Complex Clinical Presentation and Diagnostic Challenges in Metachromatic Leukodystrophy-A Narrative Review

Abstract

Metachromatic leukodystrophy is a lysosomal storage disorder characterized by the deterioration of the myelin sheath that covers the majority of nerve fibers in both the central and peripheral nervous systems. The condition arises from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA) or its associated sphingolipid activator protein B (SapB), resulting in a progressive decline in both motor and cognitive functions. Mutations in the ARSA and PSAP genes lead to the deficiency of ARSA and SapB proteins, respectively, with the clinical severity of metachromatic leukodystrophy depending on the residual ARSA activity, which varies based on the mutation type. Unfortunately, effective treatments for this disease are currently lacking. While there have been clinical reports of bone marrow or cord blood transplants, their therapeutic efficacy remains insufficient to prevent the worsening of neurological disorders. Encouraging results have been achieved through gene therapy, involving the introduction of the wild-type ARSA gene using vectors based on different adeno-associated virus serotypes. Additionally, mesenchymal stem cells and combined gene-cell therapies have shown promise in the treatment of this condition. This review examines therapeutic approaches for addressing metachromatic leukodystrophy, alongside diagnostic techniques and animal models that help evaluate the effectiveness of new treatments.