Lecture 20: X linked disorder & mitochondrial inheritance

Question 1

What is haemophilia caused by

Answer 1

Mutation in coagulation factor 8 (A disease) or 9 (B disease), leading to a block in the clotting cascade which uses thrombin to cleave fibrinogen to fibrin

Question 2

What is the clinical manifestations of haemophilia

Answer 2

Recurrent and spontaneous bleeding into joint, soft tissues, muscle and other sites eg CNS.

Question 3

How is management of Haemophilia and what risk associated with it

Answer 3

Pain relief, rest of affected joint and infusions of coagulation factors derived from blood donation to treat acute bleeding and as prophylaxis -> however was risk of transferring infections carried by blood.
Now there is recombinant factor 8 or 9 which is genetically engineered/clone grown

Question 4

For X linked diseases what is the rate of passing it down for each gender from mum or dad

Answer 4

Mum can pass it down if carrier-> both genders 50% chance of carrying damaged allele
Dad can pass it down if affected-> girls 100% carrier, boys not affected.

Question 5

Give 4 examples of X linked disorders

Answer 5

Haemophilia, colour blindness, muscular dystrophy, fragile x syndrome

Question 6

What are some ways that a female carrier of haemophilia can be found out

Answer 6

1. through pedigree can find likelihood
2. phenotypic blood testing to measure amounts of clotting factor 8 or 9 in blood, carriers have around 50% level of clotting factor
3. PCR DNA sequencing detection of mutation directly or polymorphic linkage. Need to use DNA of affected patient in the family to identify which mutation and compare to a sister/potential female carrier

Question 7

What are problems associated with phenotypic analysis for clotting factors

Answer 7

There is a range for normal clotting factor levels variation can be caused by exercise/stress
Also for prenatal diagnosis it requires fetal blood which is difficult

Question 8

How is linkage between polymorphic markers/ SNP used to track the abnormal gene in a family and what do you need for this

Answer 8

Variations in non coding DNA are inherited from parents like restriction fragment length polymorphisms and variable number tandem repeats. By tracking the variation in the gene associated with the disease causing mutation, it can be used to determine carrier status -> but only if the variation isn’t carried by everyone anyway, the variation is close enough to the target gene so that recombination doesn’t take it away and you need an index case as well as whole family

Question 9

What does mitochondrial DNA (mtDNA) usually code for and what does mutations in it cause

Answer 9

mtDNA codes for proteins forming enzyme complexes in the respiratory chain (along with genomic DNA) so mutations decrease energy producing capacity.
Affects organ systems with higher energy requirements: brain, heart, skeletal muscle.

Question 10

What is the pattern of inheritance of mitochondrial disorders

Answer 10

From mother-> passed on to all children, from father no children passed on. Mitochondrial mutations are from the egg’s mitochondria

Question 11

What is mitochondrial replacement therapy

Answer 11

Nucleus of affected mother is placed into a healthy donor egg without mutant mitochondria and fertilised, prepared for gestation