Background. Fabry disease is an X-linked disorder resulting from a deficiency of lysosomal α-galactosidase. Renal insufficiency is one of its most important manifestations and affects the prognosis of the disease. We clarified the incidence of Fabry disease in patients receiving maintenance dialysis. Methods. We measured plasma α-galactosidase activity in 722 patients (male 440, female 282) receiving maintenance dialysis. Clinical manifestations were assessed, and the patients were to be screened for mutations in the α-galactosidase gene. Results. Two male patients had low plasma α-galactosidase activity. One patient had a C-to-T transition at codon 357, resulting in substitution of the predictable termination for glutamine. The other patient died suddenly during hemodialysis, due to arrhythmia. We could not carry out further evaluation, but his daughter had moderate reduction of α-galactosidase activity in leukocytes. She was, likely, an asymptomatic heterozygote. Conclusions. Two male patients with Fabry disease were found among 440 male patients who were receiving maintenance dialysis. Fabry disease should be considered in the etiology of end-stage renal failure.
Background and Purpose-Crossed cerebellar diaschisis (CCD) refers to reduced metabolism and blood flow in the cerebellar hemisphere contralateral to a cerebral lesion. Many cortical areas have been reported to cause CCD without consideration of confounding factors. We performed single-photon emission computed tomography (SPECT) in patients with cortical infarction to identify regions independently related to CCD, controlling for possible confounding effects.
Methods-Patients
The mutant products Q279E ((279)Gln to Glu) and R301Q ((301)Arg to Gln) of the X-chromosomal inherited alpha-galactosidase (EC 3.2.1. 22) gene, found in unrelated male patients with variant Fabry disease (late-onset cardiac form) were characterized. In contrast to patients with classic Fabry disease, who have no detectable alpha-galactosidase activity, atypical variants have residual enzyme activity. First, the properties of insect cell-derived recombinant enzymes were studied. The K(m) and V(max) values of Q279E, R301Q, and wild-type alpha-galactosidase toward an artificial substrate, 4-methylumbelliferyl-alpha-D-galactopyranoside, were almost the same. In order to mimic intralysosomal conditions, the degradation of the natural substrate, globotriaosylceramide, by the alpha-galactosidases was analyzed in a detergent-free-liposomal system, in the presence of sphingolipid activator protein B (SAP-B, saposin B). Kinetic analysis revealed that there was no difference in the degradative activity between the mutants and wild-type alpha-galactosidase activity toward the natural substrate. Then, immunotitration studies were carried out to determine the amounts of the mutant gene products naturally occurring in cells. Cultured lymphoblasts, L-57 (Q279E) and L-148 (R301Q), from patients with variant Fabry disease, and L-20 (wild-type) from a normal subject were used. The 50% precipitation doses were 7% (L-57) and 10% (L-148) of that for normal lymphoblast L-20, respectively. The residual alpha-galactosidase activity was 3 and 5% of the normal level in L-57 and L-148, respectively. The quantities of immuno cross-reacting materials roughly correlated with the residual alpha-galactosidase activities in lymphoblast cells from the patients. Compared to normal control cells, fibroblast cells from a patient with variant Fabry disease, Q279E mutation, secreted only small amounts of alpha-galactosidase activity even in the presence of 10 mM NH(4)Cl. It is concluded that Q279E and R301Q substitutions do not significantly affect the enzymatic activity, but the mutant protein levels are decreased presumably in the ER of the cells.
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