Introductory Lecture

Question 1

Where are embryonic stem cells derived from?

Answer 1

Inner cell mass of trophoblasts; are a pluripotent stem cell population.

Question 2

How are stem cells induced to form different cell types?

Answer 2

Inducing signals causes differentiation into different cell types.
Cells grow into tissues/organs for transplantation.

Question 3

What is the benefit of using the patients own stems cells?

Answer 3

Genetically identical to patient.

Reduces risk of rejection and the use of immunosuppressant drugs.

Question 4

What disease did the first human stem cell trial treat?

Answer 4

Macular degeneration. By using stem cells from spare embryos leftover from IVF treatment.

Benefit: Eye has less of an immune response.

Question 5

Why was the first human transplant of stem cell successful?

Answer 5

The patients old trachea was damaged by TB.
Her own bone marrow stem cells were seeded onto a dead donor trachea (stripped of living cells, leaving only a collagenous frame), grown in vitro.

Question 6

What % of live births present with significant malformations and where is it more common?

Answer 6

5%.
Higher frequency in spontaneously aborted embryos.
Common defects seen in the heart, followed musculoskeletal and then urogenital.

Question 7

What is the % of human birth defects with no known cause?

Answer 7

60%.

Question 8

What is the major consequence of kidney defects?

Answer 8

Hypertension.

Question 9

What % of live births will have some defects, and what are the short-term and long-term consequences?

Answer 9

20%.
25% are both major and minor defects.

Short-term: 1 in 5 of infant deaths are caused by birth defects = hence it is the leading cause of infant mortality.
Long-term: 5th leading cause of years of potential life lost and long-term disability and childhood morbidity.

Question 10

What % of birth defects could be prevented?

Answer 10

50%.

By taking folate and avoiding alcohol, drugs and smoking.

Question 11

What is the commonest birth defects in the USA?

Answer 11

Heart defects - due to obese/diabetic mothers

Question 12

What is the commonest birth defects in Australia?

Answer 12

Musculoskeletal - genetic cause.

Question 13

What are examples of infectious agent teratogens?

Answer 13

Toxoplasma parasite.
Parvovirus.
Rubella virus.
Cytomegalovirus.
Herpes simplex.
HIV.
Syphilis.

Question 14

What are examples of medical treatment teratogens?

Answer 14

Vitamin A and analogues.
Anticoagulant: Warfarin.
Anticonvulsant: Valproic acid & phenytoin.
Chemotherapy.
Trimethoprim (folate antagonist).

Question 15

What are examples of recreational drug teratogens?

Answer 15

Alcohol.
Tobacco.
Cocaine.

Question 16

What was Thalidomide previously used for, and what illness is it used to treat now?

Answer 16

Previously used to treat nausea in pregnancy. Babies were born with phocomelia (shortening of limbs).
Led to FDA setting up new guidelines on drug testing (drugs tested on 2 species).

Now used for: leprosy, AIDS and some cancers.
N.B. Women taking thalidomide, need to be on 2 types of contraception.

Question 17

What are the 9 features of foetal alcohol syndrome?

Answer 17

Microcephaly (small head).
Short palpebral features (eye openings).
Epicanthal folds (folds over eyelids).
Low nasal bridge.
Short nose.
Smooth philtrum.
Flat mid face.
Thin upper lip.
Micrognathia (small jaw).

Question 18

During which period is the foetus most susceptible to birth defects?

Answer 18

In the embryonic period (3-8 weeks), in particular week 5.
Between weeks 0-3: foetus miscarries.
Between weeks 8-38 (foetal period): less pronounced defects.

Question 19

In which period is the CNS affected?

Answer 19

It can be affected throughout gestation, since it continuous to develop until full term.

Question 20

Which birth defect is decreasing in incidences?

Answer 20

Spina bifida - following introduction of folate supplements.

Question 21

Which birth defects are increasing in incidences?

Answer 21

Gastroschisis, cleft lip/palate and hypospadias (abnormal genitalia).

Question 22

Why was the infant mortality high before the harvest, but low after the harvest?

Answer 22

Before harvest: Mother were not fed well, led to thymic defects in babies.
After harvest: Mothers were fed well and their offsprings had a higher chance of survival.

Thymic and lymphoid tissue are very sensitive to lack of nutrition than other tissue types. Poor nutrition leads to heart disease and type 2 diabetes.

Question 23

Does maternal obesity and diabetes increase the risk of birth defects?

Answer 23

Yes.

Question 24

What can we do to decrease birth defects and the consequences of birth defects?

Answer 24

1. Avoid teratogens: E.g. Alcohol, drugs.
2. Take preventative supplements: Folic acid, dexamethasone for lupus and congenital adrenal hyperplasia.
3. Better screening/diagnostics tests: Amniocentesis, chorionic villus sampling, ultrasonography.
4. Foetal surgery (embryos don’t scar): E.g. For Potter’s sequence.
5. Gene therapy?

Question 25

Why is folic acid important during pregnancy?

Answer 25

Required for synthesis of DNA bases (especially thymine) and hence DNA replication and cell division.
Required for amino acid metabolism (methionine) for methylation.

Reduces neural tube defects by 70%.

Question 26

What are the daily dietary requirements of folic acid when a) trying to conceive and b) for women who have had a previous child with NTD?

Answer 26

Conceiving: 0.4mg.

Previous child: 4mg.

Question 27

How does congenital adrenal hyperplasia (CAH) develop?

Answer 27

Reduction in enzyme 21-hydroxylase –> decreases cortisol, increases ACTH –> supraadrenal hyperplasia –> excess supraadrenal androgens (testosterone).

Increases masculisation in females.

Question 28

What is the treatment for CAH?

Answer 28

Corticosteroid, dexamethasone.

Question 29

What does the breakthrough research on Down’s Syndrome involve?

Answer 29

Injecting NAP and SAL into pregnant mice with trisomic pups.

= improved cognition.

Question 30

What is a key feature to look out for in babies born with Down’s Syndrome?

Answer 30

Single palmar crease.

Question 31

What is evident on an ultrasonography in order to diagnose Down’s Syndrome?

Answer 31

Nuchal transparency at 12 weeks.

Causes accumulation of fluids, since lymphatics are not developed to drain into veins.

Question 32

What % of babies are born with polydactyl or other congenital defects?

Answer 32

15%.

Question 33

In which syndromes are radial ray abnormality seen in?

Answer 33

Holt-Oram syndrome.
Thrombocytopenia-absent radius.
VATER/VACTERL.
Fanconi's anaemia.
Trisomy 13/18.

Question 34

In which syndromes are clenched hand deformity seen in?

Answer 34

Trisomy 18.
Amniotic band syndrome.
Pena Shokeir syndrome.
Arthrogryposis.
Multiple pterygium syndrome.

Question 35

In which syndromes are sandal gap deformity seen in?

Answer 35

Down’s syndrome (45%).

Normal variant.

Question 36

How does diagnostic tests for genetic disorders work?

Answer 36

The defective gene is removed and the remaining cells of the embryo are transplanted in the mother.
Used in Tay Sachs (prevalent in Jewish community), muscular dystrophy and X-linked disorder like haemophilia.

Question 37

What does autosomal dominant mean?

Answer 37

One copy of mutation = Have the syndrome.

Question 38

What does autosomal recessive mean?

Answer 38

One copy of mutation = Fine.

Two copy up mutation = Syndrome.

Question 39

What is piebaldism?

Answer 39

Pigmentation defect in EMT –> As derived from neural crest.
A mutation in endothelin 3.
Has enteric ganglion defect.

Question 40

What is Potter’s sequence?

Answer 40

Kidney/bladder obstruction –> hydronephrosis (dilated ureters & kidney) –> megacystis (dilated bladder) –> Oligohydramnios (too little amniotic fluid) –> Lung damage & craniofacial and limb defects.

Question 41

What is craniosynostosis?

Answer 41

Sutures close too early –> abnormal head growth.
Linked to limb defects.
Required for FGF and Hh (gain of function mutation).