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Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism that results from a deficiency of the lysosomal enzyme alpha-galactosidase A. This defect leads to the accumulation of its substrates, mainly globotriaosylceramide, in lysosomes of cells of different tissues. Different studies have shown the involvement of immunopathologies in different sphingolipidoses. The coexistence of FD and immune disorders such as systemic lupus erythematosus, rheumatoid arthritis and IgA nephropathy, has been described in the literature. The aim of this study was to evaluate the prevalence of a group of autoantibodies in a series of Argentine FD patients. Autoantibodies against extractable nuclear antigens (ENAs), double-stranded DNA, anticardiolipin and phosphatidylserine were assayed by ELISA. Lupus anticoagulants were also tested. Fifty-seven per cent of the samples showed reactivity with at least one autoantigen. Such reactivities were more frequent among males than among females. Antiphospholipid autoantibodies were detected in 45% of our patients. The high rate of thrombosis associated with FD could be related, at least in part, to the presence of antiphospholipid autoantibodies in Fabry patients. We found the presence of ENAs, which are a characteristic finding of rheumatological diseases, previous a frequent misdiagnosis of FD, in around 39% of the cases. The detection of a high level of autoantibodies must be correlated clinically to determine the existence of an underlying autoimmune disease. With the recent development of therapy, the life expectancy in FD will increase and autoimmune diseases might play an important role in the morbidity of FD.

Serum erythropoietin (Epo) and soluble transferrin receptor (sTR) were measured in a locally defined reference population (n=100): healthy volunteers (n=50); iron- deficiency anaemia (n=41) and haemolytic anaemia (n=9) (beta-thalassaemia, n = 4; autoimmune, n=5). Our data demonstrated an inverse relationship between erythroid activity and Epo levels. The regression line between Ln Epo and haemoglobin (Hb) was highly significant: P < 0.0001, r2=0.8275, Ln Epo=8.5346-0.04275 Hb, confidence limit 95%. The mean observed/predicted (O/P) ratio of Ln (Epo) was 1.01 +/- 0.11. We demonstrated that the serum Epo concentration in this particular population correlated consistently with clinical measures of erythropoietic activity. sTR, a new index of erythropoiesis, varied from 16.1 to 148 nmol/l, mean 62.0 nmol/l in the anaemic patients' group. The relationship between Ln Epo and Ln sTR was highly significant: P < 0.0001. We conclude that locally defined regression analyses are crucial for correct data interpretation and can indicate whether or not Epo production is appropriate or inappropriate. Serial determinations of sTR could help in the assessment of response to therapeutic doses of Epo.

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Methotrexate, daunomycin, and chlorambucil were independently conjugated to immune goat gamma-globulins specifically raised to the Ph1 + chronic myelogenous leukemia cell line K-562. The drug-antibody conjugates were then tested against myelosarcomas made up of K-562 cells growing in nude mice and their efficacy was compared with that of the drug alone, gamma-globulins, a mixture of the two, or conjugates of drugs with normal goat gamma-globulin. Conjugation methods for methotrexate and daunomycin abrogate the antibody activity as indicated by the absence of complement-mediated cytotoxicity of the conjugates in vitro and the lack of effect on myelosarcomas in vivo. Simultaneous administration of either of these drugs and antibody partially abrogated the development of myelosarcomas. Chlorambucil-antibody conjugates, however, retained their cytotoxicity in vitro and were found effective in vivo. It is the first successful attempt to covalently bind chlorambucil to gamma-globulins without the loss of drug or antibody biological activity. Although the simultaneous administration of chlorambucil and gamma-globulins and conjugated drug gamma-globulins reduced the growth of myelosarcomas considerably, the immune gamma-globulins alone either reduced their weight to a larger degree or eliminated their growth completely. Results of this study indicate that myelosarcomas made up of K-562 cells grown in nude mice are good and reproducible models for testing various therapeutic agents. The advantage of using human cells proliferating in an in vivo environment brings experimental therapy one step closer to clinical trials.

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Anderson-Fabry disease (AFD), described independently in the 1890s by William Anderson and Johann Fabry, is the second most frequent lysosomal storage disorder (after Gaucher disease). AFD is a pan-ethnic disorder due to a deficiency of the lysosomal enzime alpha-galactosidase A (alpha-GAL), with an estimated frequency of 1 in 117,000 male births, although recent studies suggest that the incidence may be underestimated, as certain patients with residual alpha-GAL activity (5 to 35% of normal levels) have disease too. Increased incidence of thrombotic events has been demonstrated in AFD. We evaluated the prevalence of prothrombotic risk factors in Argentine patients. Patients/methods: 36 patients (15 hemizygous and 21 heterozygous from 3 families) were studied for: protein C pathway (PCSys), antithrombin (AT), protein C (PC), protein S (PS), activated protein C resistance (APCR), lupus anticoagulant (LA), total plasma homocysteine (tHcy), anticardiolipin antibodies (ACA), and antiphosphatidylserine antibodies (APA). Results: The evaluation of PCSys, APCR, plasmatic levels of PC, PS, AT and APA were normal in all patients. Elevated levels of tHcy were found in 19.4% (n=7). Positive for LA were 38.9% (n=14) and for ACA 8.3% (n=3). Conclusions: 1) Our results confirm data from the literature reporting elevated homocysteinemia in AFD patients. Nutritional deficiencies, renal failure and metabolic disturbances are probable etiologic factors. 2) Thrombophilia was more frequent in hemizygous (13 patients, 86.7%) than in heterozygous (8 patients, 38.1%). Four hemizygous patients showed coexistence of two risk factors. 3) We found an unexpected high incidence of procoagulant autoantibodies. This association has also been reported and might contribute to thrombophilia in AFD: as in Gaucher disease, the accumulation of immunogenic glucocerebrosides might induce chronic immunostimulation.

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