Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States

Laura A Adang¹, Joshua L Bonkowsky², Jaap Jan Boelens³, Eric Mallack⁴, Rebecca Ahrens-Nicklas⁵, John A Bernat⁶, Annette Bley⁷, Barbara Burton⁸, Alejandra Darling⁹, Florian Eichler¹⁰, Erik Eklund¹¹, Lisa Emrick¹², Maria Escolar¹³, Ali Fatemi⁴, Jamie L Fraser¹⁴, Amy Gaviglio¹⁵, Stephanie Keller¹⁶, Marc C Patterson¹⁷, Paul Orchard¹⁸, Jennifer Orthmann-Murphy¹⁹, Jonathan D Santoro²⁰, Ludger Schöls²¹, Caroline Sevin²², Isha N Srivastava²³, Deepa Rajan²⁴, Jennifer P Rubin⁸, Keith Van Haren²³, Melissa Wasserstein²⁵, Ayelet Zerem²⁶, Francesca Fumagalli²⁷, Lucia Laugwitz²⁸, Adeline Vanderver²⁹

Affiliations

¹ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: adangl@chop.edu.
² University of Utah, Salt Lake City, Utah, USA.
³ Department of Pediatrics, Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College of Cornell University, New York, New York, USA.
⁴ Kennedy Krieger Institute, Baltimore, Maryland, USA.
⁵ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁶ University of Iowa Stead Family Children's Hospital, Iowa City, Iowa, USA.
⁷ University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
⁸ Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
⁹ Hospital Sant Joan de Déu, Barcelona, Spain.
¹⁰ Massachusetts General Hospital, Boston, Massachusetts, USA.
¹¹ Lund University, Lund, Sweden.
¹² Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.
¹³ Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Forge Biologics, Grove City, Ohio, USA.
¹⁴ Children's National Hospital, Washington, District of Columbia, USA.
¹⁵ Division of Laboratory Services, Newborn Screening and Molecular Biology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Association of Public Health Laboratories, Silver Spring, Maryland, USA.
¹⁶ Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹⁷ Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA; Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁸ University of Minnesota, Minneapolis, Minnesota, USA.
¹⁹ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁰ University of Southern California, Children's Hospital Los Angeles, Keck School of Medicine, Los Angeles, California, USA.
²¹ Department of Neurology and Hertie-Institute for Clinical Brain Research German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
²² Université Paris-Saclay, Hôpital Bicêtre, Paris, France.
²³ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
²⁴ University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
²⁵ Department of Pediatrics, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, New York, USA.
²⁶ Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
²⁷ Ospedale San Raffaele, Milano, Italy.
²⁸ Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital Tübingen, Tübingen, Germany.
²⁹ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 38613540
PMCID: PMC11348704
DOI: 10.1016/j.jcyt.2024.03.487

Review

Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States

Laura A Adang et al. Cytotherapy. 2024 Jul.

. 2024 Jul;26(7):739-748.

doi: 10.1016/j.jcyt.2024.03.487. Epub 2024 Apr 1.

Authors

Affiliations

¹ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: adangl@chop.edu.
² University of Utah, Salt Lake City, Utah, USA.
³ Department of Pediatrics, Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College of Cornell University, New York, New York, USA.
⁴ Kennedy Krieger Institute, Baltimore, Maryland, USA.
⁵ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁶ University of Iowa Stead Family Children's Hospital, Iowa City, Iowa, USA.
⁷ University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
⁸ Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
⁹ Hospital Sant Joan de Déu, Barcelona, Spain.
¹⁰ Massachusetts General Hospital, Boston, Massachusetts, USA.
¹¹ Lund University, Lund, Sweden.
¹² Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.
¹³ Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Forge Biologics, Grove City, Ohio, USA.
¹⁴ Children's National Hospital, Washington, District of Columbia, USA.
¹⁵ Division of Laboratory Services, Newborn Screening and Molecular Biology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Association of Public Health Laboratories, Silver Spring, Maryland, USA.
¹⁶ Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
¹⁷ Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA; Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁸ University of Minnesota, Minneapolis, Minnesota, USA.
¹⁹ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁰ University of Southern California, Children's Hospital Los Angeles, Keck School of Medicine, Los Angeles, California, USA.
²¹ Department of Neurology and Hertie-Institute for Clinical Brain Research German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
²² Université Paris-Saclay, Hôpital Bicêtre, Paris, France.
²³ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
²⁴ University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
²⁵ Department of Pediatrics, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, New York, USA.
²⁶ Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
²⁷ Ospedale San Raffaele, Milano, Italy.
²⁸ Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital Tübingen, Tübingen, Germany.
²⁹ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 38613540
PMCID: PMC11348704
DOI: 10.1016/j.jcyt.2024.03.487

Abstract

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.

Keywords: gene therapy; leukodystrophy; metachromatic leukodystrophy; newborn screening; transplant.

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Conflict of interest statement

Declaration of Competing Interest No honorarium, grant, or other form of payment was received to produce the manuscript. LAA is a consultant to Biogen, Takeda Pharmaceuticals, Orchard Therapeutics, is a site subinvestigator for the Takeda trial, and serves on the scientific advisory board of Cure MLD and MLD Foundation; JLB is a site principal investigator for the Takeda SHP611 trial; JJB has received consulting fees from Sobi, Omeros, Bluebird Bio, Sanofi, SmartImmune, Merck and Bluerock; EM has no conflicts of interest to disclose; RAN has no conflicts of interest to disclose; JAB is a site principal investigator for the Takeda SHP611 trial; AB is site subinvestigator for the Takeda SHP611 trial and received travelling support by Orchard-Tx; BB is a site principal investigator for the Takeda SHP611 trial and is a consultant to Aro, AlltRNA, Orchard Therapeutics, Astella, Passage Bio, Biomarin, PTC Therapeutics, JCR Pharma, Takeda; received honoraria from Astra Zeneca, Biomarin, Chiesi, Horizon, JCR Pharma; grant funding from Biomarin Pharmaceutical, Takeda, Homology Medicines, Denali Therapeutics, Sangamo, JCR Pharma, and Ultragenyx; AD has participated in an advisory board organized by Orchard Therapeutics; FE has <1% equity in Swan Bio, and royalties from AAV9 license for AMN; receives consulting fees from Leal Therapeutics, Swan Bio, Ionis, Minoryx, UptoDate, Origen, Takeda Therapeutics and Third Rock Ventures; founder and consultant of Swan Bio and serves on the chair on the advisory board of European Leukodystrophy Association, and as a board member at United Leukodystrophy Foundation; EE has participated in several advisory boards arranged by Orchard Therapeutics; LE serves on the advisory board for Ionis pharmaceuticals; ME is Chief Medical Officer at Forge Biologics; AF receives research support from SwanBio, Autobahn Therapeutics, Poxel Therapeutics, Vertex Pharmaceuticals, and Maryland Stem Cell Research Fund, was a Data and Safety Monitoring Board (DSMB) member for BlueBird Bio, and coinvented a patent currently licensed to Ashvattha; JF is a consultant for GeneDx, Educational Consultant on the Impact of Exome and Genome Sequencing in Well-Phenoptyped Populations and is Chair of the Maryland Secretary's Advisory Council on Hereditary and Congenital Disorders; AG has received payment or honoraria from Spark Therapeutics and Orchard Therapeutics, consulting fees from Takeda; chair of the MN Rare Disease Advisory Council and the Clinical and Laboratory Standards Institute; SK is a clinical trial site principal investigator for Ionis and was a consultant for Veristat; MCP is the site principal investigator for clinical trials funded by Azafaros, Glycomine, Idorsia, Maggie's Pearl, Takeda, and Zevra, and has consulted for Azafaros, Takeda, and Zevra; serves as editor in chief of the Journal of Child Neurology and an editor for JIMD, and royalties as section editor for up to date; PO is a consultant to Orchard Therapeutics, serves on a DSMB for Ionis, and has clinical trial support from Immusoft and Allovir; JOM is a consultant to Novoglia and site principal investigator for Vigil Neuroscience; JDS is a consultant to Biogen and Cycle Pharma; LS is a consultant to Vico Therapeutics and a site principal investigator for trials of Vigil Neuroscience, Stealth Biotherapeutics and PTC Therapeutics; CS is PI of the Takeda clinical trial and consultant for Orchard Therapeutics; INS has no conflicts of interest to disclose; DR is site PI for the Takeda trial; JPR has no conflicts of interest to disclose; KVH is a consultant for Bluebird bio and Poxel, a site PI for trials funded by Minoryx, Bluebird bio, IONIS and a trial advisor for Calico; MW has received research support from Abeona Therapeutics, Alexion Pharmaceuticals, the Ara Parseghian Medical Research Foundation, BioMarin Pharmaceutical, Cure Sanfilippo Foundation, Dana's Angels Research Trust, Firefly Fund, Mirum Pharma, Noah's Hope, Orchard Therapeutic, Passage Bio, Sanofi Genzyme, Sio Gene Therapies, Takeda Pharmaceutical, Travere Therapeutics, and Ultragenyx Pharmaceutical; has received consulting fees from Sanofi Genzyme; AZ is a site subinvestigator for the Takeda trial; FF is License holder of OTL-200, I Orchard Therapeutics trial, advisor Orchard, Takeda, funding Telethon Foundation, GSK, Orchard; LL has no conflicts of interest to disclose; AV is an advisor to Takeda, Passagebio, Orchard; and is site PI Takeda trial.

Figures

**Figure 1.. Disease stratification in MLD by diagnostic testing.**
There are 2 main groupings of MLD subtype: early and late onset disease. The most common subtype, late infantile MLD, has the most defined genotype and biochemical thresholds.

**Figure 2.. Clinical manifestations of MLD.**
MLD is a disorder characterized by demyelination of the central and peripheral nervous systems accompanied by multisystemic complications. The breadth of complications is shown in (A), and the common presentations by disease subtype is shown in (B).

**Figure 3.. Initial neuroimaging studies may be nondiagnostic, even in cases of early onset MLD, but can change rapidly.**
This pair of T2 FLAIR images were obtained from a child with late infantile MRI. At the time of the first MRI (age 22-months; left panel), he was unable to walk independently and had limited vocabulary, but no abnormalities noted on MRI. By his second MRI (age 29 months; right panel) he had lost the ability to crawl and his MRI demonstrated confluent, symmetric T2 prolongation throughout the cerebral white with sparing of perivenular white matter (tigroid pattern of T2 prolongation) and subcortical U-fibers.

See this image and copyright information in PMC

References

1. Santhanakumaran V, et al. , Predicting clinical phenotypes of metachromatic leukodystrophy based on the arylsulfatase A activity and the ARSA genotype? - Chances and challenges. Mol Genet Metab, 2022. 137(3): p. 273–282. - PubMed
1. Beerepoot S, et al. , Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy. Brain, 2022. 145(1): p. 105–118. - PMC - PubMed
1. Fumagalli F, et al. , Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients. J Inherit Metab Dis, 2021. 44(5): p. 1151–1164. - PubMed
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1. Dali C, et al. , Sulfatide levels correlate with severity of neuropathy in metachromatic leukodystrophy. Ann Clin Transl Neurol, 2015. 2(5): p. 518–33. - PMC - PubMed

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Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States

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Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States

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Conflict of interest statement

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