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

Metachromatic Leukodystrophy: Differential Diagnoses & Workup

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

Differential Diagnoses

Attention Deficit Hyperactivity Disorder
Krabbe Disease
Schizophrenia and Other Psychoses

Other Problems to Be Considered

  • Arylsulfatase A pseudodeficiency: As many as 1-2% of people may have low (5-15%) or reference range levels of arylsulfatase A in the serum, but sulfatide is not stored. These individuals are usually healthy and asymptomatic. The presence of normal urinary sulfatide levels (elevated in patients with metachromatic leukodystrophy [MLD]) distinguishes arylsulfatase A pseudodeficiency from MLD. Arylsulfatase A pseudodeficiency may also be distinguished using gene mutation analysis or an evaluation of radiolabeled sulfatide fibroblast uptake and accumulation.
  • Schizophrenia
  • Antisocial personality disorder
  • X-linked adrenoleukodystrophy
  • Multiple sulfatase deficiency

Workup

Laboratory Studies

  • Arylsulfatase A enzyme activity may be decreased in leukocytes or in cultured skin fibroblasts.
  • CSF protein levels may be increased (although this finding is nonspecific).
  • Metachromatic leukodystrophy (MLD) may be distinguished from arylsulfatase A pseudodeficiency using one of the following tests:
    • Urine sulfatide levels
    • Radiolabeled sulfatide fibroblast loading
    • DNA mutation analysis
  • Arylsulfatase A activity may be measured to identify carriers and make prenatal diagnoses. This test is available in a few select laboratories. In addition, multiplexed immune-quantification assays have been developed that screen numerous lysosomal proteins. Implementation of this technique in newborn screening (using blood spots) for early identification of lysosomal storage disorders has been shown to be feasible but requires further validation.5

Imaging Studies

  • Brain MRI may be performed to identify white matter lesions and atrophy, which are characteristic of MLD but nonspecific.6

Other Tests

  • Nerve conduction studies
  • Neurocognitive, neuropsychological testing, or both

Procedures

  • Peripheral nerve biopsy (usually not needed)
  • Lumbar puncture

Histologic Findings

  • Metachromatic granules are found in biopsy specimens from peripheral nerves, the kidney, or the gallbladder.
  • Widespread loss of myelin in the CNS and peripheral nerves may be present.

Staging

Characteristics of the 4 Forms of Metachromatic Leukodystrophy

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Table
FormAge at
Onset
(y)		Inheritance
Pattern		FrequencyNeurocognitive
Deficit		ProgressionEffect of Bone
Marrow
Transplantation
Late infantile<4Autosomal
recessive		Most commonMotor milestones lost,
neurocognitive functions lost		Death within 5-6 yNot helpful in
symptomatic patients;
may halt cognitive
deterioration in
asymptomatic patients
Early juvenile4-6Autosomal
recessive		Less commonMotor milestones lost,
learning and behavior
impaired		Death within
10-15 y		May be beneficial in symptomatic and asymptomatic patients
Late juvenile6-16Autosomal
recessive		RarePersonality changes,
behavioral changes,
dementia, psychoses,
decreased school or
work performance		SlowMay be beneficial in asymptomatic or mildly symptomatic patients
Adult>16Autosomal
recessive		RarePersonality changes,
behavioral changes,
dementia, psychoses,
decreased school or
work performance		SlowMay be beneficial in asymptomatic or mildly symptomatic patients
FormAge at
Onset
(y)		Inheritance
Pattern		FrequencyNeurocognitive
Deficit		ProgressionEffect of Bone
Marrow
Transplantation
Late infantile<4Autosomal
recessive		Most commonMotor milestones lost,
neurocognitive functions lost		Death within 5-6 yNot helpful in
symptomatic patients;
may halt cognitive
deterioration in
asymptomatic patients
Early juvenile4-6Autosomal
recessive		Less commonMotor milestones lost,
learning and behavior
impaired		Death within
10-15 y		May be beneficial in symptomatic and asymptomatic patients
Late juvenile6-16Autosomal
recessive		RarePersonality changes,
behavioral changes,
dementia, psychoses,
decreased school or
work performance		SlowMay be beneficial in asymptomatic or mildly symptomatic patients
Adult>16Autosomal
recessive		RarePersonality changes,
behavioral changes,
dementia, psychoses,
decreased school or
work performance		SlowMay be beneficial in asymptomatic or mildly symptomatic patients

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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