of the CFTR, have to treat the consequences, ie. giving them nutrients, treating pneumonia, and lung transplants.

Question 25

What is Phenylketonuria (PKU)?

Answer 25

• This is an example of metabolic disease resulting from a mutation in phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine. Phenylalanine is derived from food, required for protein synthesis, and excess phenylalanine is converted to tyrosine by phenylalanine hydroxylase.
• Deficiency of phenylalanine hydroxylase leads to accumulation of phenylalanine in body fluids, and this damages the developing brain in early childhood and causes severe mental retardation. -intellectual disability, seizures and inability to walk or talk.
• This disease can be diagnosed by newborn screening and treated by a low-phenylalanine diet - restrict phenylalanine intake. This diet has to continue until 21-22 because this is when CNS development tends to come to completion. When they get pregnant they have to return to this diet.
• Almost all the offspring of female PKU patients not on a low phenylalanine diet are abnormal with mental retardation, microcephaly, growth retardation, and congenital heart disease. This is due not to their own genetic defect but to the highly teratogenic effect of elevated levels of phenylalanine in the mother’s circulation.
• Phenylalanine is also a teratogen

Question 26

Describe X-linked recessive

Answer 26

Mother carrier, 50% chance for sons to be affected. 50% chance for daughters to be carriers. Example:
- Hemophilia A

Question 27

What is Hemophilia A?

Answer 27

Affect gene coding for Factor VIII which is the coagulation cascade. Decreased or abnormal factor VIII results in prolonged bleeding, easy bruising, and spontaneous hemorrhages. Absent normal blood clotting with prolonged bleeding time, and bleeding into joints and muscles. This is due to deficiency of coagulation factor VIII which is encoded by a gene on the chromosome X.
- Give patient factor 8, replace protein involved.

Question 28

Describe multifactorial (polygenic) disorders

Answer 28

These disorders are due to the effect of multiple genes and the interaction between the genetic factors and environmental factors. Appears to run in families, and do not fit any inheritance pattern of single gene disorders. Examples: cleft palate, congenital heart disease, spina bifida, coronary heart disease, hypertension, and diabetes mellitus.