Molecular and clinical characterisation of homocystinuria in two Austrian families with cystathionine beta-synthase deficiency.

The influence of the genotype on the phenotypic expression of homocystinuria due to cystathionine beta-synthase (CBS) deficiency is frequently unclear. We therefore investigated the genotype and the phenotype of CBS deficiency in two Austrian families also considering genetic polymorphisms with a putative association with vascular disease (MTHFR 677C-->T, MTHFR 1298A-->C, F5 1691G-->A, F2 20210G-->A) and response to therapy. We identified the CBS 833T-->C/1058C-->T and CBS 828ins104/1358del134 compound heterozygous genotype in our index patients. Both patients showed mental retardation and ectopia lentis. CBS 833T-->C/1058C-->T was associated with severe vascular complications, which was not the case for CBS 828ins104/1358del134. The patient with CBS 828ins104/1358del134 was negative for F5 1691G-->A, F2 20210G-->A, MTHFR 677C-->T, and MTHFR 1298A-->C, while the patient with CBS 833T-->C/1058C-->T was heterozygous for MTHFR 1298A-->C. A combination therapy including pyridoxine, folic acid, hydroxycobalamin, and betaine failed to lower total homocysteine plasma levels below 50 mumol/L in both patients. In summary, our study demonstrates that the CBS 833C/1058T-MTHFR 1298AC genotype can be related to severe vascular disease, while the CBS 828ins104/1358del134-MTHFR 1298AA genotype presents with a somewhat milder clinical phenotype. Both genotypes do not allow for normalisation of total homocysteine plasma levels following vitamin therapy.

Detection of mi transcription factor (MITF) mRNA in a case of myelodysplastic syndrome and bone marrow mastocytosis.

Myelodysplastic syndromes (MDS) may be accompanied by systemic mastocytosis. The mechanisms which play a role in the evolution of mastocytosis, however, are not well understood. We report on a case of refractory and anemia with ringed sideroblasts (RARS), and co-existing bone marrow mastocytosis. Compact mast cell (MC) infiltrates were detected in bone marrow sections by immunohistochemistry using an antibody to tryptase. In addition, the MC were found to express c-kit, the tyrosine kinase receptor for MGF (mast cell growth factor = stem cell factor, SCF). Activating point mutations in the kinase domain of c-kit (often found in mastocytosis) were not detectable. However, the mononuclear cells (MNC) of the bone marrow expressed mRNA specific for MITF, a transcription factor that regulates expression of c-kit and differentiation of MC. Surprisingly, the c-kit ligand SCF was found to augment expression of MITF mRNA in bone marrow MNC. Whether this augmentation represents a general response (preventing loss of growth factor receptor expression during cell maturation) common to all types of hemopoietic progenitors, or is confined to (some forms of) mastocytosis, remains unknown.