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NDT Advance Access published online on July 2, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn370
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients

Gert De Schoenmakere1,2*, Bruce Poppe3,*, Birgitte Wuyts4, Kathleen Claes3, David Cassiman5, Bart Maes6,2, Dierik Verbeelen6,7, Raymond Vanholder1, Dirk R. Kuypers8, Norbert Lameire1, Anne De Paepe3 and Wim Terryn1,9*

1 Department of Nephrology, Ghent University Hospital, Ghent 2 Department of Nephrology and Internal Medicine, Heilig Hart Hospital, Roeselare 3 Center for Medical Genetics, Ghent University Hospital, Ghent 4 Department of Clinical Biology, Ghent University Hospital, Ghent 5 Metabolic Center, University Hospitals Leuven, University of Leuven 6 Representative of NBVN (Nederlandstalige Belgische Vereniging voor Nefrologie) 7 Department of Nephrology, Universitair ziekenhuis Brussel, Brussels 8 Department of Nephrology and Renal Transplantation, University Hospital Gasthuisberg, Leuven 9 Department of Nephrology and Internal Medicine, Regional Hospital Jan Yperman, Ypres, Belgium

Correspondence and offprint requests to: Gert De Schoenmakere, Department of Nephrology and Internal Medicine, Heilig Hartziekenhuis Roeselare, B-8800 Roeselare, Belgium. Tel: +32-51-23-74-95; Fax: +32-51-23-74-95; E-mail: gdeschoenmakere{at}hhr.be



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Anderson–Fabry disease (AFD) is an X-linked condition originating from a deficiency in alpha-galactosidase, a lysosomal enzyme. Multi-organ involvement ensues in early adulthood and vital organs are affected: the kidneys, brain, heart. Several reports however suggest that AFD is underdiagnosed.

Methods. We screened a kidney transplant population using a two-tier approach. The first tier was the determination of alpha-galactosidase A (AGALA) activity using a dried blood spot on filter paper (DBFP); in the second tier, patients with the lowest alpha-galactosidase levels were further subjected to mutation analysis of the GLA gene.

Results. From the database of 2328 patients, 1233 subjects met the inclusion criteria. Finally, after informed consent, 673 patients were screened (54.5%—395 women and 278 men). DBFP analysis resulted in a mean AGALA of 2.63 ± 2.48 µmol/L/h (2.5 and 97.5 percentile were 0.0001 and 5.07 µmol/L/h, respectively). Eleven patients were subjected to further genetic analysis. In a male patient a pathogenic missense mutation p.Ala143Thr (c.427A>G) was identified.

Conclusions. Our results show that the proposed approach can detect AFD patients in a until now seldomly screened high-risk group: kidney transplant patients. We conclude that screening for AFD in high-risk populations is a cost-effective, technically feasible and clinically valuable objective.

Keywords: alpha-galactosidase; Anderson–Fabry disease; screening; transplantation



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Anderson–Fabry disease (AFD) originates from a deficiency in alpha-galactosidase A (AGALA), a lysosomal enzyme. This leads to the accumulation of glycosphingolipids (compounds with a biological role in membrane structure, modulation of membrane protein function and cell–cell recognition) intracellularly in the lysosomes [1,2]. The disease is X-linked and various incidence rates of the classical phenotype have been reported ranging from 1/40 000 to 1/117 000 live births [3,4].

Following the glycosphyngolipid accumulation in various cell types, multi-organ involvement ensues and vital organs are affected: the kidneys, brain, heart. Dysfunction of these systems leads to considerable morbidity and increased mortality [4]. This clinical evolution is a continuum with a predominance in childhood of neuropathic pain and heat intolerance [5] to organ dysfunction in adolescence or adult age. It should however be pointed out that even children can present with classical signs of AFD. Due to its mode of inheritance, affected males develop clinical symptoms [4]; as a result of skewed lyonization, female carriers can develop the entire spectrum ranging from asymptomatic carriers to classical AFD [6–8].

AFD is however an underdiagnosed entity, as was demonstrated by screening studies performed in high-risk populations, such as patients on dialysis [9–13], patients with hypertrophic cardiomyopathy [14–17] and patients with cerebrovascular accidents at younger age [18,19]. Moreover, Spada et al. undertook a newborn screening by assaying the AGALA activity in blood spots from 37 104 consecutive Italian male neonates. Identification of 12 neonates with a low AGALA and corresponding mutations in the gene encoding AGALA and subsequent family screening led to an incidence of 1 in 4600 in this population, with a predominance of later onset disease over the classical presentation [20]. Hence, care should be taken in interpreting previously reported incidence rates (often referring to the classical presentation of AFD).

In recent years a safe and efficacious treatment for AFD (enzyme replacement therapy; ERT) became available [21,22]. As a consequence, implementation of screening programmes in high-risk populations now seems a clinically relevant objective. Identifying index cases is not only of vital importance to these patients, but also to their family members, offering them the opportunity to be treated by ERT in an earlier disease stage.

Following the successful screening by our group in haemodialysis patients [13], we extended our study to a risk group for Fabry disease for which data are scarce [30]: kidney transplant patients. We set up a community-wide screening programme in kidney transplant patients, based on a two-tier approach [23]: initial screening for AGALA deficiency using the dried blood spot on filter paper (DBFP) technique [13,24], followed by standard genetic GLA gene mutation analysis of the high-risk persons identified in the first part of the study [2].



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patient selection
In Flanders (the Dutch-speaking part of Belgium), the inventory of dialysis and transplant patients is well structured. The NBVN (Nederlandstalige Belgische Vereniging voor Nefrologie; a nephrology society grouping all 27 Flemish nephrology centres) issues a regularly updated database containing renal diagnosis, as well as the strength of evidence for this diagnosis. By the time of the start of this AFD screening study, 2328 patients were in the follow-up in one of the 27 Flemish nephrology centres after a successful transplantation (www.nbvn.be). Those patients without biopsy-proven renal diagnosis or without clear reason for renal failure in their history prior to transplantation (e.g. autosomal dominant polycystic kidney disease, bilateral nephrectomy for kidney tumours) were enrolled. Given the prevalence of diabetes among patients with end-stage renal disease, the latter were included in the screening provided they further complied with the inclusion criteria. Both genders older than 18 years were considered, without an upper-age limit. No known Fabry patients were enrolled.

Determination of AGALA activity using the technique of dried blood spot sampled on filter paper
The screening test was based on a technique as described by Chamoles et al. [24]. In brief, a 3.2-mm disc was punched and incubated at pH 4.4 and at 37°C with 4-methyl-umbelliferyl-alpha-galactopyranoside as substrate and N-acetyl-D-galactosamine as inhibitor for alpha-galactosidase B. Enzymatic activities measured on a Thermo life science fluorometer (Thermo Electron Corporation, Waltham, MA, USA) were expressed as micromoles of substrate hydrolyzed per litre of blood per hour.

This technique was previously validated in our laboratory as reported elsewhere [13]. Each DBFP viability was verified by measurement of beta-galactosidase; if beta-galactosidase activity was decreased in the DBFP test, the sample was rejected.

Determination of AGALA in white blood cells
Where appropriate AGALA levels in white blood cells were determined using the technique previously described by Desnick et al. [2].

Cut-off value for DNA mutation analysis
The lower cut-off limit for AGALA in our laboratory was set at 0.64 µmol/L/h. All samples with activity levels below this threshold were re-examined and sample viability was verified using beta-galactosidase. If this rendered a too low value (normal lower cut-off limit for beta-galactosidase in our laboratory is 9.1 µmol/L/h), the sample was rejected. All samples with a low alpha-galactosidase and a normal beta-galactosidase were subjected to DNA mutation analysis.

DNA mutation analysis
Genomic DNA was extracted from EDTA blood of the patients by standard protocols (Puregene DNA purification kit, Qiagen, Dusseldorf, Germany) according to the manufacturer's instructions. Mutation analysis was performed by PCR amplification followed by direct sequencing of the seven exons and flanking intronic sequences of GLA (Genbank: X14448.1 [GenBank] -genomic). Primers used were modified from Eng et al. [25].

To exclude the presence of single- and multi-exon deletions in female patients, MLPA analysis (multiplex ligation-dependent probe amplification) (MRC Holland, P159) was performed. Our mutation detection strategy allows us to obtain a mutation detection frequency in male and female patients of 100%.

Informed consent and Ethics
The study protocol was approved by the Ethics committee of the Ghent University Hospital and all patients gave written or oral witnessed consent prior to participation. The study protocol is in accordance with the Declaration of Helsinki.



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Patient selection
Twenty nephrology units (74% of the total) participated in the screening study. From the database of 2328 patients, 1233 subjects met the inclusion criteria. Finally 673 patients gave informed consent and were screened (54.5%—395 women and 278 men).

AGALA levels in the screening population (blood spot technique)
DBFP analysis of the 673 transplant patients resulted in a mean AGALA of 2.63 ± 2.48 µmol/L/h (2.5 and 97.5 percentile were 0.0001 and 5.07 µmol/L/h, respectively).

DNA mutation analysis
Based on the above-mentioned criteria, 11 patients with low AGALA (2 men and 9 women) were subjected to further genetic analysis. In one male patient, the p.Ala143Thr (c.427A>G) missense mutation was identified.

Clinical correlation and family screening
This 67-year-old male index patient started chronic haemodialysis therapy at the age of 33 because of stage 5 chronic kidney disease (CKD) without known renal diagnosis (no histological diagnosis). Prolonged dialysis therapy was complicated by secondary (β2-microglobulin) amyloidosis manifested by bilateral carpal tunnel syndrome. At the age of 42 the patient suffered an ischaemic stroke; clinical recovery was incomplete with a residual mild left-sided hemiparesis. Fourteen years after dialysis initiation, he was transplanted with a renal allograft from a deceased donor. At present, 20 years later, the patient has remained rejection free; renal allograft function is stable with a plasma creatinine concentration of 1.34 mg/dL and a calculated glomerular filtration rate of 45 mL/min. Proteinuria is absent while the urinary sediment is normal. Maintenance immunosuppressive therapy still consists of cyclosporin microemulsion (NeoralTM, Novartis, Basel, Switzerland), azathioprine (ImuranTM, GlaxoSmithKline, Genval, Belgium) and corticosteroids (MedrolTM, Upjohn, Diegem, Belgium). Thirteen years posttransplantation, at 60 years of age, a bilateral nephrectomy of the native kidneys was performed because of multifocal mixed-type renal cell carcinoma (RCC) comprising partly a papillary (chromophilic) type and an eosinophilic variant of the clear cell type (staging T1aN0M0). This was recently reported by Cassiman et al. [26]. Further posttransplant complications included arterial hypertension, hypercholesterolaemia, osteoporosis, bilateral cataracts and inguinal hernia with surgical repair. In 2005, the patient was treated for a paroxysmal supraventricular tachycardia with a beta-blocker (sotalol) but the latter had to be promptly stopped because of severe bradycardia and bifascicular conduction block. In 2006, a left-sided rolandic meningioma was diagnosed because of transient headaches; a conservative strategy was advised, postponing neurosurgical intervention in case of signs of motoric dysfunction or radiological progression.

In retrospect, symptoms and signs that could have suggested AFD were absent in this patient: there was no history of neuropathic limb pain, no typical skin lesions (telangiectasias, angiokeratomas) nor corneal alterations (cornea verticillata). The development of stage 5 CKD in the third life decade concurs with AFD-related kidney disease but histological examination of the non-malignant renal tissue obtained after bilateral nephrectomy showed chronic glomerulonephritis, hyalinization and severe arteriosclerosis, but no lesions typical for Fabry disease. Of course, these non-specific histological lesions found almost 30 years after the development of ESRD do not exclude the earlier presence of specific AFD-related changes. Cardiac involvement might have been suspected based on the echocardiographic findings revealing hypertrophy of the interventricular septum with normal systolic and diastolic left ventricular function. In this regard however, other possibly contributing factors to the septal hypertrophy not related to AFD should be taken into consideration, e.g. volume overload during dialysis, episodes of arterial hypertension. In addition, a typical thickened hyperechogenic layer [27], representing intracellular (sub)endocardial glycosphingolipid deposition, could not be clearly identified. The bifascicular block induced by a low dose of beta-blocker was only in retrospect suggestive of AFD-related cardiac conductive abnormalities. While the occurrence of ischaemic stroke at a young age is a common sign of neurological involvement in AFD, no typical or suggestive MR signs, like T1-weighted hyperintensity in the pulvinar (thalamus) [28], could be identified on repetitive brain imaging.

An extensive analysis of the family history was not helpful in establishing the presence of clinical AFD. The patient's mother died at the age of 91 years while the father died at age 63 years. Neither parent was known to have neurological, cardiac or renal disease. The patient's siblings (one brother of age 62 years and one sister of age 68 years) have no medical problems suggestive of AFD. However, the p.Ala143Thr (c.427A>G) missense mutation was detected in the sister (asymptomatic carrier) while the brother was confirmed to be non-carrier (Figure 1).


Figure 1
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  		Fig. 1 Pedigree of the index patient (arrow); black = mutation present; white = no mutation present; question mark = no genetic testing performed as yet; grey = low alpha-galactosidase A level, genetic testing pending—AFD very likely.

 
The son of the former has a clearly reduced AGALA activity [<0.05 µmol/L/h (0.64–3.82)]; genetic testing is pending. The patient has one son (age 42 years) with 3 grandchildren (females: twins of 9 years, 12 years) and one daughter (age 43 years) with one grandson (age 23 years). The 43-year-old daughter was confirmed to carry the p.Ala143Thr (c.427A>G) missense mutation. Her son (23 years) has not been tested yet. None of these family members has AFD-related signs or symptoms. Despite the delayed diagnosis, treatment with recombinant human AGALA is planned for the index patient. The results of his genetic confirmation test being pending, the nephew (37 years) of our index patient has a 50% risk of inheriting the mutation of the respective mother.



   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
AFD is a rare genetic disorder [3,4], initially characterized by discrete and often non-specific signs and symptoms [5], with a natural evolution and progression often leading to vital organ failure. Although the clinical awareness for this disease has increased significantly in the last few years, systematic detection of carriers remains worthwhile.

Screening entire populations (e.g. neonatal screening [20,23]) may be a valuable option to detect the disease in an early phase. A remarkable observation in this regard was made by Spada et al. [20] showing that the incidence of GLA mutations in male Italian neonates was considerably higher than that previously reported. The yield of population-wide screening programmes, however, is hampered by a considerable amount of false positives [23]. An additional drawback is that enzyme-based diagnosis of the disease is the gold standard in men, but using this technique only 2/3 of the female carriers are detected [29]. In women, these limitations should be appraised and taken into consideration.

Narrowing the screening programme to high-risk patient groups has already proven efficacious, as was demonstrated previously for cryptogenic stroke and for patients with hypertrophic cardiomyopathy [14–19]. In haemodialysis patients a considerable number of successful screening studies have been reported in the literature, mainly in male patients and using different diagnostic techniques (blood spot, white blood cell enzyme detection, genetic analysis [9–13]). Our group recently reported a nation-wide screening study in a predominantly female dialysis patient group [13], and proved that, even taking into consideration the lower detection limit for AFD of enzymatic tests in female patients, blood spot-based screening can be useful.

As for a considerable number of patients, haemodialysis or peritoneal dialysis is merely a transition to kidney transplantation, it can be hypothesized that in the renal transplant recipient group, some misdiagnosed or undiagnosed AFD patients may be found. It was the goal of this study to document and test this hypothesis.

We used a two-tier approach with a blood spot-based (and cheap) detection of ‘risk-patients’ followed by a more expensive and time-consuming genetic analysis. We chose to screen women also by alpha-galactosidase activity, keeping in mind the limitations as reported by Linthorst [29], showing that that only 2/3 of the female patients are detected by this approach. This enabled us however to screen more patients at lower cost.

In contrast to our previously reported dialysis screening programme, we did not impose an upper age limit in male patients, as recent reports point out that the spectrum of AFD presentations in male patients is much wider than that previously estimated. This decision is corroborated by the detection by this screening of a 67-year-old male transplanted Fabry patient.

Once the diagnosis established in the proband, screening for a genetic disease within a family can be very difficult as is illustrated by the family presented: the proband had a full clinical and genetic work-up, but his ‘hemizygous’ sister only had an enzymatic and genetic work-up (she refused further clinical and biochemical testing, because she was ‘well’ and, to her standards, ‘aged enough not to bother about that kind of things’); the hemizygous sister's son had enzyme testing which was clearly abnormal, but he has refused further testing so far (‘I’m well’). The proband's daughter is an obligatory ‘carrier’, which was confirmed genetically and enzymatically; she has no apparent cardiovascular, neurological or renal involvement. Her only son was only informed of the disease running in his family last week, due to relational problems in the family. Further family screening and detailed mapping of disease burden in possibly affected members will of course be pursued ceaselessly.

It is of interest to note that in 10 out of the 11 genetically tested patients with low AGALA, no mutation in the GLA gene was found. Mutation analysis was performed by two complementary techniques: direct sequencing of the seven GLA exons and exon-flanking boundaries in male and female individuals and MLPA, exclusively in female patients. In affected males, the sensitivity of direct sequencing is estimated to approximate 100%. In heterozygous females, the sensitivity of direct sequencing is most certainly lower as whole gene and full exonic deletions will be missed. These genetic aberrations will, however, be reliably detected by the MLPA analyses we included for female patients. Therefore, we are confident that the adopted strategy is sufficiently sensitive. Of note, direct sequencing (with or without MLPA) was the method of choice in most recent screening studies for Fabry's disease. Evidently, it should be appreciated that certain, albeit extremely rare, pathogenic genetic alterations (such as mutations in or methylation of the GLA promotor) will not be detected by the adopted strategy. As a consequence, the concern of missing pathogenic mutations remains an important issue in selected cases. In a suggestive clinical setting, clinicians are therefore encouraged to demonstrate globotriaosylceramide deposition by alternative and complementary analyses such as electronmicrosopic studies of skin or renal biopsy specimens. This however is beyond the scope of this screening project and merits further investigation.

The total cost of this screening is small, as compared to the gains. As our blood spot technique costs 6.25 euro per analysis, the first tier of our test costed 4206.25 euro. The second tier (genetic analysis) costed 11 x 337.5 euro = 3712 euro. Hence the total cost of the screening programme amounted to ~8000 euro. Had we omitted the first tier in female patients to apply the second tier directly, those costs would have been considerably higher [(278 x 6.25 euro) + (2 x 337.5 euro) + (395 x 337.5 euro) = 135 725 euro], with only a limited increase in the power of our screening.

Andrade et al. recently discussed the possible limitations of the blood spot assay [30]. These should of course be kept in mind, but need further confirmation as these statements were based on the screening of a very heterogenous patient population (chronic renal failure, patients on renal replacement therapy, transplant patients) and no GLA mutation carriers were detected. The validation of our blood spot test for alpha-galactosidase activity was reported previously [13] and showed reproducible results.

Our results show that this two-tier method can detect Fabry disease in renal transplant recipients, even in atypical clinical settings and in patients not previously considered high-risk (renal transplant recipients). As we mentioned previously [13], the detection of a GLA mutation is not only of vital importance to the patient under study, but also to putatively affected family members, who can be treated in an earlier phase of the disease, before vital organ damage is installed. Indeed, in the reported family, a hitherto asymptomatic grandson was identified. ERT in this patient may lead to prevention of organ damage, stabilization of incurred damage or even improvement. In contrast, the obligatory heterozygous carrier state of the patient's mother who died at 91 years also suggests that the possible ERT of these carriers should be carefully balanced with the life expectancy and influence of the expensive treatment on changing this life expectancy.



   Acknowledgments
 
The authors wish to thank all participating NBVN centres for their effort to cooperate in the screening programme. This screening was made possible by a grant to the NBVN registry by Genzyme Inc.

Conflict of interest statement. The results presented in this paper have not been published previously except for the description published by Cassiman et al., dealing with the supposed relationship in the index patient between renal cell carcinoma and Fabry disease (see references).



   Notes
 
* The authors contributed equally to the study. Back



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Brady R, Gal A, Bradley R, et al. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med (1967) 276:1163–1167.[Web of Science][Medline]
  2. Desnick R, K Y Allen K, Desnick S, et al. Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes. Alpha-galactosidase activities in plasma, serum, urine, and leukocytes. J Lab Clin Med (1973) 81:157–171.[Web of Science][Medline]
  3. Meikle P, Hopwood J, Clague A, et al. Prevalence of lysosomal storage disorders. JAMA (1999) 281:249–254.[Abstract/Free Full Text]
  4. Branton M, Schiffmann R, Sabnis S, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase a activity and genetic mutations on clinical course. Medicine (Baltimore) (2002) 81:122–138.[CrossRef][Medline]
  5. Desnick R, Brady R. Fabry disease in childhood. J Pediatr (2004) 144:S20–S26.[CrossRef][Web of Science][Medline]
  6. Deegan P, Baehner A, Barba Romero M. European FOS Investigators. Natural history of Fabry disease in females in the Fabry outcome survey. J Med Genet (2006) 43:347–352.[Abstract/Free Full Text]
  7. Whybra C, Kampmann C, Willers I, et al. Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis (2001) 24:715–724.[CrossRef][Web of Science][Medline]
  8. Kampmann C, Baehner F, Whybra C, et al. Cardiac manifestations of Anderson-Fabry disease in heterozygous females. J Am Coll Cardiol (2002) 40:1668–1674.[Abstract/Free Full Text]
  9. Linthorst G, Hollak C, Korevaar J, et al. Alpha-galactosidase a deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease. Nephrol Dial Transplant (2003) 18:1581–1584.[Abstract/Free Full Text]
  10. Nakao S, Kodama C, Takenaka T, et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a ‘renal variant’ phenotype. Kidney Int (2003) 64:801–807.[CrossRef][Web of Science][Medline]
  11. Kotanko P, Kramar R, Devrnja D, et al. Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. J Am Soc Nephrol (2004) 15:1323–1329.[Abstract/Free Full Text]
  12. Merta M, Reiterova J, Ledvinova J, et al. A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population. Nephrol Dial Transplant (2007) 22:179–186.[Abstract/Free Full Text]
  13. Terryn W, Poppe B, Wuyts B, et al. Two-tier approach for the detection of alpha-galactosidase A deficiency in a predominantly female haemodialysis population. Nephrol Dial Transplant (2008) 23:294–300.[Abstract/Free Full Text]
  14. Nakao S, Takenaka T, Maeda M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med (1995) 333:288–293.[Abstract/Free Full Text]
  15. Ommen S, Nishimura R, Edwards W. Fabry disease: a mimic for obstructive hypertrophic cardiomyopathy. Heart (2003) 89:819–820.[Free Full Text]
  16. Sachdev B, Takenaka T, Teraguchi H, et al. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation (2002) 105:1407–1411.[Abstract/Free Full Text]
  17. Chimenti C, Pieroni M, Morgante E, et al. Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation (2004) 110:1047–1053.[Abstract/Free Full Text]
  18. Brouns R, Sheorajpanday R, Braxel E, et al. A retrospective Belgian study on the prevalence of Fabry disease in young patients with cryptogenic stroke. Clin Neurol Neurosurg (2007) 109:479–484.[CrossRef][Web of Science][Medline]
  19. Rolfs A, Bottcher T, Zschiesche M, et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet (2005) 366:1794–1796. Erratum in: Lancet 2006; 368: 2210.[CrossRef][Web of Science][Medline]
  20. Spada M, Pagliardini S, Yasuda M, et al. High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet (2006) 79:31–40.[CrossRef][Web of Science][Medline]
  21. Eng C, Guffon N, Wilcox W. the International Collaborative Fabry Disease Study Group. Safety and efficacy of recombinant human {alpha}-galactosidase a replacement therapy in Fabry's disease. N Engl J Med (2001) 345:9–16.[Abstract/Free Full Text]
  22. Schiffmann R, Kopp J, Austin H, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA (2001) 285:2743–2749.[Abstract/Free Full Text]
  23. Meikle P, Ranieri E, Simonsen H, et al. Newborn screening for lysosomal storage disorders: clinical evaluation of a two-tier strategy. Pediatrics (2004) 114:909–916.[Abstract/Free Full Text]
  24. Chamoles N, Blanco M, Gaggioli D. Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta (2001) 308:195–196.[CrossRef][Web of Science][Medline]
  25. Eng C, Resnick-Silverman L, Niehaus D, et al. Nature and frequency of mutations in the alpha-galactosidase a gene that cause Fabry disease. Am J Hum Genet (1993) 53:1186–1197.[Web of Science][Medline]
  26. Cassiman D, Claes D, Lerut E, et al. Bilateral renal cell carcinoma development in long-term Fabry disease. J Inherit Metab Dis (2007) 30:830–831.[CrossRef][Web of Science][Medline]
  27. Pieroni M, Chimenti D, De Cobelli M, et al. Fabry's disease cardiomyopathy : echocardiographic detection of endomyocardial glycosphyngolipid compartmentalization. J Am Coll Cardiol (2006) 47:1663–1671.[Abstract/Free Full Text]
  28. Takanashi J, Barkovich AJ, Dillon WP, et al. T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabry disease. Am J Neuroradiol (2003) 24:916–921.[Abstract/Free Full Text]
  29. Linthorst G, Vedder A, Aerts J, et al. Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta (2005) 353:201–203.[CrossRef][Web of Science][Medline]
  30. Andrade J, Waters P, Singh R, et al. Screening for Fabry disease in patients with chronic kidney disease: limitations of plasma {alpha}-galactosidase assay as a screening test. Clin J Am Soc Nephrol (2008) 3:139–145.[Abstract/Free Full Text]
Received for publication: 3. 2.08
Accepted in revised form: 10. 6.08


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