Hemoglobin disorders

Hemoglobin disorders may be characterised into structural variants and thalassemias. Structural variants are produced when the amino acid composition of a protein chain is altered. A thalassemia syndrome is caused when a mutation or deletion event leads to diminished or no production of one of the globin chains of the hemoglobin molecule. Mutations leading to thalassemia syndromes mostly occur within the non- coding regions of the globin genes. Over 1000 structural variants and 300 mutations responsible for the thalassaemia syndromes have been detected so far. Details of these are housed in HbVar, a relational database of human hemoglobin variants and thalassaemia mutations, which may be found at the Globin Gene Server (Hardisonet

al. 2002). The majority of the structural variants and thalassemia syndromes identified are clinically silent, creating no ill effects in the carrier, but a small number are of significant clinical importance (Clarke and Higgins 2000).

Hemoglobin variants are often named after their place of first discovery or family name of the primary case. A systematic nomenclature is used to characterise structural variants. Thus Hb S (β6 Glu→Val) describes that Hb S is produced by an

amino acid mutation in the β-chain at position six from a glutamic acid to a valine. The common clinically significant structural variants are Hb S, C, DPunjab, E and OArab, caused by single amino acid substitutions in the β-chain, and the Lepores,

which are δ:β chain hybrids. The mutations responsible for these variants and their clinical manifestations are summarised in Table 5.1 below.

Table 5.1:The common clinically significant structural variants, the mutations which cause them and their clinical manifestations (data obtained from HbVar). Mass change shown is the change in globin chain mass produced as a result of the mutation.

Hemoglobin Mutation Mass

Change (Da)

Clinical manifestation (Heterozygote/ Homozygote)

S β6 (Glu→Val) -30 Carrier, no symptoms/ Sickle cell

disease

C β6(Glu→Lys) -1 Carrier, no symptoms/ Mild

anaemia

DPunjab β121 (Glu→Gln) -1 Carrier, no symptoms/ Mild anaemia

E β26 (Glu→Lys) -1 Mild microcytosis/ Thalassemia

minor

OArab β121 (Glu→Lys) -1 Carrier, no symptoms/ Mild

anaemia Lepore- Hollandia Hybrid: δ 1:22, δ/β 23:49, β 50:146 -30 Thalassemia minor Lepore- Baltimore Hybrid: δ 1:50, δ/β 51:85, β 86:146 -45 Thalassemia minor Lepore-Boston- Washington Hybrid: δ 1:87, δ/β 88:116, β116:146 -2 Thalassemia minor

The inheritance of homozygosity for Hb S (Hb SS, sickle cell anaemia) or Hb S with Hb C (Hb SC disease), Hb DPunjab (Hb SD disease), Hb E (Hb SE disease) or Hb OArab (Hb SO disease) result in sickling disorders. The sickling disorders are so

named because the abnormal hemoglobins they produce precipitate and polymerise in red blood cells causing the cells to become sickle in shape (Clarke and Higgins 2000). The sickling disorders are associated with severe anaemia and life-threatening vaso-occlusive crises. Anaemia (meaning lack of blood) leads to poor oxygen supply to the organs and tissues. Sickle cell crises result when the sickled red blood cells obstruct blood vessels and restrict blood supply to the organs, causing severe pain (NHS Sickle Cell and Thalassaemia Screening Programme 2009). Numerous complications can result as a consequence of these afflictions and sickle cell sufferers require life-long treatment. Heterozygotes, possessing one normal and one sickle β-globin gene, have sickle cell trait but are symptom free.

The thalassemias produce a syndrome characterised by anaemia, the severity of which depends on the type of thalassemia syndrome present. The most severe

thalassemias, α-and β-thalassemia major, result from homozygous genetic defects in

the α-globin and β-globin synthesis, respectively (Hartwellet al.2005).

There are four α-globin genes and therefore a single α-globin gene deletion (-α/αα)

gives α-thal-2 trait and has no effect on hemoglobin synthesis. A double deletion (--

/αα or -α/-α) results in mild microcytic hypochromic anaemia (production of small red blood cells with low levels of hemoglobin per cell) (Clarke and Higgins 2000). If

three α-globin genes are deleted Hb H disease is produced. The excess production of

β-chains leads to the formation of β4 tetramers. These precipitate in red cell

precursors leading to ineffective red cell production and enlargement of the spleen and liver (Clarke and Higgins 2000). If all four α-globin genes are deleted

(homozygous α-thal-1) Hb Bart’s hydrops fetalis is caused which is incompatible with postnatal life.

Single β-globin gene deletion or diminished synthesis of one β-globin chain results

in β-thalassemia minor. This disorder presents with mild microcytic hypochromic anaemia (Clarke and Higgins 2000). Sufferers of this disorder produce more Hb A2

than in normal individuals. Quantification of Hb A2 levels above 3.5 %, along with

the recording of a low mean cell hemoglobin level (as part of a full blood count), is

used to provide diagnosis of heterozygous β-thalassemia (Ryan et al. 2010). Hb E and Hb Lepore have thalassemic manifestations that lead to decreased β-globin

production and microcytic hypochromic anaemia in homozygotes. Homozygous β-

thalassemia sufferers can present with β-thalassemia intermedia or major. This

depends on whether the thalassemia results in greatly diminished (β+_{) or no β}

-chain

production (β0_{). β}

-thalassemia major sufferers present with severe microcytic hypochromic anaemia and rely on life-long regular blood transfusions. About fifty-

percent of β-thalassemia major sufferers, in the UK, die before the age of 35 (Modell et al.2000).

As well as these common clinically significant hemoglobinopathies many more of the structural variants reported so far are of clinical relevance. A simple search of the

HbVar database shows that there are 32 structural α-chain variants and 88 structural

β-chain variants which lead to anaemia in heterozygotes (Hardisonet al.2002).