Metachromatic Leukodystrophy Treatment & Management

Updated: Dec 10, 2019
  • Author: Theodore Moore, MD, MS; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Medical Care

Currently, no effective treatment is available to reverse the deterioration and loss of function that metachromatic leukodystrophy (MLD) causes. In individuals with asymptomatic late infantile and early juvenile forms of the disease, bone marrow or cord blood transplantation may stabilize neurocognitive function; [12, 13] 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 transplantation because of slower progression.

In addition to bone marrow transplantation, gene therapy is under development as a possible solution to correct the underlying genetic abnormality. [14, 15, 16, 17] Gene therapy using the patient's own cells has the advantage of not having the risks of graft versus host disease and always having a source. Researchers are developing innovative methods to overcome the barrier of getting adequate enzyme activity into the CNS. One such procedure involves transduction of neurospheres with a vector containing arylsulfatase A. [18] Gene therapy has had success in treating X-linked severe combined immune deficiency (SCID), adenosine deaminase deficiency-SCID, and chronic granulomatous disease. A phase I/II clinical trial is actively recruiting to evaluate gene therapy for metachromatic leukodystrophy.

The study has shown that this strategy 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. [19] Further information can be obtained regarding this clinical trial at the Web site under its identifier: NCT01560182.

A therapeutic strategy useful in 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 metachromatic leukodystrophy 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. [20]

In the United States and Europe, clinical trials are evaluating the safety and efficacy of a recombinant human arylsulfatase A (rhARSA) enzyme, metazym. The new drug had obtained Orphan Drug status from the US Food and Drug Administration (FDA) in early 2008. In the United States, the sponsor for rhARSA is Shire Human Genetic Therapies in Cambridge, Massachusetts. 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 due to a lack of efficacy (, identifier NCT00681811).

With the thought that the route of administration may allow for better drug concentrations in the CNS, 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 currently ongoing but closed to accrual. The open-label extension arm of this study is now open by invitation (, identifier NCT01887938).

Another therapeutic approach under study in mice is the use of oligodendroglial cell therapy. Givogri et al reported their transplantation of oligodendrocyte progenitors into mouse neonatal MLD brain. [21] 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.

Symptomatic supportive care is indicated for problems including, but not limited to, behavioral disturbances, feeding difficulties, seizures, and constipation.

Bone marrow transplantation

Carefully evaluate and counsel patients 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.

The transplantation procedure carries significant morbidity and mortality rates (see Bone Marrow Transplantation). Therefore, counsel patients regarding the risks versus the potential for later stabilization of the disease.

Evaluation for transplantation includes careful neuropsychological and developmental testing to establish current levels of function and to provide findings for comparison with future results. Assess the organ systems, including cardiac, pulmonary, liver, and kidney functions. Perform brain MRI and a thorough neurologic examination.

If patients are asymptomatic or mildly symptomatic, perform the evaluations mentioned above, and discuss multidisciplinary treatment, which may involve a geneticist, metabolic specialist, neurologist, neuropsychologist, pediatrician, transplantation specialist, or a combination.

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.



Appropriate consultations involve the following specialists:

  • Neurologist

  • Ophthalmologist

  • Pediatrician

  • Orthopedist

  • Genetic counselor

  • Neurodevelopmental psychologist

  • Bone marrow transplant physician

  • Genetic, metabolic disease specialist, or both



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


Long-Term Monitoring

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


Inpatient & Outpatient Medications

Medications are used to provide supportive care or symptomatic relief rather than to treat the underlying cause.



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