Transcript An introduction to the haemoglobinopathies

The Haemoglobinopathies
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A range of inherited conditions
Some turn up as a chance laboratory finding
Some are mild
Some cause life long illness
Some cause fetal death
All arise from genetic mutation (inherited or new)
The Haemoglobinopathies
“Classic” haemoglobinopathy arises from point mutations and result in
 Altered solubility
 unstable Hb
 altered O2 affinity
 Methaemoglobinaemias
The Haemoglobinopathies
Thalassaemias arise from
 wholesale gene deletion
 problems in gene control/expression mechanisms
These will be covered in another presentation
The Haemoglobinopathies
To recap:
•Haemoglobin A has two a and two b chains (>95% of total Hb)
•Haemoglobin A2 has two a and two d chains (2-3% of total Hb)
•Haemoglobin F has two a and two g chains (<1% of total Hb)
And these chains are all “normal”
Haemoglobins with altered solubility
1910 - J.B. Herrick described “peculiar elongated & sickle shaped cells”
in the blood of an anaemic West Indian
1949 - Neel & Beet showed this “sickle cell anaemia” was hereditary
•variant of haemoglobin
•less soluble at low oxygen concentrations
•Hb crystallises
•red cells deform into sickle-like shapes
Haemoglobin S
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A point mutation at position 6 on the b chain
Valine (neutral) replaces Glutamine (-)
Which changes the charge at a specific area
Which affects the molecule’s solubility
Haemoglobin S
In the heterozygous state, that is
Genotype a2bbs
phenotype AS
there is little clinically evident.
While sickling can occur under extreme oxygen depravation,
individuals normally lead healthy lives.
some Olympic athletes are sickle cell carriers
Haemoglobin S
In the homozygous state, that is
Genotype a2bs2
phenotype SS
Patients have classic sickle cell disease.
With their red cells sickling as Hb crystallises at low O2
concentrations there are a range of clinical problems.
Haemoglobin S
Acute painful crises caused by sickling – venous occlusion
•Leg Ulcers
•renal damage
•liver damage
•pathological bone fractures
•ulceration of extremities
•priapism
•psychological problems from the above
Haemoglobin S
There are other sickling haemoglobins:
Hb S-Providence beta 6(A3) Glu>Val AND beta 82(EF6) Lys>Asn
Hb S-South End beta 6(A3) Glu>Val AND beta 132(H10) Lys>Asn
Hb Jamaica Plain beta 6(A3) Glu>Val AND beta 68(E12) Leu>Phe
Hb S-Cameroon beta 6(A3) Glu>Val AND beta 90(F6) Glu>Lys
All of which are effectively variants of Hb S
Some have higher or lower solubity that HbS – HbS Antilles is less soluble
And sickles in the heterozygous form.
Haemoglobin C
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A point mutation at position 6 on the b chain
Lysine (neutral) replaces Glutamine (-)
Which changes the charge at a specific area
Which affects the molecule’s solubility
Haemoglobin C
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Trait is clinically asymptomatic
Disease has “bars of gold” rather than sickles
Haemoglobin D
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There are several…
D (Punjab) point mutation at position 121 on the b chain
Glycine replaces Glutamine
Trait & carrier states asymptomatic
Haemoglobin E
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Point mutation at position 26 on the b chain
Lysine replaces Glutamine
Trait & carrier states asymptomatic (microcytic)
Haemoglobinopathies
And there’s more...
•All arise from the same problem, a misplaced amino acid
•All are benign in the heterozygous
•Vary in presentation in the homozygous
•The presence of more than one mutation can complicate
the clinical picture
Combined Haemoglobinopathies
Generally “nastier” than the “straight” condition:
For example Haemoglobin SC disease
Genotype a2bsbc
phenotype SC (a2bs2 and a2bc2)
or Haemoglobin SD disease
Genotype a2bsbd
phenotype SC (a2bs2 and a2bd2)
There are variants on the a chain, but none are particularly common in
conjuction with Hb S
Unstable Haemoglobins
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Altered amino acids at points of contact between a and b chains
Some are neutral / neutral substitutions
Hence not always detectable electrophoretically
Approximately 250 of 800 known mutations of haemoglobin are found to be
unstable
eg
Hb Koln (beta 98 Val—>Met)
Hb Hb Hasharon (alpha 47 Asp—>His)
Unstable Haemoglobins
Congenital (or slightly later?) nonspherocytic haemolytic anaemia
 splenomegaly
 pigmented (bilirubin) gallstones
 sensitivity to oxidant drugs, such as sulfonamides
In the lab:
 Heinz bodies
 reticulocytosis out of proportion to the level of circulating hemoglobin
 A thalassemia-like peripheral blood picture with hypochromic red blood
cells
 Increased formation of methemoglobin
Haemoglobins with altered oxygen affinity
Reduced affinity for oxygen
Hb Jamaica Plain b6 Glu/Val, & b68 Leu/Phe (also sickles & is unstable)
Hypoxic
Increased affinity for oxygen
Hb Johnstown (b109 Val->Leu).
Polycythaemic, but otherwise well
Hereditary Methaemoglobins
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Altered amino acids at points of contact of haem residue
Thus haem function is impared (iron frozen in ferric form)
Fatal in homozygous form
eg
Hb M Saskatoon (b63 histadine replaced by tyrosine)
Hb M Boston
(a87 histadine replaced by tyrosine)
Hb M Hyde Park (b92 histadine replaced by tyrosine)
Other Point Mutations
Haemoglobin Constant Spring
Mutation at end of a chain stop codon
a chain is 31 amino acids too long
Benign as trait, but when homozygous mimics alpha-thalassemia
Other Point Mutations
Haemoglobin Lepore
Fusion of beta & gamma gene loci
Various forms
• Hb Lepore Washington Boston (δ87/β116),
• Hb Lepore Hollandia (δ22/β50),
• Hb Lepore Baltimore (δ50/β86)
Heterozygous is relatively benign (Raised Hb F - two a and two g chains)
Homozygous - clinically indistinguishable from homozygous beta-thalassemia
Gamma chain variants
Haemoglobin F has two a and two g chains
So variants are symptomatic in early life – gets better
About 70 known
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Hb Poole (gamma 130 Trp—>Gly) is unstable
Hb F-Forest Park, 75 Ile----Thr 73 Asp/Asn
Delta chain variants
Haemoglobin A2 has two a and two d chains
So variants are (pretty much) asymptomatic
About 70 known (??? How did they find them??)
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Hb A2-Wrens, 98 Val-Met (allegedly) unstable
Hb A2 Honai 90 Glu----Val) (asymptomatic)
The End……
What has gone before has barely scratched the surface
There are over 1100 reported haemoglobinopathies
http://globin.bx.psu.edu/cgi-bin/hbvar/counter has a list.....