Haemoglobinopathies Flashcards
Ahmed has β -thalassaemia (homozygous) – also called thalassaemia major . What features does he exhibit?
- Ahmed is an 13 month old boy who is taken by his parents to see the GP after the maternal child health nurse was concerned he wasn’t putting on weight
- Mother has been feeding Ahmed solid food as well as still breastfeeding, but says he lacks appetite
- On examination, the boy is pale, lethargic, and seems irritable
- Ahmed’s parents migrated to Australia from Iran 2 years ago
- FBE results indicate Ahmed is anaemic and recommend testing for haemoglobin as part of a haemoglobinopathy screen and then confirm that Ahmed has beta-thalassaemia.
- He produces α -globin chains but not β -globin chains
- α4 form aggregates, accumulate and precipitate in the red blood cells (RBCs) causing damage – the RBCs are further destroyed
- All this leads to haemolytic anaemia
Give some general features of haemoglobin disorders?
Genetically inherited diseases with changes to globin chain(s) of haemoglobin. The vast majority are inherited as autosomal recessive conditions. Common disorders affect tens of millions worldwide with a wide distribution and at least 4.5% of the world’s population are carriers.
What is haemoglobin?
Haemoglobin: haemoglobin protein in the adult (HbA) is a tetramer of globin chains: α2β2 (heterotetramer). Each globin chain has a central haem molecule.
What are some types of haemoglobinopathies?
α- & β- Thalassaemias
- decreased synthesis of one or more globin chains
- Distribution: α- thalassaemia globally distributed in South East Asia; β- thalassaemia has increased frequency in Southern European and Middle Eastern countries as well as North Africa, South East Asia, Indian subcontinent.
Structural Variants
- altered globin polypeptide without altering rate of synthesis –> 500 different variants
- sickle cell anaemia
- Distribution: Sickle Cell Disease found in West and Central Africa, Middle East and Indian subcontinent.
Hereditary Persistence of Fetal Haemoglobin (HOFH)
- clinically benign
Some haemoglobinopathies are cause by mutations resulting in combination of altered structure and synthesis with variable phenotype (example: HbE which has a mild thalassaemia phenotype)
- Carrier Frequencies can be as high as 1 to 20, even up to 40% in local populations
- Genes move with migration.
Explain some features of thalassaemia?
- Usually decreased synthesis of one or more globin chains:
- α-thalassaemia due to deficiency of α-globin chains
- β-thalassaemia due to deficiency of β-globin chains
- Get Imbalance in relative amounts of α and β chains - get homotetramers instead of heterotetramers - pathology due to these- severity relates to levels of imbalance.
What types of genetic mutations can cause thalassaemia?
- Alpha thalassaemias: majority caused by large deletions
- Beta thalassaemias: majority caused by point mutations
- promoter mutations
- RNA splicing mutations
- mRNA capping or polyA tailing mutations
- nonsense (Non-functional mRNA/short, unstable polypeptide-
- frameshift - degraded)
- Cause reduces (beta+) or no (Beta zero) beta-globin.
What is the Pathophysiology of Untreated β-thalassaemia?
- Marrow expansion - intramedullary erythropoiesis
- Frontal bossing
- thinning of long bones
- ‘Hair-on-end’ appearance of skull due to thinning of cranial bones
- Hepatosplenomegaly - extramedullary eythropoeisis and destruction of RBCs.
How is β-thalassaemia treated?
- Treat splenomegaly with splenectomy (can lead to susceptibility to bacterial infection)
- Treat anaemia with blood transfusions (can lead to systemic iron overload/secondary hemochromolosis which can be treated with chelation therapy –> diabetes; heart failure; liver cirrhosis; hypo/hyperthyroidism; endocrine complications)
- Frequent blood transfusions – typically every 3-4 weeks (risk of infection: HIV, hepatitis B & C, etc)
- Iron chelation therapy
- traditionally s.c. by pump, 6 or 7 nights a week
- now orally (once daily) where tolerated and effective
- Hormone replacement therapy
- Bone marrow transplant (haematopoietic stem cells) - cure
What are some features of α-thalassaemias?
- Affects both fetal and adult Hbs
- Get production of other homotetramers that are less soluble:
What are some features of sickle cell disease?
- Caused by point mutation; Different point mutations cause other structural variants (eg HbC, mild haemolysis)
Associated with:- Anaemia and weakness
- Failure to thrive
- Splenomegaly
- Repeated infections
- Crises: – ischaemia, thrombosis, infarctions, (especially in spleen, brain, lungs, and kidneys)
What are the implications of allelic combinations in haemoglobinopathies?
Often have individuals who have two different mutations (alleles) – called compound heterozygotes:
- eg maybe two different types of β-globin mutation eg two different
β-thalassaemia mutations, or a β-thalassaemia mutation and the sickle cell mutation; also with other Hb variants (eg HbS/HbE; HbE/β0)
- Double heterozygote:
- eg a β -globin mutation and a α-globin mutation
These can result in variable pehotypes; sometimes the disease may even be less severe.
- eg heterozygous for α -thalassaemia (αα/–) and homozygous for β+-thalassaemia
What are some future therapies for thalassaemia?
- Gene therapy
– Aim to alter the imbalance of chains, eg RNAi (interfering RNA) to target reduction in α-globin mRNA in β thalassaemia
– Epigenetic modifications by small molecules to induce HbF (NB HPFH) in thalassaemia and sickle cell disease (hydroxyureaalready used in SCD)
– Gene therapy using induced pluripotentstem (iPS) cells
Explain the concept of the heterozygote advantage.
- High frequency of alleles for haemoglobinopathies related to selection advantage
- Carriers have some resistant to malaria
- Provides selective advantage where malaria is endemic
How is screening for haemoglobinopathies done?
- The Cyprus experience (β -thalassaemia)
- The USA experience (sickle cell), newborn screening
- UK – newborn screening
- Australia
