Lecture 21- X Linked Disorders and Mitochondrial Inheritance Flashcards Preview

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X-linked Recessive DIsorder

Only males are affected. They only have one X and cannot compensate. Affected males won't transmit to sons but ALL daughter will be carriers.

Females are usually carriers, and can pass the gene on. This is because they have the normal wild type gene, ie: they are heterozygote.
50% sons are affected
50% daughters are carriers


X-Linked Recessive Disorders

Colour Blindness
Muscular Dystrophy



Deficiency of one of the clotting factors, results in a bleeding tendency.
Usually when you cut yourself > vessels contract > platelet clump forms > activation of coagulation factors in a cascade > activates thrombrin > activates fibrin that forms clot.
X-linked recessive disorder.
Factor VIII (8) 'Haemophilia A'
Factor IX (9) 'Haemophilia B'
These genes for these are on the X chromosome, and mutations of these results in deficiency.
These present the same, only can tell the difference if you genetically test.
NZ treatment budget: 20-22 million/year.
1/5000 males


Clinical Features of Haemophilia?

Sponatenous bruising, soft tissue/joint/muscle damage following mild trauma.
CNS 'brain bleeds' are also common.


Management of Haemophilia

Replacement infusion of Coagulation factors. (from blood transfusions or genetically engineered). Potential risk of Hep and HIV infection

Pain relief
Rest of joint


Small number of patients but there is significant burden to patients and family.

-Physical suffering
-ongoing therapy needs (blood replacement)
-Risks with therapy (blood replacement)
-Social, educational and work issues


The impact of genetic technology

-Improved strategies for assessment and diagnosis of females who may be carriers (options and choices)

-Potential strategies for prenatal diagnosis


The Diagnostic Challenge in X-linked Recessive disorders

-Diagnosis of asymptomatic female carriers in a family with an x-linked recessive disorder
-offering strategies for a woman carrier who wants to have children


Phenotypic analysis

Measure the level of clotting factor in blood
Levels of Factor VIII
Normal: 100% (50-150 units/L)
Haemophilia patients:


If females are 46, XX: why don't they produce twice as much protein for any X chromosome encoded gene eg) coagulation factor VIII

Why don't normal females have levels of 200%?

Principle of lyonisation.
Early on in embryonic development due to random inactivation of one X chromosome in somatic cells; inactive X= barr body, occurs early at approx day 16

In carrier females, the random inactivation, ha;f of the gene is mutated so ~50%


Issues with phenotypic Analysis

Levels of normal clotting factor are greatly influence/vary with exercise (increases), stress etc. 20% error due to this

Prenatal diagnosis would require fetal blood sample. This is difficult and could only be done later.


Now instead we do Genetic Analysis

Anything with DNA (blood, skin, CVS, amniotic fluid) shows us a
-polymorphic linkage
- direct mutation diagnosis
to allow us to diagnosis & detection of carriers!


Mutations causing Haemophilia

Mutations in factor VIII and IX genes.
Structural Changes (eg; deletions)

Point mutation


Direct mutation analysis (99%)

analyse DNA from affected patient, identify mutation.
Allow accurate confirm status of concerned female


Indirect Mutation analysis

-if mutation cant be identified (rare)

We can use linked polymorphism markers and SNP's to track the abnormal genes (in non-coding regions, not pathogenic/disease causing but can be used to track mutated gene in family)
"linkage Analysis"


"Linkage Analysis

Not looking for the disease causing mutation, just using the normal variations in the DNA to track a gene.
We detect them because they change restriction enzyme sites.
REs: made by bacteria, cut DNA into particular sequences, if that sequence is changed, it may result in a loss of a cutting site. > different sized DNA fragments we can analyse
RFLPs (restriction fragment length polymorphisms)

or VNTRs (variable number tandem repeats)


Bcl I Polymorphism in FVIII gene

Normal Factor VIII gene: have got a sequence thats recognised and cut by the Bcl 1 enzyme
On about have of us we have a polymorphic sequence that results in a new Bcl cutting site > smaller piece of DNA
This can be used to track a family


Issues with linkage analysis