by Dr. Adele Visser

Introduction

Haemoglobin is the major oxygen-carrying molecule within red blood cells and consists of a heme component (iron containing) and globin chains (proteins). Within the class of haemoglobinopathies, the fundamental problem lies with these globin chains, either in their structure (qualitative) or amount (quantitative) produced. This may lead to haemolytic anaemias, thalassaemias, familial polycythaemias or methaemoglobinemia.

Quantitative abnormalities

Mutations globin genes may give rise to phenotypic abnormalities. These may be as simple as point mutations where a single nucleotide change gives rise to a amino acid replacement with dire consequences, to more complicated mutational changes.

Sickle cell anaemia
Sickle cell anaemia is caused by a point mutation in position 6 of the beta globin chain leading to the replacement of a valine with a glutamic acid. Where this is inherited on both genes, the person is considered homozygous (HbSS), whereas a single chromosome inheritance is considered heterozygous, and therefore a HbS trait.

Patients with sickle cell anaemia (HbSS) present with haemolytic anaemia with intermittent crises. In general, patients compensate surprisingly well for low Hb levels, as the HbS molecule releases oxygen more readily at tissue level. A crisis is defined as either vaso-occlusive, visceral, aplastic or haemolytic and requires urgent intervention.

HbC
The HbC genotype occurs on the same position as HbS, position 6 of the beta globin gene where valine is replaced with lysine. The abnormal haemoglobin molecule leads to a mild haemolytic anaemia with prominent target cell formation on morphology. Clinically the patients typically present with splenomegaly.

HbE
Typically seen in patients from South Eastern origin, homozygotes present with a mild microcytic, hypochromic anaemia.

Other abnormalities
Various clinical relevant and relatively insignificant abnormalities exists, but it should be noted that these can occur as compound mutations as well which affects the clinical presentation of disease.

Laboratory diagnosis
Qualitative haemoglobinopathies can be diagnosed through Hb electrophoresis which distinguishes between various kinds of haemoglobin subtypes. Using this platform, a determination as to homozygous versus heterozygous patterns can be determined. In addition, in cases like HbSS, the HbF fraction may provide an estimation of clinical compensation and likelihood of symptoms expected.

In addition, these types of analyses may be of value to monitor treatment modalities like hydroxyurea and its induction of HbF production. Screening may also be of value to family members as part of genetic counselling.

References

Hoffbrand AV, Moss PAH, Pettit JE. 2007. Essential Haematology. 5th edition.