Metachromatic Leukodystrophy Treatment & Management

Updated: Jan 22, 2021
  • Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Medical Care

Symptomatic supportive care is indicated for problems including, but not limited to, behavioral disturbances, feeding difficulties, seizures, and constipation. No effective treatment is available to reverse the deterioration and loss of function that metachromatic leukodystrophy causes.

Several treatment approaches are promising and include bone marrow or blood transplantation, gene therapy, enzyme replacement therapy, and cell therapy.

Marrow or blood transplantation

Allogeneic blood or marrow transplantation is a standard of care for patients with certain inborn errors of metabolism. [33]  Early and late outcomes show promise for MLD pediatric patients after cord blood transplantation. [34]  Remyelination was observed after hematopoetic stem cell transplantation (HSCT), and importance of immunomodulation in addition to metabolic correction in MLD patients was highlighted for promotion of white matter recovery. [35]

In individuals with asymptomatic late infantile and early juvenile forms of the disease, bone marrow or cord blood transplantation may stabilize neurocognitive function [36, 37] ; however, symptoms of motor function loss frequently progress. Mildly symptomatic and asymptomatic late juvenile and adult-onset forms are more likely to be stabilized with bone marrow or blood transplantation because of slower disease progression.

Patients should be carefully evaluated and counseled prior to bone marrow transplantation. The migration of hematopoietically derived cells in sufficient numbers to treat the affected areas usually requires 6 months to 1 year. During this interval, the patient's condition continues to deteriorate. Although transplantation may be successful, enzyme release to surrounding tissues can widely vary, often with unpredictable benefits.

In addition, the transplantation conditioning regimen and the catabolic state of the patient during transplantation may contribute to a brief period of accelerated deterioration. A study has shown that in children with juvenile metachromatic leukodystrophy, if disease progression does happen after hematopoetic stem cell transplantation (HSCT), it happens early after HSCT and proceeds faster than in children that did not go throught the transplantation. [38]

The bone marrow transplantation procedure can potentially carry significant morbidity and mortality rates. Therefore, patient counseling regarding the risks versus the potential for later stabilization of the disease is necessary.

Evaluation for transplantation includes careful neuropsychological and developmental testing to establish current levels of function and to provide findings for comparison with future results. Organ systems, including cardiac, pulmonary, liver, and kidney functions, require assessment. Brain MRI and a thorough neurologic examination should be included.

If patients are asymptomatic or mildly symptomatic, the evaluations mentioned above should be performed and multidisciplinary treatment needs to be discussed. The treatment may involve a geneticist, a metabolic specialist, a neurologist, a neuropsychologist, a pediatrician, a transplantation specialist, or a combination of several experts.

An appropriately matched and unaffected relative, in whom the cells manufacture adequate levels of arylsulfatase A, should serve as a donor. An appropriately matched unrelated donor may be used in centers with experienced staff, although this transplantation process carries higher morbidity and mortality rates. Bone marrow or placental (cord) blood may serve as the source of stem cells.

Gene therapy

In addition to bone marrow transplantation, gene therapy is under development as a possible solution to correct the underlying genetic abnormality. [39, 40, 41, 42]  Hematopoietic stem cell gene therapy shows evidence of safety and clinical benefit for late-infantile [43] and older pediatric patients with MLD. [44]  

The study has shown that gene therapy can result in stable ARSA gene replacement with high enzyme expression, including in the cerebrospinal fluid. In the 3 patients who were treated prior to onset of symptoms, the early data suggest that the regimen is a safe method to halt progression of the disease. [45] Further information can be obtained regarding this clinical trial at the website under its identifier: NCT01560182.

Researchers are developing innovative methods to overcome the barrier of getting adequate ARSA enzyme activity into the CNS. One such procedure involves transduction of neurospheres with a vector containing arylsulfatase A. [46]  

Enzyme replacement

A therapeutic strategy that has been useful for patients with other metabolic storage diseases is direct enzyme replacement. The difficulty with this strategy has always been getting adequate enzyme activity into the CNS. Intravenous injections of a recombinant human arylsulfatase A in a mouse model of MLD initially demonstrated no evidence of impact on CNS stores of sulfatide. However, with a significant increase in the injection frequency, researchers were able to demonstrate a reduction in CNS stores. [47]  

A new strategy called evolutionary redesign was used for murinization of 1 or 3 amino acid positions in the human ARSA (hARSA) protein, which increased the hARSA activity 3- and 5-fold, respectively, and no significant impact on the protein stability was observed. [48]

In the United States and Europe, clinical trials are being carried out to evaluate the safety and efficacy of a recombinant human ARSA (rhARSA) enzyme, Metazym (Shire HGT). The drug had obtained orphan drug status from the US Food and Drug Administration in early 2008. The phase I clinical trial for its use in children with late-infantile metachromatic leukodystrophy showed that the drug was safe. Unfortunately, the extension study was terminated because of a lack of efficacy (, identifier NCT00681811).

With the theory that the route of administration may allow for better drug concentrations in the CNS [49] , a multicenter phase I/II clinical trial has been developed to evaluate the safety and efficacy of rhARSA administered intrathecally (, identifier NCT01510028). This study is ongoing but closed to accrual. The open-label extension arm of this study is now open by invitation (, identifier NCT01887938).

Results of the safety evaluation of intrathecal rhARSA administration showed that it was generally well tolerated by patients, and preliminary data suggest promise in further development of rhARSA therapy for patients with MLD. [50]  A population pharmacokinetic model was developed on the basis of the above-described trial (NCT01510028) to further evaluate and predict the potential efficacy of intrathecal enzyme replacement therapy. [51]

Cell therapy

Another therapeutic approach under study in mice is the use of oligodendroglial cell therapy. Givogri and colleagues [52] reported their transplantation of oligodendrocyte progenitors into mouse neonatal MLD brain. These cells engrafted and integrated without disruption or tumor formation. Compared with untreated control mice, the treated mice had reduced sulfatide accumulation in the CNS with increased enzyme activity and prevention of motor deficits. This therapeutic approach is not available for humans at this time.




Appropriate consultations involve the following specialists:

  • Neurologist

  • Ophthalmologist

  • Pediatrician

  • Orthopedist

  • Genetic counselor

  • Neurodevelopmental psychologist

  • Bone marrow transplant physician

  • Genetic, metabolic disease specialist, or both

Referral or transfer to a major medical center with experience in treating inherited neurodegenerative and metabolic disorders in a multidisciplinary setting is highly recommended.

Follow-up evaluation and treatment are often needed. A physical therapist, occupational therapist, orthopedist, ophthalmologist, neuropsychologist, and other specialists may be involved.




Genetic counseling is important to inform the family regarding the risk of occurrence in future pregnancies. Metachromatic leukodystrophy is transmitted as an autosomal-recessive trait. Multiple genetic mutations have been implicated as causes of this disorder. [7] Available methods of prenatal testing should be discussed. Tests for a deficiency in enzyme activity in amniocytes or amniotic chorionic villi and gene mutation analysis may be available.