The Haemoglobinopathies A range of inherited conditions Some turn up as a chance laboratory finding Some are mild Some cause life long illness Some cause.

The Haemoglobinopathies

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

To recap:

•Haemoglobin A has two and two chains (>95% of total Hb)•Haemoglobin A2 has two and two chains (2-3% of total Hb)

•Haemoglobin F has two and two chains (<1% of total Hb)

And these chains are all “normal”

The Haemoglobinopathies

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

A point mutation at position 6 on the chain Valine (neutral) replaces Glutamine (-) Which changes the charge at a specific area Which affects the molecule’s solubility

In the heterozygous state, that isGenotype 2s

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 isGenotype 2s

2

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

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>AsnHb Jamaica Plain beta 6(A3) Glu>Val AND beta 68(E12) Leu>PheHb 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

A point mutation at position 6 on the chain Lysine (neutral) replaces Glutamine (-) Which changes the charge at a specific area Which affects the molecule’s solubility

Haemoglobin C

Trait is clinically asymptomatic Disease has “bars of gold” rather than sickles

Haemoglobin D

There are several… D (Punjab) point mutation at position 121 on the chain Glycine replaces Glutamine Trait & carrier states asymptomatic

Haemoglobin E

Point mutation at position 26 on the chain Lysine replaces Glutamine Trait & carrier states asymptomatic (microcytic)

Haemoglobinopathies

And there’s more...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

Generally “nastier” than the “straight” condition:

For example Haemoglobin SC diseaseGenotype 2sc

phenotype SC (2s2

and 2c2)

or Haemoglobin SD diseaseGenotype 2sd

phenotype SC (2s2

and 2d2)

There are variants on the chain, but none are particularly common in conjuction with Hb S

Combined Haemoglobinopathies

Unstable Haemoglobins

Altered amino acids at points of contact between and 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 6 Glu/Val, & 68 Leu/Phe (also sickles & is unstable)

Hypoxic

Increased affinity for oxygen

Hb Johnstown (109 Val->Leu).

Polycythaemic, but otherwise well

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 (63 histadine replaced by tyrosine)

Hb M Boston (87 histadine replaced by tyrosine)

Hb M Hyde Park (92 histadine replaced by tyrosine)

Hereditary Methaemoglobins

Other Point Mutations

Haemoglobin Constant Spring

Mutation at end of chain stop codon

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 and two chains)

Homozygous - clinically indistinguishable from homozygous beta-thalassemia

Gamma chain variants

Haemoglobin F has two and two chains

So variants are symptomatic in early life – gets better

About 70 known

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 and two chains

So variants are (pretty much) asymptomatic

About 70 known (??? How did they find them??)

Hb A2-Wrens, 98 Val-Met (allegedly) unstable Hb A2 Honai 90 Glu----Val) (asymptomatic)

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.....

The End……