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Fabry's disease, a very unusual cause of end-stage renal disease, is actually included in the contraindications to renal transplantation. The few published studies, based on very few patients, report a high rate of life-threatening complications, mostly infectious, following kidney transplant in these patients. We have evaluated retrospectively 12 uremic patients in renal function replacement treatment for Fabry's disease. In transplanted patients (n = 8; whole observation period 241 months), no lethal complication was ever recorded. Fever and acroparesthesias ameliorated. Cardio- and cerebrovascular complications did not progress. Although no increase in serum enzymatic activity was measured, renal transplantation provided an alternative route by excretion of an amount of the metabolic product (ceramide-trihexoside). When undergoing maintenance hemodialysis (whole observation period 291 months), 3 deaths and several cardiac and cerebral complications occurred. Angiokeratomas, fever and pains were unmodified. These data disagree with what has been previously stated. The transplanted patients' survival shifts towards the all-time rate and a satisfying rehabilitation is provided. Fabry's disease should not be considered a high-risk disease; and patients suffering from it should decidedly enter a regular transplantation program.

Endocytotic internalization of alpha-galactosidase by cultured fibroblasts derived from a patient with Fabry's disease was achieved via receptor-mediated endocytosis of alpha-2-macroglobulin (alpha-2-M). alpha-galactosidase of coffee beans was conjugated to alpha-2-M when the latter was treated with trypsin. Internalization of the conjugate resulted in an increase of alpha-galactosidase activity in the crude cell extracts. The observed internalization was blocked by the presence of bacitracin, an inhibitor of binding between alpha-2-M and its receptor on the cell surface. When the cells were incubated at 4 degrees C with the conjugate, internalization was also inhibited. The alpha-galactosidase activity in the cells was saturated when the concentration of the conjugate in the medium was 40 micrograms/ml. Since non-conjugated alpha-galactosidase was not effectively internalized, the observed internalization of the conjugate was mediated by recognition of alpha-2-M by its receptor. The effective internalization of alpha-galactosidase described in this paper has a potential use in the enzyme replacement therapy of Fabry's disease.

Three men with Fabry's disease (angiokeratoma corporis diffusum universal ) are described. In the first patient, atrial fibrillation appeared, and a permanent cardiac pacemaker (VVI) was implanted. Sick sinus syndrome with complete atrioventricular block was occurred on the second patient. Transvenous pacemaker (DDD) implantation was performed for him. The last patient was younger brother of the second patient. He demonstrated complete atrio-ventricular block, so cardiac pace maker (VAT) was implanted. They showed a low value of granulocyte's alpha-galactosidase activity. During 1 to 4 year follow up period, they showed no trouble about pacemaking. Fabry's disease is an disorder of glycosphingolipid metabolism. This disorder is characterized by the accumulation of trihexosyl ceramide in many sites. Cardiac involvement and abnormal electrocardiographic manifestations are common in this disorder. Permanent cardiac pacemaker is necessary for severe bradycardia caused by this disorder.

Three patients with Fabry's disease with a similar clinical picture, including recurrent burning sensations in the extremities, hypohidrosis and slowly progressive renal insufficiency, have been investigated metabolically at different stages of renal impairment. One patient died after three unsuccessful renal transplantations in a 4-year period of intermittent haemodialysis with disabling pains. One successfully transplanted patient is still alive and well, 12 years after the start of therapy. Thermolabile alpha-galactosidase has been demonstrated in his urine. The third patient has slowly progressive renal impairment. No therapeutic enzyme replacement available today is ideal. Early diagnosis is therefore necessary to increase the possibilities of prenatal diagnosis and genetic counseling.

The clinical features, diagnosis management, aetiology and inheritance of angiokeratoma corporis diffusum (Fabry's disease) are discussed and the literature reviewed. The treatment and knowledge generally of this rare condition have not greatly improved in 75 years.

The first patient reported was a 33 years old male with clinical manifestations of Fabry's disease. The diagnosis was confirmed by ophthalmologic, histological and enzymatic studies. Because of inefficacity of treatment with plasma transfusions and of symptomatic therapies, a transplant of cells with normal enzymatic activities was envisioned. In this patient without renal failure, a renal transplant was not justified and a transplant of fetal liver cells was decided. The improvement of extra-renal manifestations of the disease with this new treatment was comparable to that obtained with kidney transplantation. In particular, objective and subjective clinical symptoms were significantly improved: sweating appeared became normal, cutaneous lesions appeared slightly decreased and pains disappeared. This improvement was still persistent 3 years after the fetal liver transplant, the viability of which was initially followed using dosages of circulating alphafoetoprotein. The second case-report is comparable. Fabry's disease was diagnosed in a 26 years old male on the clinical manifestations, the histological lesions and the enzyme deficiency. After failure of one plasma transfusion, the patient received a fetal liver transplant. It is still too early to evaluate the efficacy of the transplant in this second case, especially as the patient had normal sweating and relatively few pains except at the cold season. The mechanism which may be held responsible for possible improvement in our patients, as in recipients of a kidney transplant, is not completely elucidated. The cells, rather than steroids or azathioprine, seemed to support the efficacy. Was the enzyme activity exerted in situ? Was there a "colonization" by lysosomial enzymes? From the results observed after several years will derive the significance of this therapeutic approach in Fabry's disease, more generally, in many diseases associated with a genetic enzyme deficiency.

A deficient leucocyte immunological function could cause the reported high rate of lethal infections following renal transplantation in patients affected by Fabry's disease. We have studied humoral immunity, peripheral lymphocyte subsets, mitogenic lymphocyte response in vitro and granulocyte function in three patients with Fabry's disease. The immunological state appears to be quite similar to that of the uraemic population in general, not showing any specific impairment.

Two patients, 33 and 26 years old, presented with Fabry's disease and minimal renal involvement. They were treated with a transplant of foetal liver cells exhibiting normal enzymatic activities, after plasma transfusions and symptomatic therapies had proved ineffective. In the first patient, objective and subjective clinical symptoms were significantly improved: sweating appeared, cutaneous lesions seemed slightly decreased and pains disappeared. In the second patient, pains were also seemingly decreased. The mechanism which may be held responsible for improvement of our patients, as of recipients of a kidney transplant, is not completely elucidated. The cells, rather than steroids or azathioprine, seemed to be responsible for the improvement.

Senescent erythrocytes are considered a major source of the ceramide trihexoside which accumulates in Fabry disease patients. We have evaluated weekly phlebotomy as a method to reduce the catabolic load imposed by the senescence of erythrocytes and thereby ceramide trihexoside in one Fabry patient; no change was observed in either plasma or urinary level of ceramide trihexoside. The implications of this observation are discussed with regard to glycolipid metabolism in man.

Two brothers suffering from Fabry disease, with classical dermatological and with ophthalmological symptoms, early signs of renal lesions and diminished fertility are presented. The diagnosis is verified by electronmicroscopical investigations. Good symptomic-therapeutic effect of hydantoin-derivatives was observed.

Fifteen hemizygotes and 30 heterozygotes have been diagnosed since our investigations of Fabry's disease were started 10 years ago. They belong mainly to three Danish families. Genetic counseling and prenatal diagnoses have been performed, and in vitro studies of cultured fibroblasts and endothelial cells have been made with special reference to enzyme therapy.