Metachromatic Leukodystrophy: New Therapy Advancements and Emerging Research Directions

Abstract

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.

Figure 1. Degradation of sGAGs, Steroid Sulfates, and Sulfatides

In metachromatic leukodystrophy (MLD), variants in the ARSA gene or deficiency of the saposin B cofactor (encoded by PSAP) leads to the accumulation of sulfated sphingolipids called sulfatides in the nervous system. In multiple sulfatase deficiency (MSD), variants in the SUMF1 gene impair formylglycine-generating enzyme (FGE), inactivating all sulfatases and causing buildup of sulfated glycosaminoglycans (sGAGs), steroid sulfates, and sulfatides. Created in BioRender. Wolf N (2025). BioRender.com/yw8bb6d.

Figure 2. Functions of Sulfatides in the CNS

Sulfatides, which are critical for myelin integrity and maintenance, are embedded in the myelin membrane. In healthy oligodendrocytes, sulfatides undergo a turnover process in the lysosome, where saposin B (SapB) facilitates the interaction between the enzyme arylsulfatase A (ASA) and the sulfatide, which hydrolyses sulfatides into sulfate and galactosylceramide, maintaining a balance within the cell and myelin sheaths. In metachromatic leukodystrophy (MLD), ASA deficiency leads to accumulation of sulfatides in lysosomes of different cell types. This accumulation eventually causes the lysosome to rupture, releasing its contents into the oligodendrocyte, leading to cell death and demyelination. Sulfatide release induces secretion of cytokines and triggers a nitric oxide–mediated cell stress response, which initiates an inflammatory reaction. Created in BioRender. Wolf N (2025). BioRender.com/sifofjr.

Figure 3. Ex Vivo Gene Therapy for MLD

Patient hematopoietic stem cells are collected and treated ex vivo with a lentiviral vector coding for ARSA cDNA, leading to supranormal expression of ASA. After myeloablative chemotherapy, patients are infused with treated hematopoietic stem cells. Monocyte-derived metabolically competent macrophages migrate to the brain where they are able to digest sulfatides. Their anti-inflammatory effects are supposed to enable oligodendrocyte differentiation and remyelination. ASA = arylsulfatase A; cDNA = complementary DNA; MLD = metachromatic leukodystrophy. Created in BioRender. Wolf N (2025). BioRender.com/n59r016.

Figure 4. MRI Changes in Relation to Age at Onset and Type of Presentation

Axial T2-weighted MRI scans of 4 patients with MLD, at diagnosis. (A) Late-infantile MLD: age 2 years, (B) early-juvenile MLD: age 5 years, (C) adult MLD (mixed presentation): age 24 years, and (D) adult MLD (cognitive presentation): age 20 years. Note the diffuse white matter involvement in early-onset MLD, with the typical tigroid pattern and the sparing of the subcortical fibers. In the late-infantile patient, the parieto-occipital white matter is more affected than the frontal white matter, which also illustrated more severely abnormal splenium vs the genu of the corpus callosum. In the cases with adult onset, there is, already at diagnosis, more pronounced atrophy than in the patient with early-juvenile MLD. The tigroid pattern is less evident. Note the diffuse white matter involvement with posterior predominance in the patient with a mixed cognitive and motor presentation and the sparing of the motor tracts and a frontal predominance in the patient with cognitive presentation and otherwise normal motor function and neurologic examination. MLD = metachromatic leukodystrophy.