Cross-modular diseases

Question 1

What is the large subtype of haemoglobinopathies that show a similar phenotype and are characterised by defective synthesis of one or more haemoglobin chain?

Answer 1

Thalassaemias

Question 2

In Thalassaemias, what effect does the defective synthesis of one or more haemoglobin chains have on the overall polypeptide?

Answer 2

Imbalance in the ratio of alpha- and beta- chains (normally ratio kept close to 1:1)

Question 3

What is the result of the abnormal haemoglobin tetramers that can form in Thalassaemias?

Answer 3

These tetramers are relatively insoluble and can result in erythrocyte deformity and anaemia.

Question 4

What does the global distribution of Thalassaemia and Sickle cell anaemia suggest about the disease?

Answer 4

The distribution coincides with that of endemic malaria worldwide. It suggests that heterozygous individuals have a greater resistant to malaria (though homozygous individuals pay the penalty in increase morbidity and mortality)

Question 5

What is the global distribution of Thalassaemia?

Answer 5

Mediterranean, Indian subcontinent, South East Asia and Africa

Question 6

A patients haemoglobins were assayed for their content of alpha- and beta- chains. Overall the ratio of alpha- to beta- chains were 0.59:1 (normal 1.03:1), what can you conclude about that?

Answer 6

Either:

1. Underporduction of alpha- chains
2. Increased degradation of apha- chains
3. Overexpression of beta- chains

Question 7

What are reticulocytes and why are they present in elevated numbers in individuals with haemoglobinopathies?

Answer 7

Immature red blood cells that are released early in response to anaemia.
They are characterised by loss of nucleus but retain the translation apparatus (lots of ribosomes,
mRNA etc)

Question 8

Why can a spleen become palpable in haemoglobinppathies?

Answer 8

The spleen can become swollen and easy to feel because abnormally shaped red blood cells become trapped there and lyse

Question 9

Why can inclusion bodies been seen in erythrocytes in haemoglobinopathies?

Answer 9

Haemoglobin that is misfolded or unable to assemble properly forms insoluble aggregates
that are visible as inclusion bodies. These also contribute to the abnormal shape of the red
blood cells.

Question 10

How do the beta-chain tetramers seen in some haemoglobinopathies contribute to hypoxia seen in the patient?

Answer 10

These
tetramers have a higher affinity for oxygen than the normal (2 alpha-, 2-beta-) tetramers. Therefore, they are
inefficient at delivering oxygen to the tissues and contribute to the hypoxia seen in the patient

Question 11

Suggest possible treatment for thalassaemia

Answer 11

If the case is relatively mild, it requires no major treatment. In cases of severe haemolysis, splenectomy is often carried out to prevent premature destruction of red blood cells. Severely affected individuals may need blood transfusions.

Question 12

List some of the signs and symptoms associated with alkaptonuria

Answer 12

Dark urine
Dark ear wax
Progressive degenerative arthiritis

Question 13

What is the ‘inborn error in metabolism’ that causes alkaptonuria?

Answer 13

Loss of function mutation in the gene encoding the enzyme homogentisic acid oxidase, which catalyses the reaction of homogentisic acid –> methylacetoacetic acid.
This leads to a build up of homogentisic acid.

Question 14

How does loss of function mutation of homgentisic acid oxidase result in the signs and symptoms of alkaptonuria?

Answer 14

Homogentisic acid (a pigment) builds up in urine and earwax.
Homogenitsic acid binds to collagen and builds up in cartilage and connective tissue causing progressive degenerative arthiritis

Question 15

What ‘inborn error of metabolism’ causes phenyletonuria?

Answer 15

Defects in the phenylalanine hydroxylase gene, which catalyses the reaction of phenylalanine –> tyrosine