dentification of Fabrys disease by the screening of a-galactosidase A activity in male and female hemodialysis patients

Tanaka, Motoko; Ohashi, Toya; Kobayashi, Masahisa; Eto, Yoshikatu; Miyamura, Nobuhiro; Nishida, K; Araki, Eiichi; Itoh, Kazuko; Matsushita, Kazunori; Hara, Michiaki; Kuwahara, Koichiro; Nakano, Tamaki; Yasumoto, Naruhiro; Nonoguchi, Hiroshi; Tomita, Kanako

doi:10.5414/cnp64281

Cited by 59 publications

(47 citation statements)

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“…FD was identified exclusively in a patient with detectable plasma lyso-Gb3. Published reports on male dialysis patients screened for FD (summarized in Table 4) show that when 0.5% or fewer of the patients were given genetic testing, 100% were positive for FD (2,4,6,7,9). In those in which $4% of the patients were tested, 33% or fewer had diagnosable FD (8,10,11).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Surprisingly, approximately 1 % of these patients showed low plasma a-GAL activity (unpublished data). Other studies from Japan have also reported that the prevalence of low a-GAL activity is 0.22-0.7 % in hemodialysis patients [7][8][9]. Similarly, approximately 3 % of Japanese men with unexplained left ventricular hypertrophy have been found to have low plasma a-GAL activity [10].…”

Section: Discussionmentioning

confidence: 90%

Fabry’s disease discovered with chance urinary mulberry cells: a case report

et al. 2012

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Fabry's disease (FD) is a rare X-linked lysosomal storage disorder. Novel enzyme replacement therapy (ERT) at an early stage can slow the progression of cardiovascular and renal dysfunction. Urinary mulberry cells are occasionally found in renal FD. We report a case of variant FD in which detection of urinary mulberry cells led to an early diagnosis. A 36-year-old Japanese man was referred to our hospital because mulberry cells had been detected during urinalysis. Proteinuria and renal dysfunction were not observed. His plasma alpha-galactosidase activity was very low. Renal biopsy revealed typical foamy changes in the glomerular podocytes and tubular epithelial cells that are found in renal FD. Based on the detection of urinary mulberry cells, we successfully started ERT before the patient's renal function deteriorated. Clinical nephrologists and laboratory technicians should recognize the importance of screening for mulberry cells during urinalysis as this is a simple, inexpensive, and non-invasive method for diagnosing FD.

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Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onsetGLAmutation c.936+919G>A (IVS4+919G>A)

et al. 2009

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Fabry disease (α-galactosidase A (α-Gal A, GLA) deficiency) is a panethnic inborn error of glycosphingolipid metabolism. Since optimal therapeutic outcomes depend on early intervention, a pilot program was designed to assess newborn screening for this disease in 171,977 consecutive Taiwanese newborns by measuring their dry blood spot (DBS) α-Gal A activities and β-galactosidase/α-Gal A ratios. Of the 90,288 male screenees, 638 (0.7%) had DBS α-Gal A activity <30% of normal mean and/or activity ratios >10. A second DBS assay reduced these to 91 (0.1%). Of these, 11 (including twins) had <5% (Group-A), 64 had 5-30% (Group-B), and 11 had >30% (Group-C) of mean normal leukocyte α-Gal A activity. All 11 Group-A, 61 Group-B, and 1 Group-C males had GLA gene mutations. Surprisingly, 86% had the later-onset cryptic splice mutation c.936+919G>A (also called IVS4+919G>A). In contrast, screening 81,689 females detected two heterozygotes. The novel mutations were expressed in vitro, predicting their classical or later-onset phenotypes. Newborn screening identified a surprisingly high frequency of Taiwanese males with Fabry disease (~1 in 1,250), 86% having the IVS4+919G>A mutation previously found in later-onset cardiac phenotype patients. Further studies of the IVS4 later-onset phenotype will determine its natural history and optimal timing for therapeutic intervention.

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dentification of Fabrys disease by the screening of a-galactosidase A activity in male and female hemodialysis patients

Cited by 59 publications

References 0 publications

Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Fabry’s disease discovered with chance urinary mulberry cells: a case report

Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onsetGLAmutation c.936+919G>A (IVS4+919G>A)

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dentification of Fabrys disease by the screening of a-galactosidase A activity in male and female hemodialysis patients

Cited by 59 publications

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Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Screening of Male Dialysis Patients for Fabry Disease by Plasma Globotriaosylsphingosine

Fabry’s disease discovered with chance urinary mulberry cells: a case report

Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onsetGLAmutation c.936+919G>A (IVS4+919G>A)

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dentification of Fabrys disease by the screening of a-galactosidase A activity in male and female hemodialysis patients