Metachromatic leukodystrophy: Characterization of two (p.Leu433Val, p.Gly449Arg) arylsulfatase A mutations

Wang,Yangyang; Chen,Xiang; Liu,Chan; Wu,Shamin; Xie,Qingfeng; Hu,Quan; Chen,Shan; Liu,Yiwei

doi:10.3892/etm.2019.7760

September-2019 Volume 18 Issue 3

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September-2019 Volume 18 Issue 3

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Article Open Access

Metachromatic leukodystrophy: Characterization of two (p.Leu433Val, p.Gly449Arg) arylsulfatase A mutations

Authors:
- Yangyang Wang
- Xiang Chen
- Chan Liu
- Shamin Wu
- Qingfeng Xie
- Quan Hu
- Shan Chen
- Yiwei Liu
View Affiliations / Copyright

Affiliations: Department of Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China

Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
Pages: 1738-1744
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Published online on: July 9, 2019

https://doi.org/10.3892/etm.2019.7760
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Abstract

Metachromatic leukodystrophy disorder (MLD) is an autosomal recessive lysosomal storage disease. The disease is primarily caused by a deficiency in the enzyme arylsulfatase A (ASA), which is encoded by the ARSA gene. A total of 254 mutations have been reported in different populations. The present study aimed to detect causative gene mutations in an atypical case presenting with attention deficit hyperactivity disorder through whole‑exome sequencing. Of note, the patient's mother is from a consanguineous family. Compound heterozygous variants (c.1297C>G) + (c.1345G>A) [(p.Leu433Val) + (p.Gly449Arg)] were identified in exon 8 in the ARSA gene of the pediatric patient. The two missense mutations identified have not been previously reported, to the best of our knowledge. Furthermore, an in silico analysis and multiple phylogenetic tree analyses of ARSA homologs were performed to predict the effects of the two novel mutations. Serial changes were observed in the patient with MLD at follow‑up visits over 6 years. However, brain MRI images demonstrated no notable progression and the number of ASA enzymes was stable. Also, the results of neurodevelopmental assessment showed that the patient was diagnose with ADHD. These data may offer a potential explanation of the genotype‑phenotype correlation in MLD and enhance the spectrum of mutations associated with the condition.

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1	Coulter-Mackie MB, Gagnier L, Beis MJ, Applegarth DA, Cole DEC, Gordon K and Ludman MD: Metachromatic leucodystrophy in three families from Nova Scotia, Canada: a recurring mutation in the arylsulphatase A gene. Journal of Medical Genetics. 34:493–498. 1997. View Article : Google Scholar : PubMed/NCBI
2	Aggarwal S, Yurlova L and Simons M: Central nervous system myelin: Structure, synthesis and assembly. Trends Cell Biol. 21:585–593. 2011. View Article : Google Scholar : PubMed/NCBI
3	Bosio A, Binczek E and Stoffel W: Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebrosides synthesis. Proc Natl Acad Sci USA. 93:13280–13285. 1996. View Article : Google Scholar : PubMed/NCBI
4	Brimley CJ, Lopez J, van Haren K, Wilkes J, Sheng X, Nelson C, Korgenski EK, Srivastava R and Bonkowsky JL: National variation in costs and mortality for leukodystrophy patients in US children's hospitals. Pediatr Neurol. 49:156–162,e1. 2013. View Article : Google Scholar : PubMed/NCBI
5	Shahzad MA, Khaliq S, Amar A and Mahmood S: Metachromatic leukodystrophy (MLD): A pakistani family with novel ARSA gene mutation. J Mol Neurosci. 63:84–90. 2017. View Article : Google Scholar : PubMed/NCBI
6	Gieselmann V, Polten A, Kreysing J and von Figura K: Molecular genetics of metachromatic leukodystrophy. J Inherit Metab Dis. 13:222–227. 1994.
7	Simell O: The metabolic and molecular bases of inherited disease. JAMA. 286:23292001.
8	Lugowska A, Mierzewska H, Bekiesińska-Figatowska M, Szczepanik E, Goszczańska-Ciuchta A and Bednarska-Makaruk M: A homozygote for the c.459+1G>A mutation in the ARSA gene presents with cerebellar ataxia as the only first clinical sign of metachromatic leukodystrophy. J Neurol Sci. 338:214–217. 2014. View Article : Google Scholar : PubMed/NCBI
9	Barboura I, Ferchichi S, Dandana A, Jaidane Z, Ben Khelifa S, Chahed H, Ben Mansour R, Chebel S, Maire I and Miled A: Metachromatic leucodystrophy. Clinical, biological, and therapeutic aspects. Ann Biol Clin (Paris). 68:385–391. 2010.(In French). PubMed/NCBI
10	Kehrer C, Groeschel S, Kustermann-Kuhn B, Bürger F, Köhler W, Kohlschütter A, Bley A, Steinfeld R, Gieselmann V and Krägeloh-Mann I; German LEUKONET, : Language and cognition in children with metachromatic leukodystrophy: Onset and natural course in a nationwide cohort. Orphanet J Rare Dis. 9:182014. View Article : Google Scholar : PubMed/NCBI
11	Barrell C: Juvenile metachromatic leukodystrophy: Understanding the disease and implications for nursing care. J Pediatr Oncol Nurs. 24:64–69. 2007. View Article : Google Scholar : PubMed/NCBI
12	Patil SA and Maegawa GH: Developing therapeutic approaches for metachromatic leukodystrophy. Drug Des Devel Ther. 7:729–745. 2013.PubMed/NCBI
13	Gieselmann V, Fluharty AL, Tønnesen T and Von Figura K: Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy. Am J Hum Genet. 49:407–413. 1991.PubMed/NCBI
14	Regis S, Corsolini F, Stroppiano M, Cusano R and Filocamo M: Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity. Hum Genet. 110:351–355. 2002. View Article : Google Scholar : PubMed/NCBI
15	Polten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K and Gieselmann V: Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med. 324:18–22. 1991. View Article : Google Scholar : PubMed/NCBI
16	Tinsa F, Caillaud C, Vanier MT, Bousnina D, Boussetta K and Bousnina S: An unusual homozygous arylsulfatase: A pseudodeficiency in a metachromatic leukodystrophy tunisian patient. J Child Neurol. 25:82–86. 2010. View Article : Google Scholar : PubMed/NCBI
17	Penzien JM, Kappler J, Herschkowitz N, Schuknecht B, Leinekugel P, Propping P, Tønnesen T, Lou H, Moser H, Zierz S, et al: Compound heterozygosity for metachromatic leukodystrophy and arylsulfatase A pseudodeficiency alleles is not associated with progressive neurological disease. Am J Hum Genet. 52:557–564. 1993.PubMed/NCBI
18	Fluharty AL: Arylsulfatase A Deficiency-GeneReviews^®-NCBI Bookshelf. University of Washington Seattle. 2014.
19	Aubourg P, Sevin C and Cartier N: Mouse Models of Metachromatic Leukodystrophy and Adrenoleukodystrophy. De Deyn P and Van Dam D: Animal Models of Dementia. Neuromethods, Humana Press. 48:493–513. 2011. View Article : Google Scholar
20	Shi H: Metachromatic Leukodystrophy. Chinese Journal of Practical Pediatrics. 507–510. 2009.(In Chinese).
21	The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ARSAApril 23–2019
22	Fishler K, Graliker BV and Koch R: The predictability of intelligence with gesell developmental scales in mentally retarded infants and young children. Am J Ment Defic. 69:515–525. 1965.PubMed/NCBI
23	Huang XN, Zhang Y, Feng WW, Wang HS, Cao B, Zhang B, Yang YF, Wang HM, Zheng Y, Jin XM, et al: Reliability and validity of warning signs checklist for screening psychological, behavioral and developmental problems of children. Zhonghua Er Ke Za Zhi. 55:445–450. 2017.(In Chinese). PubMed/NCBI
24	Roessner U, Wagner C, Kopka J, Trethewey RN and Willmitzer L: Technical advance: Simultaneous analysis of metabolites in potato tuber by gas chromatography-mass spectrometry. Plant J. 23:131–142. 2010. View Article : Google Scholar
25	Dumont R and Willis JO: Wechsler Adult Intelligence Scale-3rd edition. John Wiley. (Sons, Inc). 2008.
26	Wechsler D: Wechsler Adult Intelligence Scale-3rd edition. 1997.
27	Cockcroft K, Alloway T, Copello E and Milligan R: A cross-cultural comparison between South African and British students on the Wechsler Adult Intelligence Scales Third Edition (WAIS-III). Front Psychol. 6:2972015. View Article : Google Scholar : PubMed/NCBI
28	Mailloux Z, Mulligan S, Roley SS, Blanche E, Cermak S, Coleman GG, Bodison S and Lane CJ: Verification and clarification of patterns of sensory integrative dysfunction. Am J Occup Ther. 65:143–151. 2011. View Article : Google Scholar : PubMed/NCBI
29	Mulligan S: Patterns of sensory integration dysfunction: A confirmatory factor analysis. Am J Occupational Therapy. 52:819–828. 1998. View Article : Google Scholar
30	Parham LD, Roley SS, May-Benson TA, Koomar J, Brett-Green B, Burke JP, Cohn ES, Mailloux Z, Miller LJ and Schaaf RC: Development of a Fidelity Measure for Research on the Effectiveness of the Ayres Sensory Integration(R) Intervention[J]. American Journal of Occupational Therapy. 65:133–142. 2011. View Article : Google Scholar : PubMed/NCBI
31	Wang K, Li M and Hakonarson H: Hakonarson, ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38:e1642010. View Article : Google Scholar : PubMed/NCBI
32	Carter NP: Methods and strategies for analyzing copy number variation using DNA microarrays. Nat Genet 39 (7 Suppl). S16–S21. 2007. View Article : Google Scholar
33	Jiang Y, Oldridge DA, Diskin SJ and Zhang NR: CODEX: A normalization and copy number variation detection method for whole exome sequencing. Nucleic Acids Res. 43:e392015. View Article : Google Scholar : PubMed/NCBI
34	Fromer M and Purcell SM: Purcell, using XHMM software to detect copy number variation in whole-exome sequencing data. Curr Protoc Hum Genet. 81:7.23.1–21. 2014. View Article : Google Scholar
35	Tamura K, Peterson D, Peterson N, Stecher G, Nei M and Kumar S: MEGA5: Molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol. 28:2731–2739. 2011. View Article : Google Scholar : PubMed/NCBI
36	Iverson GL: Interpreting change on the WAIS-III/WMS-III in clinical samples. Arch Clin Neuropsychol. 16:183–191. 2001. View Article : Google Scholar : PubMed/NCBI
37	Schwarz JM, Cooper DN, Schuelke M and Seelow D: MutationTaster2: Mutation prediction for the deep-sequencing age. Nat Methods. 11:361–362. 2014. View Article : Google Scholar : PubMed/NCBI
38	Shahzad MA, Khaliq S, Amar A and Mahmood S: Metachromatic leukodystrophy (MLD): A pakistani family with novel ARSA gene mutation. J Mol Neurosci. 63:84–90. 2017. View Article : Google Scholar : PubMed/NCBI
39	Özkan A and Özkara HA: Metachromatic leukodystrophy: Biochemical characterization of two (p.307Glu->Lys, p.318Trp->Cys) arylsulfatase A mutations. Intractable Rare Dis Res. 5:280–283. 2016. View Article : Google Scholar : PubMed/NCBI