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Molecules, Genes and Disease > MGD 9.2 Haemoglobinopathies > Flashcards

MGD 9.2 Haemoglobinopathies Flashcards

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1
Q

What is the structure of haemoglobin?

A

Composed of 4 globin chains: 2 alpha-like chains and 2 beta-like chains. Each chain is bound to a heme molecule, which binds oxygen reversibly.

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2
Q

How many oxygen molecules can 1 haemoglobin molecule carry?

A

One haemoglobin molecule can carry 4 oxygen molecules.

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3
Q

Where is haemoglobin located?

A

Found in erythrocytes (red blood cells).

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4
Q

What is the key function of haemoglobin?

A

Transports oxygen from the lungs to tissues and returns carbon dioxide to the lungs.

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5
Q

What is the impact of mutations in globin chains?

A

Mutations in the globin chains (e.g., Sickle Cell Disease, Thalassaemia) can impair haemoglobin’s function and oxygen transport efficiency.

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6
Q

What is the structure of erythrocytes?

A

Biconcave shape for large surface area and flexibility, allowing passage through narrow capillaries.

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7
Q

What is the function of erythrocytes?

A

Transports oxygen from lungs to tissues and removes carbon dioxide for exhalation.

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8
Q

What is the lifespan of erythrocytes?

A

Approximately 120 days.

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9
Q

How are erythrocytes removed?

A

Old/damaged erythrocytes are cleared by the spleen, and recycled components are used for new erythrocyte production.

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10
Q

What is the importance of the shape and flexibility of erythrocytes?

A

Shape and flexibility are crucial for efficient oxygen transport, with abnormalities leading to diseases such as sickle cell anemia.

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11
Q

What is anaemia?

A

Decrease in haemoglobin levels below reference values based on age and sex.

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12
Q

What are the reference levels for anaemia?

A

Males: 135–175 g/L; Females: 115–155 g/L.

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13
Q

What are the signs and symptoms of anaemia?

A

Fatigue, shortness of breath, paleness, dizziness, reduced exercise tolerance.

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14
Q

What are the causes of anaemia?

A

Can result from blood loss, nutritional deficiencies (iron, B12, folate), bone marrow disorders, and chronic diseases.

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15
Q

What are the different classifications of anaemia by MCV?

A

Microcytic Anaemia: Low MCV (e.g., iron deficiency, thalassaemia); Normocytic Anaemia: Normal MCV (e.g., acute blood loss, chronic disease); Macrocytic Anaemia: High MCV (e.g., B12 or folate deficiency).

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16
Q

How many amino acids is the alpha-like subunit of haemoglobin made of + what genes code for it?

A

141 amino acids, genes on chromosome 16.

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17
Q

How many amino acids is the beta-like subunit of haemoglobin made of + what genes code for it?

A

146 amino acids, genes on chromosome 11.

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18
Q

What are the percentages of different haemoglobin variants in normal adults?

A

HbA (α2β2) 97%; HbA2 (α2δ2) 2%; HbF (α2γ2) <1%.

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19
Q

What are the relative charges of the different haemoglobin variants?

A

Most Positive: Hb A; Hb F; Hb S/D/G; Hb A2/C/E/O: Least Positive.

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20
Q

What are the different haemoglobin variants?

A

Normal Adults = HbA; Normal Newborns = HbA + HbF; Sickle cell disease = HbS/D/G; Sickle cell trait = HbS/D/G + HbA; Hb SC disease = HbS/D/G + Hb A2/C/E/O.

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21
Q

What are the quantitative disease states (haemoglobinopathies)?

A

Quantitative = Too little (or too much) globin chain synthesis; Thalassaemia.

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22
Q

What are the qualitative disease states (haemoglobinopathies)?

A

Qualitative = Synthesis of abnormal gene product (structural variants); Sickle cell, HbE, HbC…

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23
Q

How common is Thalassaemia?

A

Commonest single gene disorders worldwide; 1.5% beta carriers and 5% alpha carriers.

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24
Q

What is the worldwide distribution of Thalassaemia?

A

Predominantly tropical and subtropical regions.

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25
What advantage does Thalassaemia provide to heterozygotes?
Heterozygotes have protection from malaria, hence high and maintained carrier frequency.
26
How is HbA normally produced?
4 alpha globin chain genes and 2 beta globin chain genes lead to balanced production of HbA (α2β2).
27
What is the genetics behind alpha Thalassaemia?
Loss of alpha globin genes; autosomal recessive inheritance.
28
What is the phenotype of alpha Thalassaemia caused by?
0-3 alpha globin chain genes and 2 beta globin chain genes (normal) lead to imbalanced production and excess of β chains.
29
What occurs in severe phenotypes of alpha Thalassaemia?
These form HbH (β4), which is unstable and has a high affinity for oxygen.
30
What is the result of alpha thalassaemia in utero?
In utero, HbBarts (γ4) is produced.
31
What are the different types of Alpha Thalassaemia?
α,α/α,- : “silent” (asymptomatic); α,-/α,- : Trait (asymptomatic); α,α/-,- : Trait (asymptomatic); α,-/-,- : “HbH disease”; -,-/-,- : Hydrops fetalis.
32
What are the features of α,α/α,- : “silent” (Alpha Thalassaemia)?
Asymptomatic, wide geographic distribution, low MCV/MCHC, raised red cell count.
33
What are the features of α,-/α,- : Trait. (Alpha Thalassaemia)?
Asymptomatic, low MCV/MCHC, raised red cell count.
34
What are the features of α,α/-,- : Trait. (Alpha Thalassaemia)?
Far East, asymptomatic, low MCV/MCHC, raised red cell count.
35
What are the features of α,-/-,- : “HbH disease”(Alpha Thalassaemia)?
HbH (β4) produced, anaemia, splenomegaly, usually not transfusion dependent.
36
What are the features of -,-/-,- : Hydrops fetalis (Alpha Thalassaemia)?
Incompatible with life, HbBarts (γ4) produced.
37
What is the importance of foetal haemoglobin?
Gives the molecule a higher affinity for oxygen, allowing oxygen transfer from the mother to the foetus during pregnancy.
38
How is anaemia categorised?
By the MCV of the erythrocytes.
39
What is the genetics behind beta Thalassaemia?
Mutations in beta globin genes.
40
What is the phenotype of beta Thalassaemia caused by?
4 alpha globin chain genes, 1-2 mutated, & 0-1 normal beta globin chain genes lead to imbalanced production and excess of α chains.
41
What is the result of excess alpha chains in beta Thalassaemia?
These precipitate in erythrocytes and cause ineffective erythropoiesis and early haemolysis.
42
Why are there different phenotypes of beta Thalassaemia?
Because the defect is mutation rather than deletion; β0: No Beta globin chains produced by this gene; β+: Some Beta globin chains produced by this gene.
43
What are the different types of beta Thalassaemia?
β/β+ or β/β0: Beta thal minor; β+/β0 (mild variants) or β+/β+; β+/β0 (severe variants) or β0/β0.
44
What are the features of β/β+ or β/β0: Beta thal minor?
Asymptomatic, low MCV, mild anaemia.
45
What are the features of β+/β0 (mild variants) or β+/β+?
Splenomegaly, anaemia, non transfusion dependent, bony deformity, gallstones, iron overload.
46
What are the features of β+/β0 (severe variants) or β0/β0?
Asymptomatic at birth, splenomegaly, severe anaemia, developmental delay, growth retardation, extramedullary erythropoiesis, marrow expansion (skulls/long bones), transfusion dependent, iron overload.
47
What would a skull x-ray of a child with beta Thalassaemia show?
'Hair-on-end' appearance.
48
What would a hand x-ray of a child with beta Thalassaemia show?
Expansion of bone marrow and a thinned cortex.
49
What are the different diagnostic techniques for identifying haemoglobinopathies?
Haemoglobin Electrophoresis, High-Performance Liquid Chromatography (HPLC), Genetic Testing, Complete Blood Count (CBC) & Blood Smear, Newborn Screening (UK NHS Programme).
50
What is Haemoglobin electrophoresis?
Separates haemoglobin variants based on charge and structure.
51
What does High-Performance Liquid Chromatography (HPLC) do?
Provides precise quantification of different haemoglobin types.
52
What does Genetic Testing do?
Identifies specific gene mutations linked to haemoglobinopathies (e.g., HBB gene mutations for SCD).
53
What does Complete Blood Count (CBC) & Blood Smear reveal?
Reveals anemia and abnormal red blood cell morphology.
54
What does Newborn Screening (UK NHS Programme) do?
Early detection using blood spot tests.
55
How are the different Thalassaemias managed (transfusions)?
Thalassaemia carrier = Thalassaemia trait = No transfusion; NTDT = Thalassaemia intermedia = intermittent transfusions; TDT = Thalassaemia major = transfusion dependence.
56
What are the different ways Thalassaemia can be managed (depends on severity)? (FIRST 5)
Long term folic acid, regular transfusions if needed to keep the Hb above 100g/L, consider splenectomy/management of iron overload, consider bone marrow transplantation, prenatal diagnosis.
57
What are the different ways Thalassaemia can be managed (depends on severity)? (LAST 4)
Bone Marrow/Stem Cell Transplantation: Potential curative option; Emerging Treatments: Gene Therapy: Corrects defective globin genes; Luspatercept: Enhances erythroid maturation; Care by specialist MDT.
58
What is Sickle Cell Disease?
Haemoglobin variant (HbS) where glutamic acid is replaced by valine at position 6 of β globin chain. First condition for which molecular defect was characterised (1952).
59
What is the phenotype of individuals who are homozygous for HbS?
2x α chains, 2x βS chains, 4x heme; HbS polymerises and forms crystals at low oxygen tension.
60
What is the phenotype of individuals who are heterozygous for HbS?
Carrier status: 2x α chains, 1x βS chain, 1x β chain, 4x heme; essentially asymptomatic.
61
What is a characteristic of individuals who are heterozygous for HbS?
Confers resistance to malaria; typically 60% HbA and 40% HbS.
62
What is the prevalence of Sickle Cell Trait in the world?
Occurs in approximately 300 million people worldwide, with the highest prevalence of approximately 30% to 40% in sub-Saharan Africa.
63
What can Sickle Cell disease lead to?
Haemolytic anaemia and microvascular occlusion.
64
What is Sickle Cell Crises?
Sickling precipitated by infection, dehydration, cold, acidosis, or hypoxia.
65
What are the different types of Sickle Cell crises?
Vaso-occlusive crisis, acute chest syndrome, bone marrow aplasia, splenic sequestration, haemolysis (excessive haemolysis is uncommon).
66
What is Vaso-occlusive crisis?
Occlusion of small or large vessels by sickled cells causing ischaemia.
67
What causes Acute chest syndrome?
Vaso-occlusion/infection/pulmonary infarction can all contribute.
68
What is Bone marrow aplasia?
Temporary cessation of erythropoiesis, causing severe anaemia; can be caused by Parvovirus B19.
69
What is Splenic sequestration?
Vaso-occlusion causing sudden enlargement of the spleen; splenic blood pooling can lead to circulatory collapse and hypovolaemic shock.
70
What are the clinical features of Sickle Cell Disease?
Chronic pain (25%), early multiple stroke, osteonecrosis, ulcers, pulmonary hypertension, sepsis (autosplenectomy), proliferative retinopathy, priapism, dactylitis.
71
What is dactylitis + What can it lead to?
Dactylitis = painful swollen fingers; can lead to hand foot syndrome, e.g., shortening of right middle finger because of dactylitis in childhood affecting growth of epiphysis.
72
What are the therapeutic strategies for Sickle Cell disease?
Pain management, hydroxycarbamide, blood transfusions, bone marrow transplantation, emerging treatments: gene therapy, voxelotor & crizanlizumab.
73
What pain management is given for patients with Sickle Cell disease?
NSAIDs, opioids for vaso-occlusive crises.
74
What does Hydroxycarbamide do?
Increases fetal haemoglobin (HbF) to reduce sickling.
75
What do Blood Transfusions do?
For acute anemia or stroke prevention.
76
How effective is Bone Marrow Transplantation as a therapeutic strategy for Sickle Cell disease?
Potential cure but limited by donor availability.
77
How can Gene Therapy be used as a therapeutic strategy for Sickle Cell Disease?
CRISPR-based techniques targeting HBB gene.
78
How can Voxelotor & Crizanlizumab be used as a therapeutic strategy for Sickle Cell Disease?
Target haemoglobin polymerization and inflammation.
79
What is Antenatal Screening?
Offered to all pregnant women to identify carrier status.
80
What is Newborn Blood Spot Screening?
Detects SCD and other haemoglobinopathies in newborns.
81
What is Targeted Screening?
Based on family origin and risk factors.
82
What is the Family Of Origin questionnaire?
Used for the interpretation of results in areas of high and low prevalence of SCD and Thalassaemia (particularly if positive); useful for accurate prenatal diagnosis.
83
What happens if women are from low prevalence areas?
Offer haemoglobin variant screening if they or the father have answers in any of the yellow boxes.
84
What happens if women are from high prevalence areas?
Offer haemoglobin variant screening to all women irrespective of answers.
85
What does the newborn blood spot screening test screen for? (Part 1)
Sickle Cell, Cystic Fibrosis, Congenital Hypothyroidism, Metabolic Diseases: phenylketonuria (PKU).
86
What is the importance of screening in public health and genetic counselling?
Early detection, informed family planning, reduction in healthcare costs, equity in healthcare.
87
What is the importance of early detection?
Reduces morbidity and mortality through prompt interventions.
88
What is the importance of Informed Family Planning?
Helps at-risk couples make informed reproductive choices.
89
What is the importance of Reduction in Healthcare Costs?
Preventative care reduces long-term complications.
90
What is the importance of Equity in Healthcare?
Ensures at-risk populations receive appropriate screening.
91
What percentage of the population have haemoglobin mutations + How many mutations are known?
Around 7% of the world’s population carry haemoglobin mutations and >1000 different mutations are known.
92
To whom is haemoglobinopathy screening offered?
Babies are tested at five days old, women are tested during pregnancy. In high-prevalence areas, screening involves the family origin questionnaire and genetic testing; in low prevalence areas, just the questionnaire.
93
What is the effect of preventative care in healthcare costs?
Preventative care reduces long-term complications.
94
What is the importance of equity in healthcare?
Ensures at-risk populations receive appropriate screening.
95
What percentage of the population have haemoglobin mutations and how many mutations are known?
Around 7% of the world’s population carry haemoglobin mutations and >1000 different mutations are known.
96
To whom is haemoglobinopathy screening offered?
Babies are tested at five days old, women are tested during pregnancy. In high-prevalence areas, screening involves the family origin questionnaire and genetic testing; in low prevalence areas, just the family origin questionnaire is used.
97
What are the different pathological haemoglobin variants?
HbS (sickle cell Hb), Hb Cowtown, Hb Memphis, Hb Milwaukee, Hb Providence, Hb Philly.
98
What causes HbS (sickle cell Hb)?
A glutamate on the surface of the protein is mutated to a valine.
99
What causes Hb Cowtown?
A pair of amino acids that make ionic interactions involved in stabilising the T state are deleted.
100
What causes Hb Memphis?
An uncharged polar amino acid on the surface of the molecule is mutated to another of similar size.
101
What causes Hb Milwaukee?
A valine is mutated to a glutamate.
102
What causes Hb Providence?
A lysine that normally projects into the centre of the tetramer is mutated to an asparagine.
103
What causes Hb Philly?
A tyrosine that makes important hydrogen bonds that stabilise the structure is mutated to a phenylalanine.
104
What does the newborn blood spot screening test screen for?
• medium-chain acyl-CoA dehydrogenase deficiency (MCADD) • maple syrup urine disease (MSUD) • isovaleric acidaemia (IVA) • glutaric aciduria type 1 (GA1) • homocystinuria (pyridoxine unresponsive) (HCU)
105
What are the different types of haemoglobin due to different globin chains?
Portland ζ γ (gamma) Embryo, HbF α γ (Fetus), HbA2 α δ (delta) (Adult), HbA α β (beta) (Adult).
106
What are the different NHS screening programmes for SCD and Thalassaemia?
What are the different NHS screening programmes for SCD and Thalassaemia?

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