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Metachromatic Leukodystrophy Workup

  • Author: Alan K Ikeda, MD; Chief Editor: Luis O Rohena, MD  more...
 
Updated: Aug 21, 2014
 

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.[6]

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Imaging Studies

Brain MRI may be performed to identify white matter lesions and atrophy, which are characteristic of metachromatic leukodystrophy but nonspecific.[7]

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Other Tests

The following tests may be indicated:

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

The following procedures may be indicated:

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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.

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Staging

Table 1. Characteristics of the 4 Forms of Metachromatic Leukodystrophy (Open Table in a new window)

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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Contributor Information and Disclosures
Author

Alan K Ikeda, MD Interim Medical Director, Director of Oncology, Children's Specialty Center of Las Vegas

Alan K Ikeda, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, American Society for Blood and Marrow Transplantation

Disclosure: Nothing to disclose.

Coauthor(s)

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

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 and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

Theodore Moore, MD, MS Professor and Chief, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Director of Pediatric Blood and Marrow Transplant Program, University of California, Los Angeles, David Geffen School of Medicine

Theodore Moore, MD, MS is a member of the following medical societies: American Society of Pediatric Hematology/Oncology, Society for Pediatric Research, American Society for Blood and Marrow Transplantation, Western Society for Pediatric Research, American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Karl S Roth, MD Retired 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 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, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

References
  1. Gieselmann V, Krägeloh-Mann I. Metachromatic leukodystrophy--an update. Neuropediatrics. 2010 Feb. 41(1):1-6. [Medline].

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

  3. von Figura K, Gieselman V, Jaeken J. Metachromatic leukodystrophy. 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.

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

  5. 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. 1999 Jun. 53(3):425-8. [Medline].

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

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

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

  9. 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. 2006 Feb. 12(2):184-94. [Medline].

  10. 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. 2001 Mar. 7(3):310-6. [Medline].

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

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

  13. Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 23. 341(6148):1233158. [Medline].

  14. 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. 2005 May. 14(9):1139-1152. [Medline].

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

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

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

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

 
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Table 1. Characteristics of the 4 Forms of Metachromatic Leukodystrophy
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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