Thalassemias and Other Hemoglobinopathies in the Republic of Macedonia

This paper summarizes the results on the epidemiology and molecular basis of thalassemias and other hemoglobinopathies in the Republic of Macedonia. Over the past 40 years, population surveys of more than 22,000 participants (school children and workers) from all over the country, have shown that the average incidence of β-thalassemia (thal) trait is 2.6%, ranging from less than 1% in the northeast to 10% in the south. The frequency of δβ-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.3%. Screening of 9,619 newborns has shown that the frequency of α-thal trait is 1.5%, of which α-thal-2 is 1.45% and α-thal-1 is 0.05%. The molecular basis of the different forms of β-thal and other hemoglobinopathies has been completely defined. Among the Macedonians, over 450 β-thal chromosomes have been studied. Fifteen different β-thal mutations have been detected, four of which [IVS-I-110 (G→A), IVS-I-6 (T→C), IVS-I-1 (G→A), codon 39 (C→T)] account for 85% of all β-thal chromosomes. Among the Albanians, 48 β-thal chromosomes have been studied. Eight different mutations have been detected, four of which [codon 39, −30 (T→A), IVS-I-110, IVS-I-1] account for 85% of all β-thal chromosomes. Four new mutations [−101 (C→A), −87 (C→G), −30, polyadenylation signal (poly A) (AATAAA→AATGAA)] have been characterized. Molecular analyses of DNA from over 20 unrelated cases with δβ-thal have shown that this condition is caused by a 13 kb deletion (Sicilian type); in two families a deletion of 18 to 23 kb (Macedonian type of δβ-thal) was discovered. Molecular analyses of α-thal in the Republic of Macedonia have shown the following types of molecular defects: 20.5 kb deletion, 17.5 kb deletion, 3.7 kb deletion, poly A mutation (AATAAA→AATGAA), and Hb Icaria [α142, Term→Lys, TAA→AAA (α2)]. The incidence of abnormal hemoglobins (Hbs) in the Republic of Macedonia is 0.4%. Three different α chain variants among 10 families, seven different β chain variants among 33 families, two γ chain variants in two newborns, one variant with an extended α chain, and Hb Lepore among 105 families, have been observed. Structural analysis of numerous cases with Hb Lepore showed that the variant was of the Washington-Boston type.