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Case report: is low α-Gal enzyme activity sufficient to establish the diagnosis of Fabry disease?

Abstract

Fabry disease is an X-linked lysosomal storage disease due to alpha-galactosidase A (α-Gal A) deficient activity which leads to the accumulation of glucoesphingolipids, such as globotriaosilceramide. There are over 700 known mutations of the enzyme gene, and most of them cause Fabry Disease. This case report describes a hemodialysis patient with a rare and controversial GLA gene mutation, the D313Y. The medecial investigation confirmed that D313Y is an alpha-galactosidase A sequence variant that causes pseudo deficient enzyme activity in plasma but not Fabry disease. Thus, clinical symptoms that prompted Fabry disease investigation could not be attributable to Fabry disease and therefore enzyme replacement therapy was not indicated.

Keywords:
Fabry disease; diagnosis; genetic diseases, X-linked; alpha-galactosidase; renal dialysis; mutation

Resumo

Doença de Fabry (DF) é uma doença de depósito lisossômico ligada ao cromossomo X, causada pela deficiência da enzima alfa-galactosidase A (α-Gal A) que leva ao acúmulo de glicoesfingolipídeos, principalmente globotriaosilceramide. Existem mais de 700 mutações conhecidas do gene da enzima, a maioria delas são causadoras de DF. Este relato de caso descreve sobre um paciente em hemodiálise com uma mutação do gene GLA rara e controversa, a D313Y. A investigação médica confirmou que D313Y é uma variante que leva à pseudodeficiência plasmática da enzima, mas não ocasiona DF. Assim, os sintomas clínicos que induziram a investigação da doença não devem ser atribuídos à DF e, portanto, não foi indicada a terapia de reposição enzimática.

Palavras-chave:
doença de Fabry; diagnóstico; doenças genéticas ligadas ao cromossomo X; alfa-galactosidase; diálise renal; mutação

Introduction

Fabry disease is an X-linked lysosomal storage disease caused by alpha-galactosidase A (GLA) gene mutation, which leads to an alfa-galactosidase A enzyme (α-Gal A) deficiency and consequently accumulation of glycosphingolipids, mainly globotriaosilceramide. Globotriaosylceramide accumulates within lysosomes throughout the body, leading to complications on different organs and systems, such as central and peripheral nervous systems, the kidneys and the cardiovascular system.11 Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30. DOI: http://dx.doi.org/10.1186/1750-1172-5-30
http://dx.doi.org/10.1186/1750-1172-5-30...
More than 700 mutations in the GLA gene have been recognized.22 HGMD® home page. The Human Gene Mutation Database [cited 2017 Aug 14]. Available from: http://www.hgmd.cf.ac.uk/ac/index.php
http://www.hgmd.cf.ac.uk/ac/index.php...
Importantly, GLA mutations can also be non-pathogenic.

Classical manifestations of Fabry disease begin on life's first decade, which comprise neuropathic pain, hypohidrosis, angiokeratomas, cochleovestibular and gastrointestinal disorders. Usually, after the second decade of life, transient vascular ischemia and stroke, chronic kidney disease (CKD), manifested by proteinuria and/or reduced glomerular filtration rate, cornea verticillata, cardiomyopathy and arrhythmia may appear.11 Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30. DOI: http://dx.doi.org/10.1186/1750-1172-5-30
http://dx.doi.org/10.1186/1750-1172-5-30...
Late-onset phenotypes with predominance of the involvement of the heart or the kidneys have also been described.33 Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med 1995;333:288-93. PMID: 7596372 DOI: http://dx.doi.org/10.1056/NEJM199508033330504
http://dx.doi.org/10.1056/NEJM1995080333...
,44 Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. Kidney Int 2003;64:801-7. DOI: http://dx.doi.org/10.1046/j.1523-1755.2003.00160.x
http://dx.doi.org/10.1046/j.1523-1755.20...

Fabry disease has been described in several ethnic groups with an estimated prevalence of 1:40,000 to 1:170,000 males.11 Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30. DOI: http://dx.doi.org/10.1186/1750-1172-5-30
http://dx.doi.org/10.1186/1750-1172-5-30...
Taking into consideration that Fabry disease is rare and its clinical manifestations may be slight, particularly in the late onset subtypes, one should be aware that the true prevalence of Fabry disease has probably been underestimated. In agreement with this hypothesis, recent screening surveys in newborn reported an incidence of 1:3,100.55 Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31-40. PMID: 16773563 DOI: http://dx.doi.org/10.1086/504601
http://dx.doi.org/10.1086/504601...
Among the high-risk population, such as individuals with idiopathic left ventricular hypertrophy or those in renal replacement therapy, the prevalence seems to be higher.11 Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30. DOI: http://dx.doi.org/10.1186/1750-1172-5-30
http://dx.doi.org/10.1186/1750-1172-5-30...

In Brazil, the prevalence of Fabry disease among male hemodialysis patients ranges from 0.12% to 0.57%.66 Silva CA, Barreto FC, dos Reis MA, Moura Júnior JA, Cruz CM. Target Screening of Fabry Disease in Male Hemodialysis Patients in Brazil Highlights Importance of Family Screening. Nephron 2016;134:221-30. DOI: http://dx.doi.org/10.1159/000448740
http://dx.doi.org/10.1159/000448740...

7 Vale NFD, Silva ABR, Veras AB, Monteiro FMR, Sousa JLM, Bezerra VL, et al. Diagnosis of Fabry Disease in Subjects on Hemodialysis in Piauí State: Role of Screening and Case Studies. J Bras Nefrol 2008;30:259-63.
-88 Porsch DB, Nunes AC, Milani V, Rossato LB, Mattos CB, Tsao M, et al. Fabry disease in hemodialysis patients in southern Brazil: prevalence study and clinical report. Ren Fail 2008;30:825-30. DOI: http://dx.doi.org/10.1080/08860220802353777
http://dx.doi.org/10.1080/08860220802353...
The development of cheaper diagnostic tools, such as the dried blood spot on filter paper, has facilitated the screening of high-risk populations. This strategy may allow the identification of Fabry disease patients in renal replacement therapy centers, spreading the diagnosis to relatives in earlier stages. In the other hand, nephrologists will be challenged to confirm or refuse the clinical diagnosis of Fabry disease from a positive screening result in each tested patient.

Herein, in this case report, we describe a carrier of the D313Y mutation, identified by screening of Fabry disease in hemodialysis male patients. This mutation is considered controversial in the literature. The patient had clinical findings, such as left ventricular hypertrophy, arrhythmia and end-stage renal disease (ESRD), which could be attributed to Fabry disease. This diagnosis was not confirmed, though. This case report highlights the importance of careful evaluation of suspected cases of Fabry disease, particularly when controversial mutations, new mutations or mutations of unknown significance are detected, in order to avoid misdiagnosis and inadequate indication of enzyme replacement therapy (ERT).

Case report

A 44-year-old man on hemodialysis for seven years was enrolled in a high risk population screening for Fabry disease in 2015. His α-Gal A enzyme activity in dried blood spot was 1.24 µmol/L/h (reference: > 2.2 µmol/L/h). Due to low enzymatic activity, genetic test was performed. The nonsense mutation p.D313Y in exon 6, in homozygosis, was detected.

Patient reported periorbital swelling and fatigue for 10 years and systemic hypertension for more than 20 years. He denied ischemic coronary artery disease or stroke. He had no family history of CKD. He was a current smoker (40 packs/year); and stopped alcohol consumption 4 years before. He was taking the following medications: clonidine, atenolol, calcium carbonate, and erythropoietin. He had episodes of arrhythmia during hemodialysis session and discoid lupus diagnosis for 3 years, for which he has been using corticosteroid and chloroquine.

The presence of clinical manifestations (Table 1) of Fabry disease was further investigated. The electrocardiogram revealed sinus rhythm, left ventricular hypertrophy and subepicardial ischemia of inferior and lateral walls. The echocardiogram showed a moderate concentric hypertrophy of the left ventricle with preserved dimension and function. Cornea verticillata was not detected. Magnetic resonance imaging (MRI), indicated to investigate white matter lesions, was not performed due to the risk of nephrogenic fibrosis secondary to gadolinium exposure.99 Karam MAH. Risk of nephrogenic systemic fibrosis with the use of gadolinium containing contrast media on chronic kidney disease. J Bras Nefrol 2008;30:66-71.

Table 1
Correspondence among main clinical manifestations in fabry disease and in d131y hemodialysis patient

Importantly, the patient was submitted to a kidney biopsy in other nephrology service, before starting hemodialysis. The kidney tissue was stained with hematoxylin and eosin, periodic acid-Schiff, Masson trichrome, and silver. It contained 8 glomerulae (5 sclerotic, 3 with hyalinosis of glomerular capillary). Tubules and intersticium presented signs of chronicity. Severe arteriosclerosis and arteriolosclerosis were the most significant alterations detected in the vascular compartment. In conclusion, histopathologic findings were suggestive of hypertensive nephrosclerosis. No histologic changes of Fabry nephropathy, such as vacuolization of podocytes, were identified by light microscopy.

Regarding his family history, the patient had 2 daughters. The genetic analysis performed in one of them unveiled, as expected, the same mutation p.D313Y. The other daughter refused the genetic test. Both daughters had no clinical manifestations of Fabry disease.

Discussion

The patient presented the mutation p.D313Y, substitution of GAT for TAT in cDNA 937 nucleotide, in the GLA gene. This mutation causes a unique substitution of an aspartate for a tyrosine, in +313 position.1010 Lenders M, Duning T, Schelleckes M, Schmitz B, Stander S, Rolfs A, et al. Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene. PLoS One 2013;8:e55565. DOI: http://dx.doi.org/10.1371/journal.pone.0055565
http://dx.doi.org/10.1371/journal.pone.0...
This leads to the formation of unstable α-Gal A in plasma pH. This mutated enzyme preserves ~60% of its physiological activity in lysosome, whose pH is 4.6. This is called enzymatic pseudodeficiency. It has been demonstrated that carriers of D313Y mutation have a diminished α-Gal A activity in plasma while its intracellular activity remains preserved.1010 Lenders M, Duning T, Schelleckes M, Schmitz B, Stander S, Rolfs A, et al. Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene. PLoS One 2013;8:e55565. DOI: http://dx.doi.org/10.1371/journal.pone.0055565
http://dx.doi.org/10.1371/journal.pone.0...
Thus, if the dosage of α-Gal A enzymatic activity in leukocytes, and not only in dried blood spot, could have been performed, it would have been normal.

Most clinical studies have supported the hypothesis that D313Y mutation is not pathogenic.1111 Oder D, Üçeyler N, Liu D, Hu K, Petritsch B, Sommer C, et al. Organ manifestations and long-term outcome of Fabry disease in patients with the GLA haplotype D313Y. BMJ Open 2016;8:e010422. DOI: http://dx.doi.org/10.1136/bmjopen-2015-010422
http://dx.doi.org/10.1136/bmjopen-2015-0...
Lyso-globotriaosylceramide, a substrate of globotriaosylceramide molecule, exerts a well-established role in Fabry disease pathogenicity, therefore considered a biomarker of disease severity and prognosis.1212 Niemann M, Rolfs A, Störk S, Bijnens B, Breunig F, Beer M, et al. Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 2014;7:8-16. DOI: http://dx.doi.org/10.1161/CIRCGENETICS.113.000249
http://dx.doi.org/10.1161/CIRCGENETICS.1...
Its plasmatic levels are increased in patients with mutations that are proven to be pathogenic, but not in D313Y carriers.1212 Niemann M, Rolfs A, Störk S, Bijnens B, Breunig F, Beer M, et al. Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 2014;7:8-16. DOI: http://dx.doi.org/10.1161/CIRCGENETICS.113.000249
http://dx.doi.org/10.1161/CIRCGENETICS.1...
Otherwise, it has been suggested an association between D313Y mutation and white matter lesions.1010 Lenders M, Duning T, Schelleckes M, Schmitz B, Stander S, Rolfs A, et al. Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene. PLoS One 2013;8:e55565. DOI: http://dx.doi.org/10.1371/journal.pone.0055565
http://dx.doi.org/10.1371/journal.pone.0...

The physical examination did not reveal any clinical sign of the disease, such as angiokeratoma and cornea verticillata. Importantly, the patient was using chloroquine, which can lead to the development of cornea verticillata, also described as a characteristic finding in Fabry disease and present in almost all heterozygous male11 Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30. DOI: http://dx.doi.org/10.1186/1750-1172-5-30
http://dx.doi.org/10.1186/1750-1172-5-30...
. Other drugs that may cause cornea verticillata include amiodarone and indomethacin.1313 Hollander DA, Aldave AJ. Drug-induced corneal complications. Curr Opin Ophthalmol 2004;15:541-8. DOI: http://dx.doi.org/10.1097/01.icu.0000143688.45232.15
http://dx.doi.org/10.1097/01.icu.0000143...
There is no difference between drug-related and Fabry disease-related cornea verticillata. The iatrogenic form disappears after discontinuation of the drug, though.1313 Hollander DA, Aldave AJ. Drug-induced corneal complications. Curr Opin Ophthalmol 2004;15:541-8. DOI: http://dx.doi.org/10.1097/01.icu.0000143688.45232.15
http://dx.doi.org/10.1097/01.icu.0000143...
Interestingly, patients in use of chloroquine and amiodarone may develop lipidic inclusions in renal tissue similar to the those found in Fabry disease patients.1414 Najafian B, Fogo AB, Lusco MA, Alpers CE. AJKD Atlas of Renal Pathology: Fabry nephropathy. Am J Kidney Dis 2015;66:e35-6. PMID: 26498420 DOI: http://dx.doi.org/10.1053/j.ajkd.2015.08.006
http://dx.doi.org/10.1053/j.ajkd.2015.08...

The detection of low α-Gal A activity associated with high plasma or urinary levels of globotriaosylceramide or lyso-globotriaosylceramide and the identification of an affected family member with classical manifestations are criteria that establish the diagnosis of Fabry disease when doubt is present.1515 Van Der Tol L, Svarstad E, Ortiz A, Tøndel C, Oliveira JP, Vogt L, et al. Chronic kidney disease and an uncertain diagnosis of Fabry disease: Approach to a correct diagnosis. Mol Genet Metab 2015;114:242-7. DOI: http://dx.doi.org/10.1016/j.ymgme.2014.08.007
http://dx.doi.org/10.1016/j.ymgme.2014.0...
Plasma levels of globotriaosylceramide or lyso-globotriaosylceramide could not be evaluated in our patient.

His daughters, the only family members with whom he had contact, are obligatory carriers of the mutation. They had no clinical manifestation. The demonstration of tissue globotriaosylceramide deposition is considered to be the gold standard for a definitive diagnosis of Fabry Disease.1515 Van Der Tol L, Svarstad E, Ortiz A, Tøndel C, Oliveira JP, Vogt L, et al. Chronic kidney disease and an uncertain diagnosis of Fabry disease: Approach to a correct diagnosis. Mol Genet Metab 2015;114:242-7. DOI: http://dx.doi.org/10.1016/j.ymgme.2014.08.007
http://dx.doi.org/10.1016/j.ymgme.2014.0...
Our patient had been submitted to a kidney biopsy few months before starting renal replacement therapy. The microscopic findings by light microscopy were suggestive of hypertensive nephrosclerosis, without histological findings of Fabry nephropathy (Table 2).1414 Najafian B, Fogo AB, Lusco MA, Alpers CE. AJKD Atlas of Renal Pathology: Fabry nephropathy. Am J Kidney Dis 2015;66:e35-6. PMID: 26498420 DOI: http://dx.doi.org/10.1053/j.ajkd.2015.08.006
http://dx.doi.org/10.1053/j.ajkd.2015.08...

Table 2
Histological findings in fabry nephropathy

A few considerations regarding kidney biopsy in Fabry disease should be mentioned. First, histological findings may be overlooked if a biopsy is not examined by an experienced nephropatologist. Second, toluidine-blue stained is helpful to demonstrate cytoplasmic deposits. Finally, a tissue fragment for electron microscopy should always be obtained, even when this technique is not immediately available, it should be required for further investigation.

A complete investigation of Fabry disease could not be performed in the present case. Semi-thin section stained with toluidine-blue and electron microscopy, Cardiac and cerebral MRI, useful tools to detect myocardial fibrosis and white matter lesions, respectively, could not be performed. Nevertheless, based on literature review and on clinical and laboratory investigation, it was concluded that the patient does not have Fabry disease. Hence, ERT was not indicated.

Conclusion

In our patient, the D313Y mutation did not cause Fabry disease. The lack of clinical manifestations and particularly the absence of histological findings of Fabry nephropathy allowed us to exclude the diagnosis and, consequently, to not indicate ERT. The diagnosis of Fabry Disease should not be based only on the presence of low enzymatic activity. In this regard, in a recent screening among male hemodialysis patients in Bahia that enrolled 2583 patients, pathogenic GLA mutation was detected in 3 out of 72 patients with low enzyme activity, suggesting that diagnosis of Fabry Disease in males may be associated with a large number of false-positive cases (i.e., low specificity) if based only on enzymatic activity. Other important information that genotyping may provide is the type of the GLA mutation, since some misense mutations have been demonstrated to be amenable for treatment with pharmacologic chaperone.1616 Germain DP, Hughes DA, Nicholls K, Bichet DG, Giugliani R, Wilcox WR, et al. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med. 2016;375:545-55 DOI: 10.1056/NEJMoal1510198
https://doi.org/10.1056/NEJMoal1510198...

Medical practice has embraced new helpful technologies during the last decades, such as genotyping. Nevertheless, the diagnosis should always be based on a detailed medical and family history as well as on physical examination. One should be aware that, beyond indicating an unnecessary treatment, an incorrect diagnosis of a hereditary disorder may impose to patients and their families an additional emotional burden, which will certainly have a negative impact in their sense of well-being and quality of life.

References

  • 1
    Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30. DOI: http://dx.doi.org/10.1186/1750-1172-5-30
    » http://dx.doi.org/10.1186/1750-1172-5-30
  • 2
    HGMD® home page. The Human Gene Mutation Database [cited 2017 Aug 14]. Available from: http://www.hgmd.cf.ac.uk/ac/index.php
    » http://www.hgmd.cf.ac.uk/ac/index.php
  • 3
    Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med 1995;333:288-93. PMID: 7596372 DOI: http://dx.doi.org/10.1056/NEJM199508033330504
    » http://dx.doi.org/10.1056/NEJM199508033330504
  • 4
    Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. Kidney Int 2003;64:801-7. DOI: http://dx.doi.org/10.1046/j.1523-1755.2003.00160.x
    » http://dx.doi.org/10.1046/j.1523-1755.2003.00160.x
  • 5
    Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31-40. PMID: 16773563 DOI: http://dx.doi.org/10.1086/504601
    » http://dx.doi.org/10.1086/504601
  • 6
    Silva CA, Barreto FC, dos Reis MA, Moura Júnior JA, Cruz CM. Target Screening of Fabry Disease in Male Hemodialysis Patients in Brazil Highlights Importance of Family Screening. Nephron 2016;134:221-30. DOI: http://dx.doi.org/10.1159/000448740
    » http://dx.doi.org/10.1159/000448740
  • 7
    Vale NFD, Silva ABR, Veras AB, Monteiro FMR, Sousa JLM, Bezerra VL, et al. Diagnosis of Fabry Disease in Subjects on Hemodialysis in Piauí State: Role of Screening and Case Studies. J Bras Nefrol 2008;30:259-63.
  • 8
    Porsch DB, Nunes AC, Milani V, Rossato LB, Mattos CB, Tsao M, et al. Fabry disease in hemodialysis patients in southern Brazil: prevalence study and clinical report. Ren Fail 2008;30:825-30. DOI: http://dx.doi.org/10.1080/08860220802353777
    » http://dx.doi.org/10.1080/08860220802353777
  • 9
    Karam MAH. Risk of nephrogenic systemic fibrosis with the use of gadolinium containing contrast media on chronic kidney disease. J Bras Nefrol 2008;30:66-71.
  • 10
    Lenders M, Duning T, Schelleckes M, Schmitz B, Stander S, Rolfs A, et al. Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene. PLoS One 2013;8:e55565. DOI: http://dx.doi.org/10.1371/journal.pone.0055565
    » http://dx.doi.org/10.1371/journal.pone.0055565
  • 11
    Oder D, Üçeyler N, Liu D, Hu K, Petritsch B, Sommer C, et al. Organ manifestations and long-term outcome of Fabry disease in patients with the GLA haplotype D313Y. BMJ Open 2016;8:e010422. DOI: http://dx.doi.org/10.1136/bmjopen-2015-010422
    » http://dx.doi.org/10.1136/bmjopen-2015-010422
  • 12
    Niemann M, Rolfs A, Störk S, Bijnens B, Breunig F, Beer M, et al. Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circ Cardiovasc Genet 2014;7:8-16. DOI: http://dx.doi.org/10.1161/CIRCGENETICS.113.000249
    » http://dx.doi.org/10.1161/CIRCGENETICS.113.000249
  • 13
    Hollander DA, Aldave AJ. Drug-induced corneal complications. Curr Opin Ophthalmol 2004;15:541-8. DOI: http://dx.doi.org/10.1097/01.icu.0000143688.45232.15
    » http://dx.doi.org/10.1097/01.icu.0000143688.45232.15
  • 14
    Najafian B, Fogo AB, Lusco MA, Alpers CE. AJKD Atlas of Renal Pathology: Fabry nephropathy. Am J Kidney Dis 2015;66:e35-6. PMID: 26498420 DOI: http://dx.doi.org/10.1053/j.ajkd.2015.08.006
    » http://dx.doi.org/10.1053/j.ajkd.2015.08.006
  • 15
    Van Der Tol L, Svarstad E, Ortiz A, Tøndel C, Oliveira JP, Vogt L, et al. Chronic kidney disease and an uncertain diagnosis of Fabry disease: Approach to a correct diagnosis. Mol Genet Metab 2015;114:242-7. DOI: http://dx.doi.org/10.1016/j.ymgme.2014.08.007
    » http://dx.doi.org/10.1016/j.ymgme.2014.08.007
  • 16
    Germain DP, Hughes DA, Nicholls K, Bichet DG, Giugliani R, Wilcox WR, et al. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med. 2016;375:545-55 DOI: 10.1056/NEJMoal1510198
    » https://doi.org/10.1056/NEJMoal1510198

Publication Dates

  • Publication in this collection
    Jul-Sep 2017

History

  • Received
    18 Oct 2016
  • Accepted
    8 Nov 2016
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