FunMed Week 3: SCA

Question 1

State the inheritance pattern of sickle cell disease? What is the probability of two carriers of disease allele having a child with sickle cell? 1 mark

Answer 1

Autosomal inheritance

25%

Question 2

If Daniel (homozygous carrier) was to marry a woman who did not carry the mutated allele what would the status of any children be and justify your answer? 2 marks

Answer 2

All would be carriers of the mutated allele as Daniel is homozygous and would pass on a mutated copy to all his children (1 mark) but the wife would pass on the normal allele to all children. (1 mark)

Question 3

Explain why Daniel does not develop symptoms until after the first 6 months of life. 2 marks

Answer 3

Babies still have fetal Hb and it is not until this starts to decline after birth (1 mark)
and is replaced by the adult but mutated Hb that RBC will start to sickle. (1 mark)

Question 4

What type of genetic mutation causes the sickle cell mutation and explain how this causes a change in the amino acid sequence? 3 marks

Answer 4

Point mutation a single nucleotide change or substitution (A to T). (1 mark)

This changes the three amino acid codon sequence leading to a mis-sense mutation (1 mark) from glutamic acid to valine. (1 mark).

Question 5

5 What is the haemocrit and why is it lower in sickle cell disease? 2 marks

Answer 5

Haematocrit is the volume percentage of red blood cells in the blood or the ratio of the volume of the red blood cells to the total volume (1 mark).

In SCD it is lower since the red blood cells are smaller and most die earlier leading to lower numbers (hence volume) of red blood cells (1 mark).

Question 6

what is the mutation the makes SCA occur? [3]

what does is the name of the Hb this mutation leads to? [1]

Answer 6

Single base mutation of Adenine to Thymine. Produces a substitution of valine for glutamic acid at the sixth codon of the beta-globin chain. Hb gene found on chromosome 11

Leads to faulty haemoglobin protein: haemoglobin S (sickle cell haemoglobin)

Question 7

what is the difference in Hb structure for normal and SCA patients?

Answer 7

1. Normal Hb: Hb A
   * *4 haem subunits,** each have one polypeptide chain and one haem group, surround a globin group.
   
   1. 2 x alpha, 2 x beta haems
   2. Each haem group has a ferrous atom (iron) – which oxygen binds to.
   3. Healthy erythrocytes:
      
      1. Rbc smooth, round and glide through blood vessels
      2. Biconcave, disc shaped, anuclear
      3. Live for around 120 days
2. Hb S:
   
   1. Oxygenated Hb S has little difference to Hb A. Deoxygenated Hb S – harmful
   2. When Hb S lose oxygen: formation of insoluble fibres and bundles form into shape of sickle

Question 8

when is it that Hb S changes to be harmful? [1]

what is the result of ^? [3]

Answer 8

when is it that Hb S changes to be harmful? [1]
when becomes deoxygenated

what is the result of ^? [2]
RBC stick together - blockages of BV
reduced flexibility of RBC
shortened life of RBC - 10 / 20 days

Question 9

what does SCA offer protection agaisnt? [1]

Answer 9

Falciparum malaria [1]

Question 10

why does being a baby protect from sickling of RBC?

Answer 10

1. Baby or fetal hemoglobin protects the red blood cells from sickling. Around 4 to 5 months of age, the baby or fetal hemoglobin is replaced by sickle hemoglobin and the cells begin to sickle.

Question 11

describe and explain the symptoms of SCA? [8]

Answer 11

1. Hand – Foot syndrome
   
   1. Swelling in the hands and feet. Cells get stuck in blood flow of hands / feet and block flow of blood
2. Pain
   
   1. Blockage of blood vessels causes mild to severe pain.
3. Anaemia
   
   1. Tiredness, irritability, dizziness, jaundice, delayed puberty, pale skin colour
4. Infection
   
   1. Especially pneumonia.
5. Splenic Sequestration
   
   1. Lots of sickle cells get trapped in the spleen and gets v large. Symptoms: sudden weakness, pale lips, fast breathing, extreme thirst
6. Vision Loss
   
   1. Blood vessels in the eye become blocked with sickle cells and the retina (the thin layer of tissue inside the back of the eye) gets damaged.
7. Vaso-Occlusive Crisis (blockage of small blood vessels - prevents oxygen supply to tissues.)
   
   1. Presents as: Children: Acute pain in hands and feet. Adults: Pain in long bones, such as femur. Vary in frequency depending on patients.
8. Acute chest syndrome (vaso-occlusive crisis of pulmonary vasculature)
   
   1. Presents as: shortness in breath, chest pain, hypoxia

Question 12

what is the inheritance pattern of SCD?

if both parents have gene for SCA, what % is

a) child being a carrier?
b) child suffering from SCA

Answer 12

1. Autosomal recessive disorder:
   
   1. Both parents have SCT: 50% child will have SCT (be a carrier)
   2. Both parents have SCT: 25% child will have SCD.

Question 13

how can you treat SCA? [4]

Answer 13

1. Drink lots of water
2. Painkillers
3. Folic acid – stimulates production of rbc
4. Episodes of pain: hydroxycarbamide.
5. Blood transfusions (if really severe)
6. Stem cell / bone marrow transplants – only cure
   
   1. Rare because of significant risks

Question 14

what are features for HbS? [3]

Answer 14

Hb S polymer injures the sickle erythrocyte, leading to:

increased density,
reduced deformability
increased adhesivity
shortened life span.

Question 15

what does HbS lead to in blood vesels? [1]

Answer 15

It is a multi-system disorder due to widespread organ dysfunction from red blood cell ‘sickling’ leading to chronic vaso-occlusion (i.e. blockage of vessels).

Question 16

what is the structure of HbS? [2]

Answer 16

HbS: two alpha, two sickle (abnormal beta)

Question 17

when does sickling process increase in HbS [4]

Answer 17

This sickling process is greatly increased by low oxygen levels, dehydration, concurrent illness (e.g. infections), cold exposure and acidosis.

Question 18

how can sickle cell diesase patients manage their disease?

Answer 18

Folic acid replacement: at risk of bone marrow aplasia due to deficiency from increased red blood cell turnover. Usually 5mg daily.

Antibiotic prophylaxis: usually penicillin prophylaxis (e.g. Pen V) or erythromycin in penicillin allergic patients

All patients require regular follow-up with a haematologist who specialises in red cell disorders

Question 19

is SCD curable?

Answer 19

Rarely, haematopoietic stem cell transplantation can be considered for patients, which would be curative.

This is because the normal blood cells in the bone marrow are replaced with donor stem cells (e.g. matched sibling donor) that can differentiate into erythrocytes that contain haemoglobin without the beta globin gene mutation causing HbS.

Question 20

The two most commonly encountered acute complications include WHAT? [2]

Answer 20

The two most commonly encountered acute complications include:

Acute painful episodes: also known as painful crisis or painful vaso-occlusive crisis.

Acute chest syndrome: also known as chest crisis.

Question 21

what happens to HbS structure after deoxygenation? [1]

Answer 21

Following deoxygenation, the mutated hemoglobin (HbS) molecules polymerize to form bundles.

. The polymer bundles result in erythrocyte sickling

Question 22

The WHAT is one of the most common and early organs to be affected in SCA?

Answer 22

The spleen is one of the most common and early organs to be affected in SCA

Question 23

why should patients with SCA avoid smoking [1] and drinking [1] ?

Answer 23

avoid alcohol and smoking – alcohol can cause you to become dehydrated and smoking can trigger a serious lung condition called acute chest syndrome

Question 24

why are SCD patients susceptible to infection?

Answer 24

SCD increases the risk for infection because of damage to the spleen. The spleen is an organ that filters blood and destroys old red blood cells. The spleen also contains the only cells in our body that can destroy certain types of pathogens (organisms that can cause disease and infection), such as encapsulated bacteria.2,3

People with SCD often have non-working spleens. This is called functional asplenia. When red blood cells become sickled in the spleen, they can block blood from flowing through the normal filtering pathway

It functions as a phagocytic filter, removing old and damaged cells and blood-borne microorganisms, and also produces antibodies.​

Question 25

what is the single nucleotide sub that causes SCA?

Answer 25

The underlying abnormality is a single nucleotide substitution (GTG for GAG)

Question 26

explain how deoxygenation causes sickling to occur

Answer 26

In HbS, deoxygenation exposes the abnormal valine residue on the surface of the molecule

which then forms hydrophobic interactions with adjacent chains.

The resulting polymers align into bundles, causing distortion of the RBC into a crescent or sickle shape and reducing flexibility and deformability, which impairs passage of the cells through narrow blood vessels.3

Question 27

why does HR increase with SCA?

why can SCD cause decreased growth in children?

Answer 27

With sickle cell anemia (HbSS), this causes a chronic anemia (a steady state Hb of 6–8 g/dl)6 with a resultant increase in cardiac output and workload, which produces cardiomegaly and reduced exercise tolerance.

The increased energy demands due to this and the chronically elevated rate of hematopoiesis contribute towards poor growth in children, and individuals are susceptible to any factor exacerbating the anemia, which can precipitate circulatory failure.7

Question 29

why high white blood cell count?
why high temperature?