Metachromatic Leukodystrophy: New Therapy Advancements and Emerging Research Directions.
Por:
Asbreuk MABC, Schoenmakers DH, Adang LA, Beerepoot S, Bergner C, Bley A, Boelens JJ, Bugiani M, Calbi V, Garcia-Cazorla A, Eklund EA, Fumagalli F, Grønborg SW, Groeschel S, Van Hasselt PM, Hollak CEM, Jones SA, de Koning TJ, van Kuilenburg ABP, Laugwitz L, Lindemans C, Mochel F, Øberg A, Ram D, Schöls L, Sevin C, Sinha J, Vaz FM, Zerem A and Wolf NI
Publicada:
22 jul 2025
Ahead of Print:
27 jun 2025
Resumen:
Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS). Traditionally, MLD has been classified according to age at onset (late-infantile, early-juvenile and late-juvenile, and adult MLD), with earlier forms leading to more rapid neurologic decline. New data show that the type of presenting symptoms further influences the dynamic of disease progression. Patients with a cognitive presentation have a much slower or even no motor decline than patients with a mixed motor and cognitive presentation. Research advancements have enabled improved understanding of the effects of allogeneic hematopoietic stem cell transplantation and the development of novel therapeutic approaches, including hematopoietic stem cell gene therapy, which is now authorized in the EU, United Kingdom, and United States as treatment for selected patients with early-onset forms of MLD. Both hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy are most effective when administered before disease onset. To identify presymptomatic patients, NBS for MLD is becoming available in several countries, resulting in new challenges. Decisions regarding patient eligibility for these treatments in already symptomatic individuals, as well as the timing of treatment for patients identified through NBS, require thorough understanding of disease progression. Biomarkers may be helpful for disease staging and prediction of disease evolution. Moreover, apart from timing, challenges remain regarding optimal treatment strategies across MLD subtypes, especially late-onset MLD, and management of the clinical heterogeneity and course of the disease. Another important issue is ensuring therapy accessibility, which forms a substantial barrier for equitable care. Continued research and international collaboration are essential to address these challenges, with the goal of improving care and outcomes for patients with MLD and their families.
Filiaciones:
Asbreuk MABC:
Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC location Vrije Universiteit, the Netherlands
Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, the Netherlands
Medicine for Society, Platform at Amsterdam UMC location University of Amsterdam, the Netherlands
Schoenmakers DH:
Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC location Vrije Universiteit, the Netherlands
Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, the Netherlands
Medicine for Society, Platform at Amsterdam UMC location University of Amsterdam, the Netherlands
Adang LA:
Children's Hospital of Philadelphia, PA
Department of Neurology, University of Pennsylvania, Philadelphia
Beerepoot S:
Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC location Vrije Universiteit, the Netherlands
Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, the Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Bergner C:
Leukodystrophy Center, Department of Neurology, University Hospital Leipzig, Germany
Bley A:
University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany
Boelens JJ:
Department of Pediatrics, Stem Cell Transplant and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY
Bugiani M:
Department of Paediatrics/Child Neurology, VU University Medical Centre, Amsterdam Neuroscience, the Netherlands
Department of Pathology, VU University Medical Centre, Amsterdam Neuroscience, the Netherlands
Calbi V:
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy
Pediatric Immuno-Hematology Unit, IRCCS Ospedale San Raffaele Milan, Italy
Garcia-Cazorla A:
Neurometabolic Unit, Neurology Department, Hospital Sant Joan de D'eu, Barcelona, Spain
Eklund EA:
Pediatrics, Clinical Sciences, Lund University, Sweden
Fumagalli F:
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Milan, Italy
Pediatric Immuno-Hematology Unit, IRCCS Ospedale San Raffaele Milan, Italy
Unit of Neurology, IRCCS Ospedale San Raffaele Milan, Italy
Grønborg SW:
Center for Inherited Metabolic Diseases, Department of Pediatrics and Adolescent Medicine and Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Denmark
Groeschel S:
Neuropediatrics, General Pediatrics, Diabetology, Endocrinology and Social Pediatrics, University of Tübingen, University Hospital Tübingen, Germany
Van Hasselt PM:
Department of Metabolic Diseases, University Medical Center Utrecht, the Netherlands
Hollak CEM:
Medicine for Society, Platform at Amsterdam UMC location University of Amsterdam, the Netherlands
Department of Endocrinology and Metabolism, Amsterdam UMC location University of Amsterdam, the Netherlands
Jones SA:
Genomic Medicine, Manchester University NHS FT, United Kingdom
de Koning TJ:
Pediatrics, Clinical Sciences, Lund University, Sweden
Department of Pediatrics, Lund University, Sweden
Department of Neurology and Genetics, University of Groningen and University of Medical Center Groningen, the Netherlands
van Kuilenburg ABP:
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Gastroenterology & Metabolism, the Netherlands
Laugwitz L:
Neuropediatrics, General Pediatrics, Diabetology, Endocrinology and Social Pediatrics, University of Tuebingen, University Hospital Tübingen, Germany
Institute for Medical Genetics and Applied Genomics, University of Tübingen, Germany
Lindemans C:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Pediatric Hematopoietic Stem Cell Transplantation, UMC Utrecht and Princess Maxima Center, the Netherlands
Regenerative Medicine Institute, University Medical Center Utrecht, the Netherlands
Mochel F:
Reference Center for Adult Leukodystrophy, Department of Medical Genetics, Sorbonne University, Paris Brain Institute, La Pitié-Salpêtrière University Hospital, France
Øberg A:
Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Norway
Ram D:
Department of Pediatric Neurology, Royal Manchester Children's Hospital, United Kingdom
Schöls L:
Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany
German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
Sevin C:
Reference Center for Leukodystrophies, Pediatric Neurology Department, Hôpital Bicêtre, Le Kremlin Bicêtre, France
Sinha J:
Department of Pediatric Neurology, Center of Neurosciences, Narayana Hospital, RN Tagore Hospital, Kolkata, India
Vaz FM:
Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine and Pediatrics, Emma Children's Hospital, Amsterdam UMC location University of Amsterdam, the Netherlands
Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, the Netherlands
Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, the Netherlands
and
Zerem A:
Pediatric Neurology Institute, Leukodystrophy Center, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Israel
Wolf NI:
Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC location Vrije Universiteit, the Netherlands
Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, the Netherlands
Green Submitted, Green Published, hybrid
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