Clinical and molecular variability in congenital dyserythropoietic anaemia type I.
ABSTRACT Congenital dyserythropoietic anaemia (CDA) type I is a rare, inherited disorder characterised by ineffective erythropoiesis and macrocytic anaemia. Complex bone disease has only occasionally been associated with this disease. CDA I is caused by mutations in the CDAN1 gene encoding for codanin-1. Our aim was to characterise the CDAN1 mutation in eight unrelated patients with sporadic CDA I, three of whom had complex bone disease. Six novel mutations in the CDAN1 gene were identified. In two patients, one mutation and in another, both mutations were elusive. No patient was homozygous for a null-type mutation. However, one patient with complex bone disease was homozygous for a splice-site mutation (IVS-12+5G>A). Western blotting revealed that codanin-1 synthesis was 65% less than the control. Five single nucleotide polymorphisms (SNPs) previously unreported in the literature or the SNP database were also identified. Although the absence of codanin-1 is probably lethal, the presence of 35% of the protein was compatible with life but was associated with severe clinical manifestations. However, in most patients studied, no correlation could be established between the expected levels of codanin-1 or the nature of the mutation and the severity of the clinical manifestations.
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ABSTRACT: The authors attempted to assess the utility of interferon alpha2b treatment in a Polynesian girl with a relatively severe form of congenital dyserythropoietic anemia, type 1. The diagnosis was established using routine hematologic and biochemical tests, light and electron microscopy, and electrophoresis of red cell membrane proteins. Response to the treatment was monitored using the blood count and reticulocyte count. The patient was age 14 when interferon treatment was started. Previously, she had been partially dependent on transfusions, and gallstones and iron overload had developed. The dose of interferon alpha2b was initially 3 x 10 units three times a week for 1 year and 3 x 10 units twice a week thereafter. On this treatment, hemoglobin and reticulocytes increased and transfusions became unnecessary. In keeping with a few previous reports, interferon alpha2b proved to be effective in congenital dyserythropoietic anemia, type 1. The patient became transfusion-independent. More cases need to be studied to optimize the dosage of interferon alpha2b and determine how long the treatment can be tolerated.Journal of Pediatric Hematology/Oncology 24(6):503-6. · 0.97 Impact Factor
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ABSTRACT: We report a case of congenital dyserythropoietic anaemia, type I, with severe pre- and postnatal manifestations. Exchange transfusions were required for fetal anaemia (3.5 g/dl) at 28 and 30 weeks of gestation. Transfusions were administered at birth (Caesarean section at week 35) and at regular intervals thereafter. At 14 months, alpha-interferon therapy was initiated (106 units three times a week). This resulted in stabilization of the haemoglobin at or above 11 g/dl and a reduction in the percentage of erythroblasts with ultrastructurally abnormal heterochromatin. After 9 months, the dose of alpha-interferon was decreased to 106 units twice a week. No relapse of anaemia was noted during an additional 4 months of follow-up.British Journal of Haematology 09/2000; 110(2):420-3. · 4.94 Impact Factor
Article: Eukaryotic DNA methylation.[show abstract] [hide abstract]
ABSTRACT: Eukaryotic genomes contain 5-methylcytosine (5mC) as a rare base.5mC arises by postsynthetic modification of cytosine and occurs, at least in animals, predominantly in the dinucleotide CpG. The base is not distributed randomly in these genomes but conforms to a pattern. This pattern varies between taxa but appears to be inherited in a semi-conservative fashion. At the level of the genome, gross changes in the level of DNA methylation have been noted. This has encouraged speculation that the modification may play a role in cellular differentiation. Tissue-specific patterns of DNA methylation, predicted by various models of differentiation, have been found for most vertebrate genes so far examined. A correlation has emerged between the undermethylation of these regions and their transcription, but this is not always the case. While data for eukaryotic viral sequences are less equivocal, studies of this kind cannot in isolation distinguish between undermethylation being a cause or a consequence of gene activity. If it were a cause, it is probable that the demethylation of specific CpG sites would be a necessary yet not a sufficient condition for transcription to occur. The introduction of artificially methylated DNA sequences into individual eukaryotic cells by microinjection or transformation may provide the means to elucidate these questions in the future. In the meantime, the study of eukaryotic DNA methylation promises to contribute much to our understanding of the regulation of gene expression in these organisms.Human Genetics 02/1983; 64(4):315-33. · 4.63 Impact Factor