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Open Access 01-10-2020 | Leukodystrophy | Original Article

Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

Authors: Shanice Beerepoot, Silvy J.M. van Dooren, Gajja S. Salomons, Jaap Jan Boelens, Edwin H. Jacobs, Marjo S. van der Knaap, André B.P. van Kuilenburg, Nicole I. Wolf

Published in: Neurogenetics | Issue 4/2020

Abstract

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds.

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Von Figura K, Gieselmann V, Jaeken J (2001) Metachromatic leukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease McGraw-Hill, New York, pp 3695–3724

van Rappard DF, Boelens JJ, Wolf NI (2015) Metachromatic leukodystrophy: disease spectrum and approaches for treatment. Best Pract Res Clin Endocrinol Metab 29(2):261–273. https://doi.org/10.1016/j.beem.2014.10.001CrossRefPubMed

Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A (2016) Mutation update of ARSA and PSAP genes causing metachromatic leukodystrophy. Hum Mutat 37(1):16–27. https://doi.org/10.1002/humu.22919CrossRefPubMed

Lorioli L, Cesani M, Regis S, Morena F, Grossi S, Fumagalli F, Acquati S, Redaelli D, Pini A, Sessa M, Martino S, Filocamo M, Biffi A (2014) Critical issues for the proper diagnosis of metachromatic leukodystrophy. Gene 537(2):348–351. https://doi.org/10.1016/j.gene.2013.11.062CrossRefPubMed

Lugowska A, Amaral O, Berger J, Berna L, Bosshard NU, Chabas A, Fensom A, Gieselmann V, Gorovenko NG, Lissens W, Mansson JE, Marcao A, Michelakakis H, Bernheimer H, Ol'khovych NV, Regis S, Sinke R, Tylki-Szymanska A, Czartoryska B (2005) Mutations c.459+1G>A and p.P426L in the ARSA gene: prevalence in metachromatic leukodystrophy patients from European countries. Mol Genet Metab 86(3):353–359. https://doi.org/10.1016/j.ymgme.2005.07.010CrossRefPubMed

Rafi MA, Coppola S, Liu SL, Rao HZ, Wenger DA (2003) Disease-causing mutations in cis with the common arylsulfatase A pseudodeficiency allele compound the difficulties in accurately identifying patients and carriers of metachromatic leukodystrophy. Mol Genet Metab 79(2):83–90. https://doi.org/10.1016/s1096-7192(03)00076-3CrossRefPubMed

Biffi A, Cesani M, Fumagalli F, Del Carro U, Baldoli C, Canale S, Gerevini S, Amadio S, Falautano M, Rovelli A, Comi G, Roncarolo MG, Sessa M (2008) Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation. Clin Genet 74(4):349–357. https://doi.org/10.1111/j.1399-0004.2008.01058.xCrossRefPubMed

Elgun S, Waibel J, Kehrer C, van Rappard D, Bohringer J, Beck-Wodl S, Just J, Schols L, Wolf N, Krageloh-Mann I, Groeschel S (2019) Phenotypic variation between siblings with metachromatic leukodystrophy. Orphanet J Rare Dis 14(1):136. https://doi.org/10.1186/s13023-019-1113-6CrossRefPubMedPubMedCentral

Gieselmann V, Polten A, Kreysing J, von Figura K (1989) Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and N-glycosylation site. Proc Natl Acad Sci U S A 86(23):9436–9440. https://doi.org/10.1073/pnas.86.23.9436CrossRefPubMedPubMedCentral

10.

Lee-Vaupel M, Conzelmann E (1987) A simple chromogenic assay for arylsulfatase A. Clin Chim Acta 164(2):171–180. https://doi.org/10.1016/0009-8981(87)90068-4CrossRefPubMed

11.

Baum HD, Dodgson KS, Spencer B (1959) The assay of arylsulfatase a and B in human urine. Clin Chim Acta 4(3):453–455. https://doi.org/10.1016/0009-8981(59)90119-6CrossRefPubMed

12.

Galjaard H, Van Hoogstraten JJ, De Josselin de Jong JE, Mulder MP (1974) Methodology of the quantitative cytochemical analysis of single or small numbers of cultured cells. Histochem J 6(4):409–429. https://doi.org/10.1007/bf01012433CrossRefPubMed

13.

den Dunnen JT, Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Hum Genet 109(1):121–124. https://doi.org/10.1007/s004390100505CrossRef

14.

Benson DA, Cavanaugh M, Clark K, Karsch-Mizrachi I, Ostell J, Pruitt KD, Sayers EW (2018) GenBank. Nucleic Acids Res 46(D1):D41–D47. https://doi.org/10.1093/nar/gkx1094CrossRefPubMed

15.

DeLano WL (2002) The PyMOL molecular graphics system. DeLano Scientific, San Carlos

16.

Lukatela G, Krauss N, Theis K, Selmer T, Gieselmann V, von Figura K, Saenger W (1998) Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis. Biochemistry 37(11):3654–3664. https://doi.org/10.1021/bi9714924CrossRefPubMed

17.

Team RC (2019) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

18.

Bohringer J, Santer R, Schumacher N, Gieseke F, Cornils K, Pechan M, Kustermann-Kuhn B, Handgretinger R, Schols L, Harzer K, Krageloh-Mann I, Muller I (2017) Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells. Hum Mutat 38(11):1511–1520. https://doi.org/10.1002/humu.23306CrossRefPubMed

19.

von Bulow R, Schmidt B, Dierks T, Schwabauer N, Schilling K, Weber E, Uson I, von Figura K (2002) Defective oligomerization of arylsulfatase a as a cause of its instability in lysosomes and metachromatic leukodystrophy. J Biol Chem 277(11):9455–9461. https://doi.org/10.1074/jbc.M111993200CrossRef

20.

Polten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K, Gieselmann V (1991) Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med 324(1):18–22. https://doi.org/10.1056/NEJM199101033240104CrossRefPubMed

21.

Marcão A, Amaral O, Pinto E, Pinto R, Sá Miranda MC (1999) Metachromatic leucodystrophy in Portugal–finding of four new molecular lesions: C300F, P425T, g. 1190-1191insC, and g. 2408delC. Hum Mutat 13(4):337–338. https://doi.org/10.1002/(sici)1098-1004(1999)13:4<337::aid-humu14>3.0.co;2-9CrossRefPubMed

22.

Kappler J, Sommerlade HJ, von Figura K, Gieselmann V (1994) Complex arylsulfatase A alleles causing metachromatic leukodystrophy. Hum Mutat 4(2):119–127. https://doi.org/10.1002/humu.1380040205CrossRefPubMed

23.

Lugowska A, Wlodarski P, Ploski R, Mierzewska H, Dudzinska M, Matheisel A, Swietochowska H, Tylki-Szymanska A (2009) Molecular and clinical consequences of novel mutations in the arylsulfatase A gene. Clin Genet 75(1):57–64. https://doi.org/10.1111/j.1399-0004.2008.01108.xCrossRefPubMed

24.

Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3(4):285–298. https://doi.org/10.1038/nrg775CrossRefPubMed

25.

Bonkowsky JL, Wilkes J, Bardsley T, Urbik VM, Stoddard G (2018) Association of diagnosis of leukodystrophy with race and ethnicity among pediatric and adolescent patients. JAMA Netw Open 1(7):e185031. https://doi.org/10.1001/jamanetworkopen.2018.5031CrossRefPubMedPubMedCentral

26.

Grineski S, Morales DX, Collins T, Wilkes J, Bonkowsky JL (2020) Geographic and specialty access disparities in US pediatric leukodystrophy diagnosis. J Pediatr 220:1–7. https://doi.org/10.1016/j.jpeds.2020.01.063CrossRef

27.

Hettiarachchi D, Dissanayake VHW (2019) Three novel variants in the arylsulfatase A (ARSA) gene in patients with metachromatic leukodystrophy (MLD). BMC Res Notes 12(1):726. https://doi.org/10.1186/s13104-019-4773-3CrossRefPubMedPubMedCentral

28.

Froukh T (2019) First record mutations in the genes ASPA and ARSA causing leukodystrophy in Jordan. Biomed Res Int 2019:7235914–7235917. https://doi.org/10.1155/2019/7235914CrossRefPubMedPubMedCentral

29.

Shahzad MA, Khaliq S, Amar A, Mahmood S (2017) Metachromatic leukodystrophy (MLD): a Pakistani family with novel ARSA gene mutation. J Mol Neurosci 63(1):84–90. https://doi.org/10.1007/s12031-017-0959-0CrossRefPubMed

30.

Issa AB, Feki FK, Jdila MB, Khabou B, Rhouma BB, Ammar-Keskes L, Triki C, Fakhfakh F (2018) Clinical, molecular, and computational analysis showed a novel homozygous mutation among the substrate-binding site of ARSA protein in consanguineous family with late-infantile MLD. J Mol Neurosci 66(1):17–25. https://doi.org/10.1007/s12031-018-1141-z

31.

Golchin NHM, Malamiri RA, Aminzadeh M, Mohammadi-Asl J (2017) Identification of a novel mutation in ARSA gene in three patients of an Iranian family with metachromatic leukodystrophy disorder. Genet Mol Biol 40(4):759–762. https://doi.org/10.1590/1678-4685-GMB-2016-0110CrossRefPubMedPubMedCentral

32.

Dehghan Manshadi M, Kamalidehghan B, Aryani O, Khalili E, Dadgar S, Tondar M, Ahmadipour F, Yong Meng G, Houshmand M (2017) Four novel ARSA gene mutations with pathogenic impacts on metachromatic leukodystrophy: a bioinformatics approach to predict pathogenic mutations. Ther Clin Risk Manag 13(13):725–731. https://doi.org/10.2147/TCRM.S119967CrossRefPubMedPubMedCentral

33.

Narayanan DL, Matta D, Gupta N, Kabra M, Ranganath P, Aggarwal S, Phadke SR, Datar C, Gowrishankar K, Kamate M, Jain JMN, Dalal A (2019) Spectrum of ARSA variations in Asian Indian patients with Arylsulfatase A deficient metachromatic leukodystrophy. J Hum Genet 64(4):323–331. https://doi.org/10.1038/s10038-019-0560-1CrossRefPubMed

Title: Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients
Authors: Shanice Beerepoot
Silvy J.M. van Dooren
Gajja S. Salomons
Jaap Jan Boelens
Edwin H. Jacobs
Marjo S. van der Knaap
André B.P. van Kuilenburg
Nicole I. Wolf
Publication date: 01-10-2020
Publisher: Springer Berlin Heidelberg
Keyword: Leukodystrophy
Published in: Neurogenetics / Issue 4/2020
Print ISSN: 1364-6745
Electronic ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-020-00621-6

At a glance: The STEP trials

Springer Medicine

Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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