Haem synthesis in sideroblastic anaemia

Measurement of delta-aminolaevulinic acid (ALA) synthetase has been performed in bone marrow of 24 normal subjects and 20 patients with sideroblastic anaemia (five congenital, two pyridoxine-responsive, 12 primary acquired and one secondary form due to isoniazid therapy). ALA-synthetase activity without added pyridoxal-phosphate in vitro was decreased in four of the congenital cases, and in all 12 primary acquired cases. In two of these 16 cases with low ALA-synthetase activity and in a case with sideroblastic change secondary to isoniazid therapy, the enzyme activity was corrected to normal by pyridoxal-phosphate in vitro. ALA-synthetase activity was normal in both cases of pyridoxine-responsive anaemia while they were receiving pyridoxine therapy but in one of these cases, studied at repeated intervals after withdrawal of pyridoxine therapy, the bone marrow ALA-synthetase activity fell to very low levels unless pyridoxal-phosphate was added in vitro. In this case the Km of the enzyme for pyridoxal-phosphate was substantially greater than that of a control sample. Haem synthetase activity was reduced in the bone marrow of two of six cases of primary acquired sideroblastic anaemia and in one congenital case tested but was normal in the pyridoxine-responsive patient studied on pyridoxine therapy. Nevertheless, this patient showed reduced incorporation of 14C-labelled delta-aminolaevulinic acid into bone marrow haem. It is concluded that both congenital and primary acquired sideroblastic anaemia are a heterogenous group of disorders, with different defects in haem synthesis, reduced activity of delta-aminolaevulinic acid synthetase being common but not invariable in both types. Pyridoxine-responsive (congenital) sideroblastic anaemia may be due to the presence of an abnormal ALA-synthetase apoenzyme which requires excessive amounts of the coenzyme, pyridoxal-phosphate, to achieve normal activity; other abnormalities of haem synthesis may also be present.