Genetic Disorders of Haemoglobin Flashcards
Basic structure and production of Hb, main Hb proteins in humans
4 globin subunits
alpha-like genes (chr 16)
- a1 and a2 expressed in late 1st trimester and for the rest of life
beta-like genes (chr 11)
- Agamma and Ggamma for foetal Hb
- beta expressed at 6 months and becomes most important
- delta (small proportion of total haemin in normal adults)
Hb proteins
- Foetal – HbF (a2g2)
- Adults – HbA (a2b2) or HbA2 (a2d2)
HbA is the main Hb after 6 months
Thalassaemia syndromes - defect, main types and their pathogenesis
Commonest single gene disorders
- imbalance of globin chain synthesis
Alpha thalassaemia
- defective alpha globin chain production
- excessive beta/gamma globin chains form tetramers –> unstable = CHRONIC HAEMOLYSIS; very high oxygen affinity = not good for O2 transport
Beta thalassaemia
- defective beta globin chain production
- excess alpha globin chains which are highly unstable –> precipitate in red cell precursors and interfere with maturation ==> INEFFECTIVE ERYTHROPOIESIS
Clinical significance
- most carriers are asymptomatic (only mild hypochromic microcytic anaemia; RBC normal or high)
- antenatal screening concern (severe phenotypes in babies)
Alpha thalassaemia - classification of severity
4 alpha genes in each person
- severity depends on number of genes DELETED
1/2 genes deleted = thalassaemia trait
3 = HbH disease
4 = hydrops fetalis
Hb Bart’s Hydrops Fetalis - genetic defect, predominant Hb formed, severity, clinical effects
Most severe form of alpha thalassaemia with all 4 genes deleted
==> Total absence of alpha globin chain production = excess gamma globins forming g4 tetramers (Hb Bart’s)
INCOMPATIBLE WITH LIFE
- Hb Bart’s has very high O2 affinity and can’t carry out normal O2 transport –> develop anaemia –> foetal heart tries to compensate by increasing CO –> high output cardiac failure
HbH disease - genetic defect, predominant Hb formed, severity, clinical effects/ complications, blood smear appearance
3 alpha genes affected with only one functional gene remaining
==> Anaemia of intermediate severity, can survive foetal life
Excess beta globin chains forms b4 (HbH) –> unstable leading to chronic HA and high O2 affinity leading to poor transport
Clinically:
- transfusion independent unless in acute illness
- complications from chronic HA and iron overload
Blood smear:
- “golf ball” appearance (HbH)
- variation in cell shapes and sizes
Alpha thalassaemia trait - genetic defects possible (3), clinical effects, implications for antenatal screening
Mildest form of thalassaemia
a+ = only 1 gene affected
a+ homozygous = 2 genes affected (one on each chr)
a0 = 2 genes affected on same chr
a0 –SEA deletion common in HK
a+ –a3.7 or a4.2 deletions
Clinically: asymptomatic
- mild microcytic hypochromic anaemia
- less variation in cell shapes and sizes
Implications for antenatal screening
–> 2 at carriers (a0) have 25% chance of baby with hydrops fetalis
Antenatal screening for alpha thalassaemia trait - methods, which couples are high risk, approach
Microcytosis
New methylene blue stain for HbH inclusion bodies (but highly labour intensive, operator dependent, false negative with Fe deficiency, beta thalassaemia minor)
- *Molecular study with GAP-PCR for –SEA deletion
- -> sensitive, specific and not affected by other conditions
For high risk couples (i.e. both parents –SEA carriers)
- counselling
- USG to monitor for foetal anaemia and hydrops
Beta thalassaemia syndromes - genetic defect, possible phenotypes, severity, clinical effects
Majority due to point mutations, small insertions and small deletions of 1-2 bases
- affects various steps in globin chain production
- gamma to beta switching occurs at 6 months so symptoms appear after
b0 = complete inactivation b+ = reduced production
2 genes for beta globin in humans
- minor = b/b0 or b/b+
- intermedia = b+/b+ or b+/b0
- major = b0/b0 or b+/b0
- -> Excess alpha chains accumulate in BM precursors and interfere with maturation leading to ineffective erythropoiesis
- -> Degraded products of excess alpha globin chains reduce RBC membrane deformability = shortened red cell survival
Beta thalassaemia major - genetic defect and clinical consequences
Cooley’s anaemia
- total absence of HbA
Clinical features
- severe anaemia beginning from 3-6 months -> TRANSFUSION DEPENDENT
- bone expansion (as compensation for ineffective erythropoiesis) –> frontal bossing, prominent maxilla, “hair-on-end” sign on Xray
- extramedullary haematopoiesis -> HEPATOSPLENOMEGALY
- Fe overload due to repeated transfusions
- infections (yersinia, klebsiella due to Fe overload; viral hepatitis, HIV due to transfusions)
- osteoporosis
- failure to thrive
Beta thalassemia major - diagnosis and treatment
High performance liquid chromatography (HPLC)
- normal peaks seen (in order): HbF small peak, HbA very large, HbA2 small
- beta major: HbF very large, HbA ABSENT, HbA2 small
Treatment
- regular transfusion (may consider splenectomy, allogeneic SCT)
- iron chelation to handle iron overload
- folic acid supplement
- monitor for endocrinopathy and replace accordingly
- -> DM, hypopituitarism, hypoPTH
- immunisation for HBV
- vitamin D, bisphosphonates for osteoporosis
Beta thalassaemia intermedia - severity, transfusion requirement, clinical effects, diagnosis
Less severe anaemia than major
TRANSFUSION INDEPENDENT
Clinical effects: long term similar to major but with later onset
May need temporary transfusion support in acute illness
Diagnosis
- HcMc anaemia
- HbA2 normal or increased
- most have increased HbF
Beta thalassaemia minor - severity, diagnosis, implications for antenatal screening
Completely asymptomatic
HcMc anaemia
Diagnosis
- raised HbA2 (>3.5%)
Antenatal screening
- carrier parents have 25% of baby with major/intermedia
- genetic counselling
- anaemia present after birth so USG not helpful
Non-transfusion dependent thalassaemias - examples, complications
HbH disease and Beta thalassaemia intermedia
Complications
- iron overload
- pulmonary HT
- osteoporosis
- extramedullary haematopoiesis
Regular FU and treated for complications accordingly
Variant haemoglobins - genetic defect, examples and clinical effects
Missense mutations in coding region of globin genes resulting in production of Hb showing different physical properties
- sickling, stability, oxygen affinity etc.
HbE (beta globin chain variant)
- common in SE Asia
- Glutamic acid –> Lysine at position 26
- reduced rate of synthesis of beta globin chain –> mild thalassaemia or normal blood picture
- clinical effects: harmless unless co-inherited with beta thalassaemia (leads to severe beta thalassaemia)
HbS (beta globin chain variant)
- valine for glutamine substitution
- sickling of red cells at low oxygen tension
- treatment: regular transfusion and SCT
- debilitating with multiple systemic complications e.g. anaemia, stroke, DI, skin ulcers, vaso-occlusive crisis etc.
- large HbS peak (after HbA2) on HPLC
