Renal Manifestations of Fabry Disease

Warnock, David G.; Valbuena, Carmen; West, Michael; Oliveira, João Paulo

doi:10.1007/978-90-481-9033-1_12

Cited by 4 publications

(6 citation statements)

References 133 publications

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“…This is in agreement with an earlier report describing a significant increase of GSL concentration in extracts of kidney tissue in 48-week-old Fabry mice as compared to 24-week-old mice [23]. It has been postulated that the Fabry nephropathy in humans results from progressive accumulation of GSL in the kidney parenchyma [31]. However, we are not aware of any biopsy studies in Fabry patients demonstrating an age-related increase in the size of deposits in renal cells, as we have observed in Fabry mice.…”

Section: Discussionsupporting

confidence: 93%

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Kidney histologic alterations in α-Galactosidase-deficient mice

et al. 2011

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Fabry disease is a rare X-linked disorder caused by mutations in the α-galactosidase gene (GLA), the resultant deficiency of lysosomal α-galactosidase enzyme activity leading to systemic accumulation of globotriaosylceramide and other glycosphingolipids. GLA knockout mice ("Fabry mice") were generated as an animal model for Fabry disease but, as they do not manifest progressive chronic kidney disease (CKD), their relevance as a model for human Fabry nephropathy is uncertain. We evaluated the histological alterations in the kidneys of Fabry mice at different ages, as contrasted to those observed in wild-type mice. Furthermore, we compared the renal histological alterations of Fabry mice to the kidney pathology reported in patients with Fabry disease at comparable age ranges and across different CKD stages, using a scoring system that has been developed for Fabry nephropathy. Fabry mice are phenotypically different from wild-type mice, displaying progressive age-related accumulation of glycosphingolipids in all types of renal cells. There were no statistically significant differences between Fabry mice and Fabry patients in the prevalence of glycosphingolipid storage per renal cell type with the exceptions of mesangial (higher in humans) and proximal tubular cells (higher in mice). However, Fabry mice lack the nonspecific histological glomerulosclerotic and interstitial fibrotic renal lesions that best correlate with progressive CKD in Fabry patients, and do not develop large podocyte inclusions. We postulate that the elucidation of the mechanisms underlying these species differences, may contribute important clues to a better understanding of the pathogenesis of Fabry nephropathy.

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Section: Discussionsupporting

confidence: 93%

“…Glomerular sclerosis and tubulo-interstitial fibrosis are the histological features that best correlate with the progression of Fabry nephropathy in humans [14,15,31]. In our study, such nonspecific lesions were virtually absent in both the Fabry and wild-type mice in all three age groups studied.…”

Section: Discussionmentioning

confidence: 40%

Kidney histologic alterations in α-Galactosidase-deficient mice

et al. 2011

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“…4, blue bars) was found that exactly corresponded to the sulfatide kidney profile of the prosaposin deficient patient. This can be taken as an indirect evidence for changes in the composition of cellular types in the urinary sediment - desquamated urothelial cells in controls [45] and lipid-laden renal tubule cells [43] in patients with LSD.…”

Section: Discussionmentioning

confidence: 99%

Direct tandem mass spectrometric profiling of sulfatides in dry urinary samples for screening of metachromatic leukodystrophy

Kuchař

Asfaw

Poupětová

et al. 2013

Clinica Chimica Acta

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Background Prediagnostic steps in suspected metachromatic leukodystrophy (MLD) rely onclinical chemical methods other than enzyme assays. We report a new diagnostic method which evaluates changes in the spectrum of molecular types of sulfatides (3-O-sulfogalactosyl ceramides) in MLD urine. Methods The procedure allows isolation of urinary sulfatides by solid-phase extraction on DEAE-cellulose membranes, transportation of a dry membrane followed by elution and tandem mass spectrometry (MS/MS) analysis in the clinical laboratory. Major sulfatide isoforms are normalized to the least variable component of the spectrum, which is the indigenous C18:0 isoform. This procedure does not require the use of specific internal standards and minimizes errors caused by sample preparation and measurement. Results Urinary sulfatides were analyzed in a set of 21 samples from patients affected by sulfatidosis. The combined abundance of the five most elevated isoforms, C22:0, C22:0-OH, C24:0, C24:1-OH, and C24:0-OH sulfatides, was found to give the greatest distinction between MLD-affected patients and a control group. Conclusions The method avoids transportation of liquid urine samples and generates stable membrane-bound sulfatide samples that can be stored at ambient temperature. MS/MS sulfatide profiling targeted on the most MLD-representative isoforms is simple with robust results and is suitable for screening.

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“…Urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease [ 76 , 77 ].…”

Section: Reviewmentioning

confidence: 99%

Fabry disease

Germain

2010

Orphanet J Rare Dis

1,021

1,289

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Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

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Renal Manifestations of Fabry Disease

Cited by 4 publications

References 133 publications

Kidney histologic alterations in α-Galactosidase-deficient mice

Kidney histologic alterations in α-Galactosidase-deficient mice

Direct tandem mass spectrometric profiling of sulfatides in dry urinary samples for screening of metachromatic leukodystrophy

Fabry disease

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