Questioning the Pathogenic Role of the GLA p.Ala143Thr "Mutation" in Fabry Disease: Implications for Screening Studies and ERT.

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

Acral myxoinflammatory fibroblastic sarcoma in a renal transplant patient: a case report.

Herein, we have reported a case of a 62-year-old patient who presented at 10 months after renal transplantation with a nodular mass on the dorsum of his foot. Local excision was performed and an acral myxoinflammatory fibroblastic sarcoma was diagnosed. This is a rare, low-grade sarcoma with a high rate of local recurrence, sometimes leading to amputation. Metastasis to the lungs and liver has been reported, but is rare. Since our patient received triple immunosuppressive therapy, our major concern was a much more aggressive behavior. However, more than 2 years after excision of the tumor, the patient is still free of disease.

Relationship between gastric emptying and clinical and biochemical factors in chronic haemodialysis patients.

BACKGROUND: Gastroparesis is an important side-effect of end-stage renal disease because of its influence on nutritional status. METHODS: In this study, 56 equilibrated haemodialysis patients were evaluated by radioisotopic examination for gastric emptying time. These data were correlated to anthropometrical as well as biochemical parameters. RESULTS: The half-life time for gastric emptying was 83+/-34 min in the overall population, compared to 50+/-15 min in a normal reference population. Prealbumin, mean fibular nerve-conduction velocity and intra- as well as extracorpuscular folic acid were significantly different between patients with the lowest and highest gastric emptying times. Linear correlation analysis between the half-life for residual radioactivity and the remaining parameters yielded a significant correlation for blood urea nitrogen, serum folic acid, intracorpuscular folic acid, serum vitamin B(12), serum C-reactive protein, serum prealbumin and mean fibular nerve-conduction velocity. CONCLUSIONS: This study demonstrates that gastric emptying is significantly delayed in end-stage renal disease patients. The delay is associated with changes in biochemical indicators of nutritional status such as serum albumin and prealbumin.

Progression of renal failure in patients with compromised renal function is not always present: evaluation of underlying disease.

BACKGROUND: It has been proposed that, once renal function has been restricted in chronic kidney disease, compensatory hyperfiltration results in a compulsory deterioration of renal function. PATIENTS AND METHODS: In this study, 83 patients originally starting from a serum creatinine (S(crea)) between 2.0 and 5.0 mg/dl were followed for the evolution of renal function. This overall population, with a follow-up (FU) of(M +/- SD) 67 +/- 50 months, was stratified into two groups based upon their slope of 1/S(crea), whereby the median of this slope (-0.0019) was taken as the cut-off value. RESULTS: There was an expected decline of renal function in the group with the lowest slope (group A = progression) whereas renal function remained stable in the group with the highest slope (group B = no progression). This evolution occurred in spite of a similar S(crea) in both groups at the start of the study (group A: 2.45 +/- 0.71 mg/100 ml (n = 41) vs. group B: 2.94 +/- 0.88 mg/100 ml (n = 42); p = ns) and an even higher creatinine clearance in group A (group A: 46.43 +/- 18.65 mg/100 ml(n = 41)vs. group B: 34.03 +/- 20.11 mg/100 ml (n = 42); p = 0.0049). Group B contained a higher number of patients with interstitial nephritis (34/42 = 81% vs. 6/41 = 15%; p < 0.00001) while patients with chronic glomerulopathy could be found especially in group A (23/41 = 56% vs. 8/42 = 19%; p < 0.00001). Proteinuria was continuously higher in group A (start FU: p = 0.0097; FU 72 months: p = 0.0155) and tended to decrease in group B (start FU, 0.89 +/- 1.42 g/l (n = 42) vs. FU 72 months, 0.41 +/- 0.78 g/l (n = 26); p = 0.0474) whereas no significant decrease was observed in group A (start FU, 2.16 +/- 2.83 g/l (n = 41) vs. FU 72 months, 1.77 +/- 0.72 g/l (n = 6); p = ns). CONCLUSION: Within the time limit and patient inclusion criteria of this FU, a compromised renal function does not necessarily result in a further decline. This study points more towards a major role for the underlying nature of renal disease.

The haematopoietic effect of recombinant human erythropoietin in haemodialysis is independent of the mode of administration (i.v. or s.c.).

BACKGROUND: Previous studies comparing intravenous (i.v.) and subcutaneous (s.c.) administration of recombinant human erythropoietin (rHuEpo) often did not achieve optimal iron reserve, were restricted to a limited follow-up period (not allowing equilibration) and/or did not exclude the role of other confounding factors. In addition all papers focused on the conversion from i.v. to s.c. METHODS: In this study, 30 equilibrated patients on s.c. rHuEpo were randomized into two groups, one converting to i.v. after 6 months of follow-up and one remaining on s.c. rHuEpo. In both groups rHuEpo was administered three times weekly. Only patients completing a further 6 months follow-up were considered for statistical evaluation. Serum ferritin was targeted at 200 ng/ml and haematocrits between 28 and 36% were pursued. RESULTS: The average haematocrit levels before conversion were 31.9 +/- 1.1% in the conversion group and 31.4 +/- 1.6% at the same time point in the nonconversion group (P = NS). After 6 months haematocrits were 31.5 +/- 0.5% in the conversion group and 31.1 +/- 0.9% in the non-conversion group (P = NS). Ferritin concentration in the conversion group was 219 +/- 49 ng/ml before and 230 +/- 83 ng/ml after the conversion. For the non-conversion group ferritin was 224 +/- 25 ng/ml and 236 +/- 52 ng/ml respectively (P = NS). The weight-standardized average rHuEpo dose per injection remained the same in the conversion group before and after conversion (44.0 +/- 1.8 U/kg/injection vs 45.4 +/- 4.7 U/kg/injection) (P = NS). In the non-conversion group the corresponding rHuEpo doses were 32.9 +/- 4.2 U/kg/injection and 39.6 +/- 7.0 U/kg/injection respectively (P = NS). There were no differences in serum PTH, aluminium, vitamin B12, folic-acid levels, and intake of co-trimoxazole, ACE inhibitors or theophylline. CONCLUSION: No changes in rHuEpo dose were observed after conversion from s.c. to i.v. There were no significant differences between the conversion and non-conversion group. These results are in contrast to some earlier studies suggesting lower rHuEpo requirements in case of s.c. administration.