Congenital dyserythropoietic anemias

Congenital dyserythropoietic anemia (CDA) is the current designation for a group of rare inherited disorders that have a common feature: abnormalities in the maturation of the ery-throid lineage. It is evident from genetics and from morphology that they are heterogeneous, and it is likely that they may be even more heterogeneous at the molecular level. Of the three classical forms of CDA (Table 12.2), CDA II (or HEMP-AS) is the best defined, on account of a pathognomonic serological test; CDA I is defined by characteristic ultrastructural

Table 12.2 Defining features of CDA types MIL

Type I

Type II

Type III

Inheritance

Autosomal recessive

Autosomal recessive

(a) Autosomal dominant

(b) Autosomal recessive

Location of gene

I5ql5.1—15.3

20q11.2

15q21-25

Identity of gene

CDAN1

Not known

Not known

Red cells

Macrocytes

Normocytes

Erythroblasts

(a) Light microscopy

Megaloblastic; internuclear

Normoblastic; binuclearity

Megaloblastic; up to 12 nuclei per cell

chromatin bridges

predominates

(b) Electron microscopy

Swiss cheese appearance of

Peripheral double membranes

heterochromatin

Serology

Ham's test

Negative

Positive

Negative

Anti-i agglutinability

Normal/strong

Strong

Normal/strong

SDS-PAGE

Normal

Band 3 thinner and faster

Band 3 slightly faster

Modified from Wickramasinghe SN. (1997) Dyserythropoiesis and congenital dyserythropoietic

anaemias. British Journal of Haematology, 98,

785-797.

changes in the chromatin of erythroblasts and by autosomal recessive inheritance; CDA III is defined by large, sometimes multinucleated, erythroblasts and by autosomal dominant inheritance. A variety of terms have been used to classify patients who have features of CDA but do not fit neatly in any of these three categories.

As a result of a deranged developmental program, the mature red cells that are produced in CDA are macrocytic and abnormal in their membrane; this often entails a hemolytic component in their anemia. In addition, and most characteristically, a significant proportion of erythroid cells fail to achieve full maturity, and as a result they are destroyed in the bone marrow. Thus, the pathophysiological hallmark in CDA, just as in acquired megaloblastic anemias (see above), is ineffective erythropoiesis.

The biochemical basis for abnormal maturation has been well characterized in the case of CDA II. Sodium dodecylsul-fate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of red cell membrane proteins reveals an increased sharpness of band 3, the size heterogeneity of which is normally produced by the variable size of its carbohydrate moiety. This finding has focussed attention on the enzymes required for glycosylation of membrane proteins: decreased activity of a-mannosidase and of fucosyl transferase has been reported in individual cases. Targeted inactivation of the gene encoding the latter enzyme has produced mice with features of CDA II. On the other hand, very recently it has been reported that in-activation of AE1, the gene encoding band 3, produces in ze-brafish some features of human CDA II. However, by linkage analysis CDA II maps to 20q11.2 in most families, whereas fu-cosyl transferase maps to 11q21 and AE1 maps to 17q21-q22. Thus, the gene that is mutated in human CDA II still needs to be identified. Variability of clinical expression of CDA II could be due to different underlying genetic lesions (and of course also to different mutant alleles at the same locus). In fact, there is some indirect evidence that alleles causing mild CDA may be relatively common, because two cases have been reported as causing chronic hemolytic anemia in association with glucose-6-phosphate dehydrogenase (G6PD)-deficient variants which do not, on their own, cause this condition. We do not know whether the CDA mutations present in these patients would have caused clinical manifestations in the absence of G6PD deficiency.

The gene for CDA I has been mapped to chromosome 15 by linkage analysis in a single Swedish family (one of the first from which the concept of CDA developed). Very recently this linkage has been confirmed in Bedouin families, and this has led to the identification of a gene that is mutated in all of these families, which has been called codanin-1. Codanin-1 has a 150-residue amino-terminal domain with sequence similarity to collagens, and two shorter segments that show weak similarities to the microtubule associated proteins, MAP1B (neuraxin) and synapsin.

In view of the fact that in the various forms of CDA the abnormal phenotype is almost exclusively restricted to the erythroid lineage, it is likely that the genes that are mutated in any patient with CDA serve some important role in the program of erythroid differentiation. For instance, it seems likely that in erythroid cells codanin-1 is involved in nuclear envelope integrity, conceivably related to microtubule attachments. Thus, each one of the CDA genes will be of great interest, quite out of proportion to the rarity of CDAs as clinical entities.

It has been reported that three patients with CDA I have responded to treatment with interferon-a with near normalization of the hemoglobin values. Although the clinical data seem convincing, at the moment it is not clear by what mechanism an intrinsic erythroid molecular abnormality can benefit from this treatment.

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