Haemoglobin structure Alpha- type Alpha- type Beta- type Beta- type Haem

Normal Haemoglobin Always 2 Beta-type and 2 Alpha-type globin chains carrying haem molecule Beta-type –epsilon, gamma, beta, theta Alpha-type –zeta, alpha

Haemoglobin structure So functional Hb is always a heterotetramer there must be 2 Beta and 2 Alpha for oxygen carrying function different types at different stages of fetal and early neonatal life by 6 months we have adult proportions

Hb development Up to 8/40 –zeta2/epsilon2, alpha2/epsilon2, zeta2/gamma2 From 8/40 to birth –85% alpha2/gamma2 (HbF) –5-10% alpha2/beta2 (HbA) –remainder alpha2/theta2 (HbA2) + others By 6/12, adult proportions of A, A2, F

Normal adult Hb HbA (alpha2/beta2) –97% + HbA2 (alpha2/theta2) –2-3% HbF (alpha2/gamma2) –0.5% or less NOTE ALL NEED ALPHA!

Haemoglobin abnormalities Haemoglobinopathies –normal amounts of abnormal beta chains –crystalline disorders (S, C, D, E) –familial polycythaemia, M Hb, unstable Hb, HPFH Thalassaemias –reduced amounts of normal alpha or beta chains Can be BOTH!

Thalassaemias (simplistic) Reduced production of BETA chains –BETA thalassaemias Reduced production of ALPHA chains –ALPHA thalassaemias –more severe clinical disease

Beta thalassaemias Beta chain deficiency So reduced HbA BUT retained production of other beta-type chains, so increased –theta production (HbA2) –gamma production (HbF)

Beta thalassaemias Encoded by a single gene pair Autosomal recessive (but not totally) heterozygotes have beta thalassaemia trait homozygotes have beta thalassaemia (thalassaemia MAJOR) –but they are ALIVE at birth –variable clinical severity - why?

Inheritance of beta thalassaemia Usually due to point mutation Effect on Beta chain production variable

Beta plus thalassaemia genes If the mutation causes total shutdown of the beta chain gene –no beta chain produced –Beta nought thalassaemia If the mutation reduces beta chain production (but does not shut it down) –some beta chain produced –Beta plus thalassaemia

Combinations Beta/beta plus heterozygote –microcytosis, Hb normal –raised A2 and F Beta/beta nought heterozygote –more severe microcytosis, Hb normal –raised A2 and F

Combinations Beta plus/beta plus –microcytosis, +/- anaemia Beta nought/beta nought –microcytosis, red cell changes, transfusion dependent Beta plus/beta nought –microcytosis, variably anaemic

Inheritance of alpha thalassaemia More complex as encoded by 2 gene pairs (so four genes per person, not two) However, usually due to whole gene deletions, so total gene loss/shutdown haematology and clinical presentation depends on how many genes are lost

Gene deletions in alpha thalassaemia Normal One gene deletion (alpha/alpha +)

Gene deletions in alpha thalassaemia Two gene deletion (alpha +/alpha +) Two gene deletion (alpha/alpha 0)

Gene deletions in alpha thalassaemia Three gene deletion (alpha +/alpha 0) Four gene deletion

Clinical disorders Alpha/alpha + –alpha thalassaemia trait, normal Hb, normal or slightly reduced MCV Alpha +/Alpha + or alpha/alpha 0 –normal Hb, microcytic

Clinical disorders Alpha +/alpha 0 –HbH disease, reduced Hb, splenomegaly, may or may not be transfusion dependent –presence of beta tetramers (HbH) on film (“golf ball” cells) –unlike in beta thalassaemia, there is no substitute for alpha

Hydrops fetalis Four gene deletion –no alpha chain production –incompatible with life –fetus dies in utero –gamma tetramers instead - Hb Barts

HbH and Hb Barts HbA HbF HbH HbBarts

Laboratory diagnosis Beta thalassaemia –relies on raised F and A2 Alpha thalassaemia –F and A2 normal –may see “golf balls” on HbH prep –gene analysis