Congenital dyserythropoietic anemia type II (CDA-II) is the most frequent form of CDA. The inheritance pattern is autosomal recessive and its prevalence as well as the frequency of the gene are still unknown; this is due to the heterogeneity of clinical manifestations and to the fact that the majority of cases were probably undiagnosed.

The clinical findings result from a combination of the death of erythroblasts in the bone marrow (ineffective erythropoiesis) and an increased breakdown of released red cells (peripheral hemolysis). Anemia appears in infancy and childhood and it shows a great variability from mild to severe. Jaundice from an increase of indirect bilirubin, hepatosplenomegaly and gallstones are common. Hemosiderosis is the most important long term complication.

CDA-II is characterized by the positivity of acidified serum hemolysis (Ham test) and anti-i agglutination. For some years bone smear observation allowed the diagnosis: presence of bi- and multinucleated (10-40%) erythroblasts with karyorrhexis. Extensive studies on rbc membrane demonstrated several morphological and biochemical anomalies, the most peculiar being the presence of the so-called double membrane. Moreover SDS-PAGE revealed a narrower aspect and a faster migration of the anion exchanger (band 3). This peculiar aspect is due to slightly decreased molecular weight of band 3, consistent with a decreased glycosylation of this protein. The latter in combination with the demonstration of three minor proteins (74,59 e 58 Kd) strongly supported the hypothesis that the second membrane arise from the endoplasmic reticulum.

Carbohydrate structure analysis and biochemical data of membrane and soluble glycoproteins indicate that CDA II is associated with defects in the biosynthesis of complex N-linked oligosaccharides. The characteristic presence in the CDA II patients of tri-mannosyl and penta-mennosyl hybrid type oligosaccharides suggested that the glycosylation defect is the result of a deficiency of either GnT-II or α-Man II activity. Enzyme deficiencies that could account at least in part for these structural findings have been demonstrated by in vitro enzymatic assays.

Up to now the genetic mutations responsible for the glycosylation defect in CDA-II have not been identified. An analysis of carbohydrate structures and biochemical data indicate that the activity of either GnT-II or α-Man II is reduced in different families, suggesting that the disease is genetically heterogenous.