Results of a Nationwide Screening for Anderson-Fabry Disease among Dialysis Patients

Kotanko, Peter; Kramar, Reinhard; Devrnja, Danijela; Paschke, Eduard; Voigtländer, Till; Auinger, Martin; Pagliardini, Severo; Spada, Marco; Demmelbauer, Klaus; Lorenz, Matthias; Hauser, Anna; Kofler, Hans-Jörg; Lhotta, Karl; Neyer, Ulrich; Pronai, Wolfgang; Wallner, Manfred; Wieser, Clemens; Wiesholzer, Martin; Zodl, Herbert; Födinger, Manuela; Sunder‐Plassmann, Gere

doi:10.1097/01.asn.0000124671.61963.1e

Cited by 177 publications

(114 citation statements)

References 18 publications

(21 reference statements)

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“…This makes CE-MS particularly useful as a noninvasive diagnostic screening test in unexplained renal, cardiac or cerebrovascular disease. Several recent studies have shown a high prevalence of Fabry disease in populations with unexplained renal failure [21], [22], [23], [24], stroke [25], [26], [27] or hypertrophic cardiomyopathy [28], [29], [30]. However, screening these populations for Fabry disease is hampered by the low sensitivity of GLA activity measurement in female patients (50% [31]–67% [32]) whereas diagnostic sequencing of the GLA gene is not feasible given the high cost (currently ca.…”

Section: Discussionmentioning

confidence: 99%

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

et al. 2011

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Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naïve female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naïve Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.

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Section: Discussionmentioning

confidence: 99%

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

et al. 2011

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“…This enzyme deficiency causes the systemic lysosomal accumulation of glycolipids, primarily globotriaosylceramide (Gb3), in the vascular endothelium and other tissues. Morbidity and mortality from FD, caused by renal failure, cardiac disease, and early onset stroke, increase with age, and screens of male patients on dialysis show an FD prevalence of 0.2%-1.7% (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The advent of an effective treatment, enzyme replacement therapy (ERT), has increased the importance of identifying people with FD.…”

Section: Introductionmentioning

confidence: 99%

“…a-Gal A deficiency screens have used plasma (2,3,6,7) and dried blood spot (5,(9)(10)(11) samples; low leukocyte a-Gal A activity is also used to identify candidates for further testing (3,(5)(6)(7)9). Patients positive for the a-Gal A activity screen (i.e., with low activity) are subsequently tested for mutations in the a-Gal A gene (GLA) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…Patients positive for the a-Gal A activity screen (i.e., with low activity) are subsequently tested for mutations in the a-Gal A gene (GLA) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The genetic tests revealed that a-Gal A activity screening lacks specificity, in that some patients without GLA mutations test positive (5,8,10,11). In addition, many females who are heterozygous for pathogenic GLA mutations have normal plasma a-Gal A activity, so screening studies for FD have predominantly focused on male dialysis patients (3,4,6).…”

Section: Introductionmentioning

confidence: 99%

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Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Maruyama

Takata²,

Tsubata

et al. 2013

Clinical Journal of the American Society of Nephrology

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Summary Background and objectives Previous reports of Fabry disease screening in dialysis patients indicate that α-galactosidase A activity alone cannot specifically and reliably identify appropriate candidates for genetic testing; a marker for secondary screening is required. Elevated plasma globotriaosylsphingosine is reported to be a hallmark of classic Fabry disease. The purpose of this study was to examine the usefulness of globotriaosylsphingosine as a secondary screening target for Fabry disease. Design, setting, participants, & measurements This study screened 1453 patients, comprising 50% of the male dialysis patients in Niigata Prefecture between July 1, 2010 and July 31, 2011. Screening for Fabry disease was performed by measuring the plasma α-galactosidase A enzyme activity and the globotriaosylsphingosine concentration, by high-performance liquid chromatography. Genetic testing and genetic counseling were provided. Results A low level of plasma α-galactosidase A activity (≤4.0 nmol/h per milliliter) was observed in 47 patients (3.2%). Of these, 3 (0.2%) had detectable globotriaosylsphingosine levels. These patients all had α-galactosidase A gene mutations: one was p.Y173X and two were the nonpathogenic p.E66Q. The patient with p.Y173X started enzyme replacement therapy. Subsequent screening of his family identified the same mutation in his elder sister and her children. Genetic testing for 33 of the other 44 patients detected 7 patients with p.E66Q. Thus, the plasma lyso-Gb3 screen identified Fabry disease with high sensitivity (100%) and specificity (94.3%). Conclusions Plasma globotriaosylsphingosine is a promising secondary screening target that was effective for selecting candidates for genetic counseling and testing and for uncovering unrecognized Fabry disease cases.

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“…Various studies included hemodialysis patients; with a frequency of confirmed diagnosis between 0.2 and 1.2% (79,80). Other studies have focused on patients with cryptogenic stroke or unexplained left ventricular hypertrophy with frequencies between 3 and 6% (81,82).…”

Section: Screeningsmentioning

confidence: 99%

Fabry Disease: Treatment and diagnosis

Rozenfeld

2009

IUBMB Life

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SummaryFabry disease is an X-linked lysosomal disorder that results from a deficiency of the lysosomal enzyme a-galactosidase A leading to accumulation of glycolipids, mainly globotriaosylceramide in the cells from different tissues. Classical Fabry disease affects various organs. Clinical manifestations start at early age and include angiokeratoma, acroparesthesia, hypohydrosis, heat/exercise intolerance, gastrointestinal pain, diarrhea, and fever. The main complications of Fabry disease are more prominent after the age of 30 when kidney, heart, and/or cerebrovascular disorders appear. Most of the heterozygous females are symptomatic. Enzyme replacement therapy (ERT) is the only specific treatment for Fabry disease. The beneficial effect of ERT on different organs/systems has been extensively evaluated. Quality of life of patients receiving ERT is improved. Enzyme replacement stabilizes or slows the decline in renal function and reduces left ventricular hypertrophy. Fabry disease may be underdiagnosed because of nonspecific and multiorgan symptoms. Different screening strategies have been carried out in different at-risk populations in order to detect undiagnosed Fabry patients. An increasing knowledge about Fabry disease within the medical community increases the chances of patients to receive a timely diagnosis and, consequently, to access the appropriate therapy.

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Results of a Nationwide Screening for Anderson-Fabry Disease among Dialysis Patients

Cited by 177 publications

References 18 publications

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Fabry Disease: Treatment and diagnosis

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