Metachromatic leukodystrophy(MLD) is an autosomal recessive hereditary neurodegenerative lysosomal storage disorder caused by the mutations in arylsulfatase A gene (ARSA), which results in the deficiency of ARSA enzyme. The common clinical characteristics of MLD are abnormal gait, and then gradually appears ataxia, spastic quadriplegia, optic atrophy, cortical blindness, and dementia. We describe two patients in China who were diagnosed with MLD and find that the four ARSA gene mutations (c.1115G>A, c.302G>T, c.893 G> T, and c.302G>T) are associated with MLD, in which c.893 G>T and c.302G>T are novel mutations by gene sequence and clinical manifestations, to further understand the relationship between MLD and ARSA gene.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, di Serio C, Schmidt M, von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L (2013) Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341(6148):1233151
Arbour LT, Silver K, Hechtman P, Treacy EP, Coulter-Mackie MB (2000) Variable onset of metachromatic leukodystrophy in a Vietnamese family. Pediatr Neurol 23:173–176
Biffi A, Capotondo A, Fasano S, Carro U, Marchesini S, Azuma H, Malaguti MC, Amadio S, Brambilla R, Grompe M, Bordignon C, Quattrini A, Naldini L (2006) Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J Clin Investig 116(11):3070–3082
Biffi A, Lucchini G, Rovelli A, Sessa M (2008) Metachromatic leukodystrophy: an overview of current and prospective treatments. Bone Marrow Transplant 42(Suppl 2):S2–S6
Bredius RG et al (2007) Early marrow transplantation in a pre-symptomatic neonate with late infantile metachromatic leukodystrophy does not halt disease progression. Bone Marrow Transplant 39(5):309–310
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
Chen L et al (2018) Identification of novel ARSA mutations in Chinese patients with metachromatic leukodystrophy. Int J Genomics 2018:2361068
Coulter Mackie M et al (1995) Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22. J Med Genet 10:787–791
Doerr J, Böckenhoff A, Ewald B, Ladewig J, Eckhardt M, Gieselmann V, Matzner U, Brüstle O, Koch P (2015) Arylsulfatase a overexpressing human iPSC-derived neural cells reduce CNS sulfatide storage in a mouse model of metachromatic leukodystrophy. Mol Ther 23(9):1519–1531
Eckhardt M (2008) The role and metabolism of sulfatide in the nervous system. Mol Neurobiol 37(2–3):93–103
Gieselmann V, Krageloh-Mann I (2010) Metachromatic leukodystrophy--an update. Neuropediatrics 41(1):1–6
Gieselmann V et al (1994) Molecular genetics of metachromatic leukodystrophy J. Inher Metab Dis 17:500–509
Gort L, Coll MJ, Chabás A (1999) Identifification of 12 novel mutations and two new polymorphisms in the arylsulfatase a gene: haplotype and genotype–phenotype correlation studies in Spanish metachromatic leukodystrophypatients. Hum Mutat 14:240–248
Harvey JS, Nelson PV, Carey WF, Robertson EF, Morris CP (1993) An arylsulfatase a(ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy. Hum Mutat 2:261–267
Heinisch U et al (1995) Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. Am J Hum Genet 56:51–57
Kolnikova M, Jungova P, Skopkova M, Foltan T, Gasperikova D, Mattosova S, Chandoga J (2019) Late infantile metachromatic leukodystrophy due to novel pathogenic variants in the PSAP gene. J Mol Neurosci 67(4):559–563
Kreysing J, Figura KV, Gieselmann V (1990) The structure of the arylsulfatase a gene. Eur J Biochem 191:627–631
Kreysing J, Bohne W, Bösenberg C, Marchesini S, Turpin JC, Baumann N, von Figura K, Gieselmann V (1993) High residual arylsulfatase a (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy. Am J Hum Genet 53:339–346
Martino S, Consiglio A, Cavalieri C, Tiribuzi R, Costanzi E, Severini GM, Emiliani C, Bordignon C, Orlacchio A (2005) Expression and purification of a human, soluble Arylsulfatase a for metachromatic leukodystrophy enzyme replacement therapy. J Biotechnol 117(3):243–251
Matthes F, Stroobants S, Gerlach D, Wohlenberg C, Wessig C, Fogh J, Gieselmann V, Eckhardt M, D'Hooge R, Matzner U (2012) Efficacy of enzyme replacement therapy in an aggravated mouse model of metachromatic leukodystrophy declines with age. Hum Mol Genet 21(11):2599–2609
Matzner U, Herbst E, Hedayati KK, Lüllmann-Rauch R, Wessig C, Schröder S, Eistrup C, Möller C, Fogh J, Gieselmann V (2005) Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet 14(9):1139–1152
Maxson JE, Ries RE, Wang YC, Gerbing RB, Kolb EA, Thompson SL, Guidry Auvil JM, Marra MA, Ma Y, Zong Z, Mungall AJ, Moore R, Long W, Gesuwan P, Davidsen TM, Hermida LC, Hughes SB, Farrar JE, Radich JP, Smith MA, Gerhard DS, Gamis AS, Alonzo TA, Meshinchi S (2016) CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML. Blood 127(24):3094–3098
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
Patil SA, Maegawa GH (2013) Developing therapeutic approaches for metachromatic leukodystrophy. Drug Des Dev Ther 7:729–745
Stein C, Gieselmann V, Kreysing J, Schmidt B, Pohlmann R, Waheed A, Meyer HE, O'Brien JS, von Figura K (1989) Cloning and expression of human arylsulfatase a. J Biol Chem 264:1252–1259
Voorn JPVD et al (2005) Histopathologic correlates of radial stripes on MR images in lysosomal storage disorders. AJNR Am J Neuroradiol 26:442–446
Wang RY, Bodamer OA, Watson MS, Wilcox WR, ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases (2011) Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med 13(5):457–484
Wang Y, Chen X, Liu C, Wu S, Xie Q, Hu Q, Chen S, Liu Y (2019) Metachromatic leukodystrophy: characterization of two (p.Leu433Val, p.Gly449Arg) arylsulfatase a mutations. Exp Ther Med 18(3):1738–1744
We thank the patients and their parents for their cooperation.
This study was supported by the National Nature Science Foundation of China (grant number 81871246). Kangso Medical Inspection (Beijing, China) supports our study.
The study protocol was approved by the Ethical Committee of the Affiliated Hospital of Qingdao University (Qingdao, China). Informed consent was obtained from all individual participants included in this study.
Conflict of Interest
The authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Wu, S., Hou, M., Zhang, Y. et al. Chinese Cases of Metachromatic Leukodystrophy with the Novel Missense Mutations in ARSA Gene. J Mol Neurosci 71, 245–251 (2021). https://doi.org/10.1007/s12031-020-01643-3