Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2024

Open Access 01-12-2024 | Leukodystrophy | Research

Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries

Authors: Daphne H. Schoenmakers, Fanny Mochel, Laura A. Adang, Jaap-Jan Boelens, Valeria Calbi, Erik A. Eklund, Sabine W. Grønborg, Francesca Fumagalli, Samuel Groeschel, Caroline Lindemans, Caroline Sevin, Ludger Schöls, Dipak Ram, Ayelet Zerem, Holm Graessner, Nicole I. Wolf

Published in: Orphanet Journal of Rare Diseases | Issue 1/2024

Login to get access

Abstract

Background

For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care.

Methods

A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics.

Results

Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1–3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1–5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries.

Conclusion

HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians’ struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.
Appendix
Available only for authorised users
Literature
1.
von Figura KGV, Jaeken J. Metachromatic leukodystrophy. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001.
2.
Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, et al. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999;105(1–2):151–6.CrossRefPubMed
3.
Lugowska A, Poninska J, Krajewski P, Broda G, Ploski R. Population carrier rates of pathogenic ARSA gene mutations: is metachromatic leukodystrophy underdiagnosed? PLoS One. 2011;6(6): e20218.ADSCrossRefPubMedPubMedCentral
4.
van der Knaap MS, Schiffmann R, Mochel F, Wolf NI. Diagnosis, prognosis, and treatment of leukodystrophies. Lancet Neurol. 2019;18(10):962–72.CrossRefPubMed
5.
Schoenmakers DH, Beerepoot S, van den Berg S, Adang L, Bley A, Boelens JJ, et al. Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy: The European Metachromatic Leukodystrophy initiative (MLDi). Orphanet J Rare Dis. 2022;17(1):48.CrossRefPubMedPubMedCentral
6.
Kehrer C, Elgun S, Raabe C, Bohringer J, Beck-Wodl S, Bevot A, et al. Association of age at onset and first symptoms with disease progression in patients with metachromatic leukodystrophy. Neurology. 2021;96(2):e255–66.CrossRefPubMed
7.
Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, et al. Mutation update of ARSA and PSAP genes causing metachromatic leukodystrophy. Hum Mutat. 2016;37(1):16–27.CrossRefPubMed
8.
Fumagalli F, Calbi V, Natali Sora MG, Sessa M, Baldoli C, Rancoita PMV, 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. Lancet. 2022;399(10322):372–83.CrossRefPubMedPubMedCentral
9.
Hong X, Daiker J, Sadilek M, Ruiz-Schultz N, Kumar AB, Norcross S, et al. Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots. Genet Med. 2021;23(3):555–61.CrossRefPubMed
10.
Trinidad M, Hong X, Froelich S, Daiker J, Sacco J, Nguyen HP, et al. Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix. Genome Biol. 2023;24(1):172.CrossRefPubMedPubMedCentral
11.
Boelens JJ, Prasad VK, Tolar J, Wynn RF, Peters C. Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr Clin North Am. 2010;57(1):123–45.CrossRefPubMed
12.
Wolf NI, Breur M, Plug B, Beerepoot S, Westerveld ASR, van Rappard DF, et al. Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. Ann Clin Transl Neurol. 2020;7(2):169–80.CrossRefPubMedPubMedCentral
13.
Boucher AA, Miller W, Shanley R, Ziegler R, Lund T, Raymond G, Orchard PJ. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis. 2015;10:94.CrossRefPubMedPubMedCentral
14.
Beerepoot S, Nierkens S, Boelens JJ, Lindemans C, Bugiani M, Wolf NI. Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective. Orphanet J Rare Dis. 2019;14(1):240.CrossRefPubMedPubMedCentral
15.
16.
Beschle J, Doring M, Kehrer C, Raabe C, Bayha U, Strolin M, et al. Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy. Mol Cell Pediatr. 2020;7(1):12.CrossRefPubMedPubMedCentral
17.
Gieselmann V, Krageloh-Mann I. Metachromatic leukodystrophy–an update. Neuropediatrics. 2010;41(1):1–6.CrossRefPubMed
18.
van Rappard DF, Boelens JJ, van Egmond ME, Kuball J, van Hasselt PM, Oostrom KJ, et al. Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience. Blood. 2016;127(24):3098–101.CrossRefPubMed
19.
Krageloh-Mann I, Groeschel S, Kehrer C, Opherk K, Nagele T, Handgretinger R, Muller I. Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort. Bone Marrow Transplant. 2013;48(3):369–75.CrossRefPubMed
20.
de Hosson LD, van de Warrenburg BP, Preijers FW, Blijlevens NM, van der Reijden BA, Kremer HP, et al. Adult metachromatic leukodystrophy treated by allo-SCT and a review of the literature. Bone Marrow Transplant. 2011;46(8):1071–6.CrossRefPubMed
21.
Solders M, Martin DA, Andersson C, Remberger M, Andersson T, Ringden O, Solders G. Hematopoietic SCT: a useful treatment for late metachromatic leukodystrophy. Bone Marrow Transplant. 2014;49(8):1046–51.CrossRefPubMed
22.
Groeschel S, Kuhl JS, Bley AE, Kehrer C, Weschke B, Doring M, et al. Long-term outcome of allogeneic hematopoietic stem cell transplantation in patients with juvenile metachromatic leukodystrophy compared with nontransplanted control patients. JAMA Neurol. 2016;73(9):1133–40.CrossRefPubMed
23.
24.
25.
Kehrer C, Blumenstock G, Raabe C, Krageloh-Mann I. Development and reliability of a classification system for gross motor function in children with metachromatic leucodystrophy. Dev Med Child Neurol. 2011;53(2):156–60.CrossRefPubMed
26.
Eichler F, Grodd W, Grant E, Sessa M, Biffi A, Bley A, et al. Metachromatic leukodystrophy: a scoring system for brain MR imaging observations. AJNR Am J Neuroradiol. 2009;30(10):1893–7.CrossRefPubMedPubMedCentral
27.
Bonkowsky JL, Wilkes J, Bardsley T, Urbik VM, Stoddard G. Association of diagnosis of leukodystrophy with race and ethnicity among pediatric and adolescent patients. JAMA Netw Open. 2018;1(7): e185031.CrossRefPubMedPubMedCentral
28.
29.
30.
31.
32.
FACT-JACIE. FACT-JACIE International Standards Eighth Edition – Version 8.1. Foundation for the Accreditation of Cellular Therapy (FACT) and Joint Accreditation Committee - ISCT and EBMT (JACIE) (2021).
33.
Tumiene B, Graessner H. Rare disease care pathways in the EU: from odysseys and labyrinths towards highways. J Commun Genet. 2021;12(2):231–9.CrossRef
34.
Strolin M, Krageloh-Mann I, Kehrer C, Wilke M, Groeschel S. Demyelination load as predictor for disease progression in juvenile metachromatic leukodystrophy. Ann Clin Transl Neurol. 2017;4(6):403–10.CrossRefPubMedPubMedCentral
35.
36.
Beerepoot S. Genotypes leading to a cognitive presentation with long-term sparing of central and peripheral motor function in metachromatic leukodystrophy. in preparation.
37.
Tumiene B, Graessner H, Mathijssen IM, Pereira AM, Schaefer F, Scarpa M, et al. European reference networks: challenges and opportunities. J Commun Genet. 2021;12(2):217–29.CrossRef
Metadata
Title
Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries
Authors
Daphne H. Schoenmakers
Fanny Mochel
Laura A. Adang
Jaap-Jan Boelens
Valeria Calbi
Erik A. Eklund
Sabine W. Grønborg
Francesca Fumagalli
Samuel Groeschel
Caroline Lindemans
Caroline Sevin
Ludger Schöls
Dipak Ram
Ayelet Zerem
Holm Graessner
Nicole I. Wolf
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2024
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-024-03075-3

Other articles of this Issue 1/2024

Orphanet Journal of Rare Diseases 1/2024 Go to the issue

Research

Genetic diagnosis of endocrine disorders in Cyprus through the Cyprus Institute of Neurology and Genetics: an ENDO-ERN Reference Center

Research

Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies

Research

The effects of etidronate on brain calcifications in Fahr’s disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial

Research

Rare neurodevelopmental conditions and parents’ mental health – how and when does genetic diagnosis matter?

Research

Hyperphagia and impulsivity: use of self-administered Dykens’ and in-house impulsivity questionnaires to characterize eating behaviors in children with severe and early-onset obesity

Research

A shock to the (health) system: experiences of adults with rare disorders during the first COVID-19 wave