Journal of Clinical Pediatrics >

2025 , Vol. 43 >Issue 10: 734 - 741

DOI: https://doi.org/10.12372/jcp.2025.25e0117

Original Article

Clinical phenotypes, genetic analysis and allogeneic hematopoietic stem cell transplantation efficacy of 8 children with metachromatic leukodystrophy

  • HU Jiayue ,
  • YING Lingwen ,
  • CHANG Guoying ,
  • LI Juan ,
  • YANG Fan ,
  • WANG Cuijin ,
  • YU Tingting ,
  • YAO Ruen ,
  • LUO Chengjuan ,
  • Wang Xiumin
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  • 1. Department of Clinical Research Ward, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
    2. Department of Endocrinology and Metabolism, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
    3. Shanghai Rare Disease Clinical Research Center, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
    4. Department of Neurology, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
    5. Department of Genetic and Molecular Diagnosis, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
    6. Department of Blood and Marrow Transplantation Ceuter, Shanghai Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China

Received date: 2025-02-17

  Accepted date: 2025-05-26

  Online published: 2025-09-29

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Abstract

Objective To analyze the clinical characteristics and genetic variations in 8 children with metachromatic leukodystrophy (MLD), and to explore the correlation between genotype and clinical phenotype as well as the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods The study collected data from children diagnosed between 2013 and 2024, confirmed through whole exome sequencing, and found that all children had symptoms such as developmental delay, with ages at diagnosis ranging from 1 year and 3 months to 9 years and 6 months. Results Based on the age of onset and clinical manifestations, 4 cases were late infantile type, with 2 deaths; 4 cases were juvenile type, with a survival rate of 100%. Genetic sequencing revealed compound heterozygous variations in the ARSA gene, a total of 15 mutations, of which 3 were newly reported and all were deleterious variations. Three children received allo-HSCT treatment and all survived but with progression of symptoms. Conclusion MLD mainly manifests as central nervous system damage, and diagnosis should be confirmed in combination with clinical manifestations, ARSA enzyme activity, and genetic testing. Early diagnosis and treatment are crucial for improving prognosis, and allo-HSCT can increase survival rates, but the therapeutic effect is limited.

Key words： metachromatic leukodystrophy; ARSA gene; lysosomal storage disease; allogeneic hematopoietic stem cell transplantation

Cite this article

HU Jiayue , YING Lingwen , CHANG Guoying , LI Juan , YANG Fan , WANG Cuijin , YU Tingting , YAO Ruen , LUO Chengjuan , Wang Xiumin . Clinical phenotypes, genetic analysis and allogeneic hematopoietic stem cell transplantation efficacy of 8 children with metachromatic leukodystrophy[J]. Journal of Clinical Pediatrics, 2025 , 43(10) : 734 -741 . DOI: 10.12372/jcp.2025.25e0117

References

[1] Adang A, Lucchini G, Rovelli A, et al. Metachromatic leukodystrophy: an overview of current and prospective treatments[J]. Bone Marrow Transplant, 2008, 42(Suppl 2): S2-S6.
[2] Soong BW, Casamassima AC, Fink JK, et al. Multiple sulfatase deficiency[J]. Neurology, 1988, 38(8): 1273-1275.
[3] van Rappard DF, Bugiani M, Boelens JJ, et al. Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy[J]. Neurology, 2016, 87(1): 103-111.
[4] Lorioli L, Cicalese MP, Silvani P, et al. Abnormalities of acid-base balance and predisposition to metabolic acidosis in Metachromatic Leukodystrophy patients[J]. Mol Genet Metab, 2015, 115(1): 48-52.
[5] Beerepoot S, Nierkens S, Boelens JJ, et al. Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective[J]. Orphanet J Rare Dis, 2019, 14(1): 240.
[6] van Rappard DF, Boelens JJ, Wolf NI. Metachromatic leukodystrophy: disease spectrum and approaches for treatment[J]. Best Pract Res Clin Endocrinol Metab, 2015, 29(2): 261-273.
[7] 李懋, 解媛媛, 杨飞, 等. 中国异染性脑白质营养不良携带者筛查临床实践指南[J]. 国际神经病学神经外科学杂志, 2024, 51(2): 13-17.
  Li M, Xie YY, Yang F, et al. Clinical Practice Guidelines for Carrier Screening of Metachromatic Leukodystrophy in China[J]. Guoji Shenjingbingxue Shenjingwaikexue Zazhi, 2024, 51(2): 13-17.
[8] K?hler W. Leukodystrophies with late disease onset: an update[J]. Curr Opin Neurol, 2010, 23(3): 234-241.
[9] Shaimardanova AA, Chulpanova DS, Solovyeva VV, et al. Metachromatic leukodystrophy: diagnosis, modeling, and treatment approaches[J]. Front Med (Lausanne), 2020, 7: 576221.
[10] Cesani M, Lorioli L, Grossi S, et al. Mutation update of ARSA and PSAP genes causing metachromatic leuko-dystrophy[J]. Hum Mutat, 2016, 37(1): 16-27.
[11] Patil SA, Maegawa GH. Developing therapeutic approaches for metachromatic leukodystrophy[J]. Drug Des Devel Ther, 2013, 7: 729-745.
[12] Groeschel S, Kühl J, Bley AE, et al. Long-term outcome of allogeneic hematopoietic stem cell transplantation in patients with juvenile metachromatic leukodystrophy compared with nontransplanted control patients[J]. JAMA Neurol, 2016, 73(9): 1133-1140.
[13] Adang L, Bonkowsky J, Boelens J, et al. Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States[J]. Cytotherapy, 2024, 26(7): 739-748.
[14] Fumagalli F, Calbi V, Natali Sora MG, et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access[J]. Lancet, 2022, 399(10322): 372-383.
[15] I Dali C, Sevin C, Krageloh-Mann I, et al. Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: Results from a phase 1/2 clinical trial[J]. Mol Genet Metab, 2020, 131(1-2): 235-244.
[16] Chen L, Yan H, Cao B, et al. Identification of novel ARSA mutations in Chinese patients with metachromatic leukodystrophy[J]. Int J Genomics, 2018: 2361068.
[17] Li T, Huang Y, Tao C, et al. Biochemical and molecular analysis of pediatric patients with metachromatic leukodystrophy in South China: functional characterization of five novel ARSA variants[J]. Metab Brain Dis, 2024, 39(5): 753-762.
[18] Strobel S, Hesse N, Santhanakumaran V, et al. Optimization of enzyme essays to enhance reliability of activity measurements in leukocyte lysates for the diagnosis of metachromatic leukodystrophy and gangliosidoses[J]. Cells, 2020, 9(12): 2553.
[19] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424.
[20] Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)[J]. Genet Med, 2020, 22(2): 245-257.
[21] Kafert S, Heinisch U, Zlotogora J, et al. A missense mutation P136L in the arylsulfatase A gene causes instability and loss of activity of the mutant enzyme[J]. Hum Genet, 1995, 95(2): 201-204.
[22] Niida Y, Kuroda M, Mitani Y, et al. Paternal uniparental isodisomy of chromosome 22 in a patient with meta-chromatic leukodystrophy[J]. J Hum Genet, 2012, 57(10): 687-690.
[23] Gort L, Coll MJ, Chabás A. Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients[J]. Hum Mutat, 1999, 14(3): 240-248.
[24] Trinidad M, Hong X, Froelich S, et al. Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix[J]. Genome Biol, 2023, 21, 24(1): 172.
[25] Gieselmann V, von Figura K. Advances in the molecular genetics of metachromatic leukodystrophy[J]. J Inherit Metab Dis, 1990, 13(4): 560-571.
[26] Fumagalli F, Zambon AA, Rancoita PMV, et al. Metachromatic leukodystrophy: A single-center longi-tudinal study of 45 patients[J]. J Inherit Metab Dis, 2021, 44(5): 1151-1164.
[27] Beerepoot S, Salomons GS, et al. Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients[J]. Neurogenetics, 2020, 21(4): 289-299.
[28] von Bülow R, Schmidt B, Dierks T, et al. Crystal structure of an enzyme-substrate complex provides insight into the interaction between human arylsulfatase A and its substrates during catalysis[J]. J Mol Biol, 2001, 305(2): 269-277.
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