Thalassemia mutations and their clinical aspects in Japan

Thalassemia (thal) is one of the most prevalent congenital disorders in a world, especially in an endemic area of Plasmodium falciparum. The thal is relatively rare in northeast Asia including Japan where malaria is uncommon. However, thal in Japan has peculiar mutation spectrum and characteristics. Most b-thal patients in Japan are heteorozygote and thal minor as a phenotype. They are prone to be misdiagnosed as iron deficiency anemia. Thirty-four mutations of b-thal were thus far identified, and ten of which comprise 80% of beta-thal carriers. Among them 60% are unique to Japanese and 40% possibly from abroad. The exception is homozygote for -31G-A which leads to thal intermedia by beta(+)-thal phenoytpe. More than a half of patients with alpha-thal are of Southeast Asian type, but mutations of the remaining patients seem to be unique to Japanese and yet undetermined. Thus, Japanese thal's have dual origin. The frequency of beta-thal is one in 600 to approximately 1,000 of general population, and that of alpha(+)-thal (- alpha/) is one in 400. Thus, alpha-thal trait (- alpha/- alpha) is extremely rare. Another alpha-thal trait (- -/alpha alpha) would be one fifth of beta-thal. Seventeen families of HbH disease (- -/- alpha) were found. Many of them are related to Southeast Asian. Cases of non-iron deficient microcytosis and positive in the screening for hemoglobinopathies are subjected to gene analysis using allele-specific PCR, SSCP, direct sequencing and gap PCR. Precise breakpoints with large deletion are being identified by gene dosage and PCR instead of conventional Southern blotting and cloning. Most Japanese thal's are asymptomatic (or not hemolytic) except for microcytosis. However, dominant-type b-thal (or Heinz body beta-thal) are found, and their clinical phenotype vary with mutations. Some of them become symptomatic transiently. This is also seen in beta-thal coexisting with alpha-triplication. Acute exacerbation or transient appearance of Heinz body is seen in ordinary thal mutations on physical conditions such as pregnancy.