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

Metachromatic Leukodystrophy

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

Introduction

Background

Metachromatic leukodystrophy (MLD) is part of a larger group of lysosomal storage diseases, some of which are progressive, inherited, and neurodegenerative disorders (MLD included). Four types of MLD occur with varying ages of onset and courses (ie, late infantile, early juvenile, late juvenile, adult). All forms of the disease involve a progressive deterioration of motor and neurocognitive function. The typing is somewhat arbitrary because the types overlap and some cases do not fall neatly within a single type. MLD actually describes a continuum of clinical severity. As the term implies, the presence of white matter abnormalities on brain images is characteristic.

Pathophysiology

In patients, the inability to degrade sulfated glycolipids, especially the galactosyl-3-sulfate ceramides, characterizes MLD. A deficiency in the lysosomal enzyme sulfatide sulfatase (arylsulfatase A) is present in MLD. Some patients with clinical MLD have normal arylsulfatase A activity but lack an activator protein that is involved in sulfatide degradation. Both defects result in the accumulation of sulfatide compounds in neural and in nonneural tissue, such as the kidneys and gallbladder. These defects may result from a number of different mutations, and many new causative mutations have been identified.1,2

Histologic examination of the tissues often reveals metachromatic granules. Central and peripheral myelination are abnormal, with a widespread loss of myelinated oligodendroglia in the CNS and segmental demyelination of peripheral nerves. The sulfatide accumulations produce extensive damage and result in loss of both cognitive and motor functions.

Frequency

United States

Incidence is estimated to be 1 case per 40,000 births.

Mortality/Morbidity

Morbidity and mortality rates vary with each form of the disease. In general, young patients have the most rapidly progressive disease, whereas patients with adult onset experience a more chronic and insidious progression of disease.

Race

No differences have been identified based on race.

Sex

No differences have been identified based on sex.

Age

For a summary of distinguishing characteristics of each form, see the Table.

  • Patients with the late infantile form are usually aged 4 years or younger and typically present initially with gait disturbances, loss of motor developmental milestones, optic atrophy, and diminished deep tendon reflexes. In addition, progressive loss of both motor and cognitive functions is fairly rapid, and death results within approximately 5 years after the onset of clinical symptoms.
  • Patients with the early juvenile form (4-6 y) tend to present with loss of motor developmental milestones; the most obvious signs are gait disturbances, ataxia, hyperreflexia followed by hyporeflexia, seizures, and decreased cognitive function. Although progression is typically less rapid than in the infantile form, death usually occurs within 10-15 years of diagnosis, and most patients die before age 20 years. Gradual deterioration in school performance may be the first sign. Rarely, the presenting problem is acute cholecystitis or pancreatitis secondary to gallbladder involvement. Abdominal masses and GI tract bleeding have been reported.
  • The late juvenile (6-16 y) and adult (>16 y) forms progress slowly, and patients tend to present with behavioral disturbances or decreased cognitive function. Decreased school or work performance may be recognized first. Seizures may occur in any form of MLD and may be the only presenting symptom. Motor dysfunction often follows. Initial behavioral disturbances are commonly mistaken for those of various psychiatric disorders.3,4 Patients with the late juvenile form often survive into early adulthood. Patients with the adult form may have an even slower progression than those with the late juvenile form. Rarely, patients with the adult form may present with choreiform movements, dystonia, or both.

Clinical

History

Features of symptoms found in patients with each of the 4 forms of metachromatic leukodystrophy (MLD) include the following:

  • Infantile form
    • Gait disturbances
    • Memory deficits
    • Seizures (may be present)
    • Loss of motor developmental milestones
    • Decreased attention span
    • Speech disturbances
    • Decline in school performance
  • Early juvenile form
    • Gait disturbances
    • Tremors
    • Clumsiness
    • Loss of previously achieved skills
    • Intellectual decline
    • Behavioral changes
    • Seizures (possible)
  • Late juvenile and adult forms
    • Decreased work or school performance
    • Behavioral changes
    • Memory loss
    • Seizures (may be present)
    • Psychoses
    • Gradual loss of motor skills

Physical

  • Neurodevelopmental tests demonstrate the following findings in patients with infantile or early juvenile MLD:
    • Loss of previously achieved developmental milestones
    • Tremors
    • Truncal ataxia
    • Hyperreflexia progressing to hyporeflexia
    • Hypotonia
    • Gait abnormalities
    • Optic atrophy
  • Neurocognitive tests demonstrate the following abnormalities in patients with late juvenile or adult MLD:
    • Dementia
    • Memory loss
    • Disinhibition
    • Impulsiveness
    • Decreased motor function
    • Optic atrophy

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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