eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Metachromatic Leukodystrophy: Treatment & Medication

Author: Alan K Ikeda, MD, Assistant Professor, Department of Pediatrics, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA; Assistant Director of Pediatric Blood and Marrow Transplantation, Mattel Children's Hospital
Coauthor(s): Theodore Moore, MD, MS, Associate Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Clinical Director of Pediatric Hematology/Oncology, Director of Pediatric Blood and Marrow Transplant Program, University of California at Los Angeles School of Medicine; Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Deputy Director, Oregon Clinical and Translational Research Institute
Contributor Information and Disclosures

Updated: Sep 15, 2008

Treatment

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;7,8 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.9,10 Researchers are developing innovate ways 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.11 As of this writing, gene therapy 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.12 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 and a Phase II (efficacy) clinical trial is currently in development for patients with late-infantile MLD. 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 (2006) reported their transplantation of oligodendrocyte progenitors into mouse neonatal MLD brain.13 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 may proceed as follows:

  • 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 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

Medication

Drug therapy is currently not a component of the standard of care for this disease. Provide supportive care for complications. Recombinant human arylsulfatase A (rhARSA) enzyme is available in Europe and has been designated orphan status in the United States.

More on Metachromatic Leukodystrophy

Overview: Metachromatic Leukodystrophy
Differential Diagnoses & Workup: Metachromatic Leukodystrophy
Treatment & Medication: Metachromatic Leukodystrophy
Follow-up: Metachromatic Leukodystrophy
References
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References

  1. Anlar B, Waye JS, Eng B. Atypical clinical course in juvenile metachromatic leukodystrophy involving novel arylsulfatase A gene mutations. Dev Med Child Neurol. May 2006;48(5):383-7. [Medline].

  2. von Figura K, Gieselman V, Jaeken J. Metachromatic leukodystrophy. In: Scriver C, Beadet A, Valle D, Sly W, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill Professional; 2001.

  3. Estrov Y, Scaglia F, Bodamer OA. Psychiatric symptoms of inherited metabolic disease. J Inherit Metab Dis. Feb 2000;23(1):2-6. [Medline].

  4. Fukutani Y, Noriki Y, Sasaki K, et al. Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia. Psychiatry Clin Neurosci. Jun 1999;53(3):425-8. [Medline].

  5. Meikle PJ, Grasby DJ, Dean CJ. Newborn screening for lysosomal storage disorders. Mol Genet Metab. Aug 2006;88(4):307-14. [Medline].

  6. Faerber EN, Melvin J, Smergel EM. MRI appearances of metachromatic leukodystrophy. Pediatr Radiol. Sep 1999;29(9):669-72. [Medline].

  7. Krivit W. Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases. Springer Semin Immun. 2004;26:119-132. [Medline].

  8. Martin PL, Carter SL, Kernan NA. Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases. Biol Blood Marrow Transplant. Feb 2006;12(2):184-94. [Medline].

  9. Consiglio A, Quattrini A, Martino S, et al. In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice. Nat Med. Mar 2001;7(3):310-6. [Medline].

  10. Matzner U, Habetha M, Gieselmann V. Retrovirally expressed human arylsulfatase A corrects the metabolic defect of arylsulfatase A-deficient mouse cells. Gene Ther. May 2000;7(9):805-12. [Medline].

  11. Kawabata K, Migita M, Mochizuki H. Ex vivo cell-mediated gene therapy for metachromatic leukodystrophy using neurospheres. Brain Res. Jun 13 2006;1094(1):13-23. [Medline].

  12. Matzner U, Herbst E, Hedayati K, et al. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet. May 2005;14(9):1139-1152. [Medline].

  13. Givogri MI, Galbiati F, Fasano S. Oligodendroglial progenitor cell therapy limits central neurological deficits in mice with metachromatic leukodystrophy. J Neurosci. Mar 22 2006;26(12):3109-19. [Medline].

  14. Alessandri MG, De Vito G, Fornai F. Increased prevalence of pervasive developmental disorders in children with slight arylsulfatase A deficiency. Brain Dev. Oct 2002;24(7):688-92. [Medline].

  15. Hernandez-Palazon J. Anaesthetic management in children with metachromatic leukodystrophy. Paediatr Anaesth. Oct 2003;13(8):733-4. [Medline].

  16. Sevin C, Aubourg P, Cartier N. Enzyme, cell and gene-based therapies for metachromatic leukodystrophy. J Inherit Metab Dis. Apr 2007;30(2):175-83. [Medline].

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Further Reading

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Keywords

metachromatic leukodystrophy, arylsulfatase A deficiency, MLD, neurodegenerative disorders, cerebroside sulfatide, galactosyl sulfatide, bone marrow transplantation, sulfatide sulfatase deficiency, sulfatide accumulation, cholecystitis, pancreatitis

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Contributor Information and Disclosures

Author

Alan K Ikeda, MD, Assistant Professor, Department of Pediatrics, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA; Assistant Director of Pediatric Blood and Marrow Transplantation, Mattel Children's Hospital
Alan K Ikeda, MD is a member of the following medical societies: American Academy of Pediatrics, American Society for Blood and Marrow Transplantation, and American Society of Pediatric Hematology/Oncology
Disclosure: emedicine Honoraria author

Coauthor(s)

Theodore Moore, MD, MS, Associate Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Clinical Director of Pediatric Hematology/Oncology, Director of Pediatric Blood and Marrow Transplant Program, University of California at Los Angeles School of Medicine
Theodore Moore, MD, MS is a member of the following medical societies: American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Deputy Director, Oregon Clinical and Translational Research Institute
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Medical Editor

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia
David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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