When the carriers are homozygous, or compound het­erozygous for another α chain abnormality, they may suf­fer from a severe hemolytic anemia, with the presence of α low percentage of Hb H. Having no deleterious conse­quence in the heterozygous state, they may be common in some populations, and thus found in several members of α family, explaining the possibility for homozygous cases. Hb Taybe [α1; 38 or 39 (Thr→0)] illustrates this situation: the variant was initially found in an Arabic family from Israel where the proband, who was homozygous, suffered from a severe hemolytic anemia with Hb H and some de­gree of dyserythropoiesis [38-40]. This variant was later found in several families belonging to this population, and also in other, completely different ethnic groups, as for example in China. Hb Sallanches [α104(G11)Cys→Tyr (α2)], was initially described in France in α homozygous patient with hemolytic anemia, while it is totally silent in the heterozygous state [41]. It was recently found to be a cause of nondeletional α-thal in Pakistan, leading also to Hb H when associated with another a chain abnormality [42,43]. The group of unstable a chain variants due to protein elongation at their C-terminal, such as Hbs Con­stant Spring or Paksé, are considered as a frequent and classic cause of nondeletional α-thal in Southeast Asia. Homozygous cases of Hb Constant Spring suffer from α chronic macrocytic hemolytic anemia with traces of Hb H. A few similar examples of unstable a chain variants with elongated chains were found in Greece, likely as the result of an intensive search for thalassemic mutations in this population.
It may be important to know about the possibility of the presence of such unstable a chain variants, even in populations free of thalassemias, since today, with the large mobility of people, unexpected associated cases may occur. For example, a severe neonatal anemia was recently reported in twins born to an Irish-Scottish and Asian cou­ple. Hemoglobin studies showed that the father was het­erozygous for Hb Dartmouth [α66(E15)Leu→Pro (α2)] α silent unstable variant, while the mother was heterozygous for a Southeast Asian α0-thal [44].
In the past few years, the diagnosis of some unstable α chain variants was difficult when the structural abnor­mality resulted in α disturbed protein folding and in α defective subunit assembly. Paradoxical biosynthetic data with a β-thalassemic-like biosynthetic ratio after 1 hour of incubation, were then observed but not after short incuba­tion times. Hb Questembert [α131(H14)Ser→Pro] [45,46] and Hb Ann Arbor [α80(F1)Leu→Arg] [47] illustrate this situation. These kinds of problems should easily be solved today by the use of ESI-MS, which would readily show that the abnormality is carried by an α chain, and by se­quencing the α genes to find the abnormality.
Due to the high frequency of the 3.7 kb deletion, the possibility exists for the mutation to be carried by the remaining recombinant α2α1 gene, which product nor­mally amounts to 30-35% of the total α chains. Under these circumstances, the level of expression of an unstable a chain variant will become similar to that of a stable α1 mutation. To solve this problem, the recombinant α2α1 gene, which by PCR is usually amplified together with the α1 gene, should be isolated by electrophoresis before sequencing [48].