IX. GENETICS AND HUMAN HEMOGLOBIN CHEMISTRY 455 



observed in Negroes is quite surprising, Hb-Bart's disappears almost at 

 the same time that Hb-F disappears and usually no Hb-H is observed 

 in the infants, when Hb-A substitutes Hb-F. The presence of Hb- 

 Bart's in cord blood has been attributed in these cases to heterozygosity 

 for a chain thalassemic genes. These genes may manifest themselves with 

 the presence of Hb-Bart's only in periods of stress for the erythropoietic 

 system, when the production of red cells is accelerated by environmental 

 or physiological factors around birth. The frequency with which Hb- 

 Bart's is observed in newborns would correspond to the true frequency 

 of such genes in population, unaffected by expressivity or penetrance 

 factors. 



If the frequency of a^^ genes is as high as estimated by the above- 

 mentioned authors, one wonders why homozygous cases of a-thalassemia 

 have not been observed and reported in the literature. An answer to this 

 question may be found in the description by Lie-Injo (1961) of several 

 cases of severe hydrops and erythroblastosis fetalis in stillborn babies 

 or in babies who died shortly after birth. The hematological picture was 

 that of a severe hemolytic disease and the red cells showed sickling 

 although no Hb-S was present. The hemoglobin of these stillborn babies 

 consisted mainly of Hb-Bart's with small amounts of Hb-F and Hb-A 

 (Lie-Injo and Lie, 1961). In a cord blood sample examined by the author 

 (obtained through the courtesy of Dr. Lie-Injo, Institute for Medical 

 Research, Kuala Lumpur, Malaya) approximately 80% of the hemo- 

 globin was found to be Hb-Bart's! Lie-Injo (personal communication) 

 has suggested that these babies were affected by homozygous «-thalas- 

 semia. The failure to observe cases of homozygous a-thalassemia in 

 adults may thus be due to the fetal or stillborn lethality of this geno- 

 type. Since a chains are common to Hb-F, Hb-A, and Hb-Aa, the 

 synthesis of these hemoglobins will be equally affected by a deficiency 

 of a chain production. Moreover, no compensatory effect is possible in 

 homozygous a thalassemia, while in /? thalassemia the production of 

 high quantities of Hb-F allows the affected individuals to live for a 

 few to several years. 



It is interesting that no abnormal aggregation of « chains to form 

 a hypothetical 0:4 hemoglobin is observed in a thalassemia. The a^ mole- 

 cule does not form either because of steric hindrance or because of a 

 lack of chemical affinity of the a chains to polymerize. It has indeed 

 been observed that upon prolonged exposure of Hb-A to acid pH and 

 recombination, small quantities of (3^ chains polymerize to form Hb-H 

 and that an equivalent amount of a^ chains are liberated as monomers 

 and not as «4^ tetramers (Huehns et al., 1961b) ; it is not known whether 

 these a chains arc altered or partially denaturatcd. 



