Treatments For Metachromatic Leukodystrophy (MLD)

MLD is a progressive lysosomal storage disorder, and for many years, treatment was limited to supportive care. This included symptom management such as nutritional support, respiratory physiotherapy, and psychological care for both the patient and family. Dr. Fumagalli begins by reiterating the importance of maintaining quality of life for patients ineligible for causal treatment due to late diagnosis.

Established therapeutic options now include allogeneic hematopoietic stem cell transplantation (HSCT), which provides enzyme delivery across the blood-brain barrier via donor-derived cells. While some studies suggest benefits, results vary depending on timing, disease severity, and subtype. Transplantation is most effective in early juvenile and late-onset forms when performed at a very early stage, ideally before major motor or cognitive symptoms develop.

Dr. Fumagalli then presents data on gene therapy, specifically the use of autologous hematopoietic stem cells modified with a functional copy of the ARSA gene (Lipmelty). Clinical trials have shown encouraging outcomes, especially in pre-symptomatic late infantile and early juvenile patients. Improvements include stabilised or slowed motor and cognitive decline, better nerve conduction velocities, and prevention of brain atrophy. Importantly, gene therapy avoids the risks of graft-versus-host disease and rejection associated with HSCT.

She also discusses a separate approach involving intrathecal enzyme replacement therapy, where the enzyme is administered directly into the spinal fluid via an implanted device. Although early trials focus on safety, preliminary data suggest potential benefits, especially at higher doses and more frequent infusions. A new trial is now underway to evaluate efficacy.

Dr. Fumagalli stresses that all these treatments are most beneficial when initiated pre-symptomatically. She highlights the urgent need for newborn screening, referencing ongoing validation efforts in Germany and elsewhere. The session concludes with a call for pediatricians to remain alert to early motor stagnation and subtle neurological signs and to refer suspected cases promptly to specialists.

In summary, the window for effective treatment in MLD is narrow, and the evolving therapeutic landscape reinforces the necessity of early identification through clinical vigilance and newborn screening.