Metachromatic Leukodystrophy Treatment & Management
- Author: Alan K Ikeda, MD; Chief Editor: Bruce Buehler, MD more...
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;[8, 9] 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.[10, 11] 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.[12] Although gene therapy has had success in treating X-linked severe combined immune deficiency (SCID), adenosine deaminase deficiency-SCID, and chronic granulomatous disease, as of this writing, gene therapy for metachromatic leukodystrophy remains under investigation and is not yet ready for clinical trials.
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 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.[13] In Europe, ongoing clinical trials are evaluating the safety and efficacy of a recombinant human arylsulfatase A (rhARSA) enzyme, metazym. The new drug has obtained Orphan Drug status from the US Food and Drug Administration (FDA) in early 2008. The Phase I and II clinical trials for patients with late-infantile metachromatic leukodystrophy have been completed, but the results of the Phase II trial are being analyzed.
A Phase III clinical trial that provides compassionate use of metazym for those who were on the previous clinical trial is ongoing until the drug is available for purchase. In the United States, the orphan sponsor for rhARSA is Shire Human Genetic Therapies in Cambridge, Massachusetts.
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.[14] 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.
Consultations
Appropriate consultations involve the following specialists:
- Neurologist
- Ophthalmologist
- Pediatrician
- Orthopedist
- Genetic counselor
- Neurodevelopmental psychologist
- Bone marrow transplant physician
- Genetic, metabolic disease specialist, or both
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| Form | Age at Onset (y) | Inheritance Pattern | Frequency | Neurocognitive Deficit | Progression | Effect of Bone Marrow Transplantation |
| Late infantile | < 4 | Autosomal recessive | Most common | Motor milestones lost, neurocognitive functions lost | Death within 5-6 y | Not helpful in symptomatic patients; may halt cognitive deterioration in asymptomatic patients |
| Early juvenile | 4-6 | Autosomal recessive | Less common | Motor milestones lost, learning and behavior impaired | Death within 10-15 y | May be beneficial in symptomatic and asymptomatic patients |
| Late juvenile | 6-16 | Autosomal recessive | Rare | Personality changes, behavioral changes, dementia, psychoses, decreased school or work performance | Slow | May be beneficial in asymptomatic or mildly symptomatic patients |
| Adult | >16 | Autosomal recessive | Rare | Personality changes, behavioral changes, dementia, psychoses, decreased school or work performance | Slow | May be beneficial in asymptomatic or mildly symptomatic patients |
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