Australasian Anaesthesia 2011 - Australian and New Zealand ...

146 Australasian Anaesthesia 2011Sickle Cell Disease in Australia – a phantom menace? 147SCD comprises a collection of autosomal recessive genetic disorders characterised by the presence of anabnormal haemoglobin S (HbS).The abnormal Hb S molecule arises from a point substitution of one amino acid. The gene coding for synthesisof the β globin chain lies on the short arm of chromosome 11, and in Hb S, this defective gene codes for the aminoacid valine to be present in position 6 of the β globin chain instead of glutamine.Hb S represents one of many abnormal haemoglobins in existence, another clinically important one beinghaemoglobin C (Hb C). In this mutated haemoglobin, the amino acid lysine replaces glutamine in this position 6.Currently, over 475 β globin gene variants have been identified 1 , but most of these genotypes do not result inclinically significant phenotypes.Figure 2. Map detailing the historic distribution of the malarial parasiteTable 1. The major sickle genotypesCondition Genotype Disease expressionHbSS – sickle cell anaemia (SCA) Homozygote for HbS Moderate to severeHbS/β 0 thalassaemia Double heterozygote Moderate to severeHbSC Double heterozygote ModerateHbS/β+ thalassaemia Double heterozygote Mild to moderateHbS/HPFHDouble heterozygoteHbS + hereditary persistenceof fetal HbHbS/HbE Double heterozygote MildAsymptomaticAs an autosomal recessive disorder, a carrier state exists whereby an individual inherits one gene for Hb S and theother for the normal Hb A. This state is called sickle trait.Rarer combinations of Hb S with a number of other abnormal haemoglobins also exist e.g. Hb D Los Angeles,Hb O Arab, Hb G Philadelphia.Disease expression appears dependent on genotype, β globin haplotype 2 and fetal Hb levels 3 , although thebalance of these determinants on disease severity is not fully understood.From http://en.wikipedia.org/wiki/File:Malaria_distribution.jpgFigure 3. Map showing the distribution of the sickle cell gene. Darker shading denotes highergene frequencyHISTORYIn 1904, Melvin Dresbach published a letter in Science, noting “a peculiar anomaly in human red blood corpuscles”that were “elliptical and not circular”. 4These cells had been visualised in the blood film of an apparently healthy medical student, who a year later,was reported to have died suddenly from “cardiac failure subsequent to an attack of acute inflammatory rheumatism…preceded by tonsillitis”. 5 Dresbach’s account likely describes typical SCD complications; an infective trigger leadingto a pain crisis with subsequent acute chest syndrome and death.The term sickle cell anaemia was used first by Vernon Mason in 1922 6 but it was not until 1949 that Linus Paulinglinked sickle cell disease with an abnormality of the haemoglobin molecule. His paper, “Sickle Cell Anaemia –A Molecular Disease” was the first to link a disease to a single molecular flaw. 7ORIGINS OF THE SICKLE GENEGenetic studies indicate the sickle gene arose as an independent mutation in at least four separate geographicallocations; the Central African Republic, Benin, Senegal and either Saudi Arabia or central India. 8Hb S and to a lesser extent Hb C strongly protect against clinical Plasmodium falciparum malaria in a dosedependent manner. Heterozygotes present a lower risk of infection than non-carriers; homozygotes even less ofan infection risk but with the increased risk of fatality if infected. 9This correlation between malarial parasite immunity and the prevalence of the Hb S and Hb C genes is reflectedin the geographical distribution of both conditions.From http://en.wikipedia.org/wiki/File:Sickle_cell_distribution.jpg