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

Krabbe Disease: Differential Diagnoses & Workup

Author: David H Tegay, DO, FACMG, Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center
Contributor Information and Disclosures

Updated: Dec 4, 2008

Differential Diagnoses

Gaucher Disease
GM2 Gangliosidoses
Metachromatic Leukodystrophy
Niemann-Pick Disease

Other Problems to Be Considered

Alexander disease
Canavan disease
Encephalitis
Metachromatic leukodystrophy
Multiple sclerosis
Pelizaeus-Merzbacher disease
Tay-Sachs disease
X-linked adrenoleukodystrophy

Workup

Laboratory Studies

  • Routine blood chemistries and urinalysis do not provide any significant abnormalities that assist in establishing a diagnosis of Krabbe disease.
  • Galactosylceramide beta-galactosidase (GALC) activity measurement can help confirm a diagnosis of Krabbe disease when GALC activity levels are 0-5% of reference values in peripheral blood leukocytes, cultured fibroblasts, cultured amniocytes, and chorionic villi. Because overlap is often observed between unaffected noncarriers and heterozygote carriers, screening for heterozygote carriers by enzyme analysis is unreliable. The level of GALC activity does not absolutely delineate clinical subtypes.4,25,26
  • After establishing a diagnosis of Krabbe disease by GALC assay, molecular analysis to provide GALC genotyping can help detect heterozygous carriers and identify candidates for prenatal testing.25
  • CSF analysis in patients with Krabbe disease reveals highly elevated protein levels in patients with types 1 and 2 Krabbe disease, an abnormal protein electrophoresis pattern (elevated albumin and alpha2-globulin levels, decreased beta1-globulin and gamma-globulin levels), and a cell count within the reference range.5
  • Assay of GALC activity levels in cultured amniocytes or chorionic villi has helped provide successful prenatal diagnoses. Accurate interpretation requires that parental GALC activity levels be determined. Molecular diagnostic procedures are also available.5

Imaging Studies

  • Brain CT scans5,27 may reveal the following:
    • Progressive, diffuse, symmetric cerebral atrophy usually develops, involving both gray and white matter.
    • White matter may appear diffusely hypodense, predominantly in the parieto-occipital region.
    • Focal areas of altered signal intensity have been reported.
  • Brain MRI is a more sensitive modality with which to detect high-intensity areas of demyelination in the brainstem and cerebellum.28
  • Brain MR spectroscopy may reveal elevated myoinositol-containing and choline-containing compounds with decreased N -aspartylaspartate in affected white-matter areas.28
  • Diffusion tensor imaging is being investigated as a sensitive and noninvasive quantitative imaging technique for assessing and monitoring white-matter development in patients who have received hematopoietic stem cell transplants.29

Other Tests

  • Electroencephalography (EEG) reveals a nonspecific slowing and disorganization of background rhythm and may show evidence of epileptogenic activity.
  • Electromyography (EMG) changes often are consistent with peripheral neuropathy.
  • Tests for brainstem-evoked auditory responses (BEAR) and visual-evoked potentials (VEP) show only nonspecific abnormalities.

Procedures

  • Lumbar puncture is helpful, especially to help identify elevated CSF protein levels and an abnormal protein electrophoretic pattern.
  • Skin biopsy to quantitate GALC activity in cultured fibroblasts is not necessary for diagnosis because GALC activity levels can be detected in peripheral blood leukocytes.
  • Brain biopsy was, is, and will continue to be the last resort for diagnosis. Brain biopsy has rarely been necessary since the advent of enzymatic and molecular testing.

Histologic Findings

  • White matter demonstrates gliosis, demyelination, secondary axonal degeneration, severely diminished numbers of oligodendroglial cells, and multinucleated macrophages with abundant cytoplasm (globoid cells) that cluster around blood vessels.5,30
  • Gray matter may show neuronal degeneration.
  • Peripheral nerves demonstrate demyelination, endoneural fibrosis, fibroblast proliferation, and perivascular histiocyte-macrophage aggregation.19

More on Krabbe Disease

Overview: Krabbe Disease
Differential Diagnoses & Workup: Krabbe Disease
Treatment & Medication: Krabbe Disease
Follow-up: Krabbe Disease
References
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References

  1. Suzuki K, Suzuki Y. Globoid cell leucodystrophy (Krabbe's disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci U S A. Jun 1970;66(2):302-9. [Medline].

  2. Cleland WW, Kennedy EP. The enzymatic synthesis of psychosine. J Biol Chem. Jan 1960;235:45-51. [Medline]. [Full Text].

  3. Krabbe K. A new familial, infantile form of diffuse brain sclerosis. Brain. 1916;39:74.

  4. Suzuki K. Globoid cell leukodystrophy (Krabbe's disease): update. J Child Neurol. Sep 2003;18(9):595-603. [Medline].

  5. Wenger DA, Suzuki K, Suzuki Y, Suzuki K. 147. In: Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID). McGraw-Hill; New York, NY: McGraw-Hill:2005.

  6. Caniglia M, Rana I, Pinto RM, et al. Allogeneic bone marrow transplantation for infantile globoid-cell leukodystrophy (Krabbe's disease). Pediatr Transplant. Oct 2002;6(5):427-31. [Medline].

  7. Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med. May 19 2005;352(20):2069-81. [Medline].

  8. Krivit W, Shapiro EG, Peters C, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. Apr 16 1998;338(16):1119-26. [Medline]. [Full Text].

  9. Martin PL, Carter SL, Kernan NA, et al. 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].

  10. Meikle PJ, Ranieri E, Simonsen H, et al. Newborn screening for lysosomal storage disorders: clinical evaluation of a two-tier strategy. Pediatrics. Oct 2004;114(4):909-16. [Medline]. [Full Text].

  11. Igisu H, Suzuki K. Progressive accumulation of toxic metabolite in a genetic leukodystrophy. Science. May 18 1984;224(4650):753-5. [Medline].

  12. Miyatake T, Suzuki K. Globoid cell leukodystrophy: additional deficiency of psychosine galactosidase. Biochem Biophys Res Commun. Aug 7 1972;48(3):539-43. [Medline].

  13. Zlotogora J, Regev R, Zeigler M, et al. Krabbe disease: increased incidence in a highly inbred community. Am J Med Genet. Aug 1985;21(4):765-70. [Medline].

  14. Wenger DA, Rafi MA, Luzi P. Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications. Hum Mutat. 1997;10(4):268-79. [Medline].

  15. Loonen MC, Van Diggelen OP, Janse HC, Kleijer WJ, Arts WF. Late-onset globoid cell leucodystrophy (Krabbe's disease). Clinical and genetic delineation of two forms and their relation to the early-infantile form. Neuropediatrics. Aug 1985;16(3):137-42. [Medline].

  16. Lyon G, Hagberg B, Evrard P, et al. Symptomatology of late onset Krabbe's leukodystrophy: the European experience. Dev Neurosci. 1991;13(4-5):240-4. [Medline].

  17. Hagberg B. The clinical diagnosis of Krabbe's infantile leucodystrophy. Acta Paediatr Scand. 1963;52:213.

  18. Dunn HG, Lake BD, Dolman CL, Wilson J. The neuropathy of Krabbe's infantile cerebral sclerosis (globoid cell leucodystrophy). Brain. 1969;92(2):329-44. [Medline].

  19. Korn-Lubetzki I, Dor-Wollman T, Soffer D, et al. Early peripheral nervous system manifestations of infantile Krabbe disease. Pediatr Neurol. Feb 2003;28(2):115-8. [Medline].

  20. Sedel F, Tourbah A, Fontaine B, Lubetzki C, Baumann N, Saudubray JM. Leukoencephalopathies associated with inborn errors of metabolism in adults. J Inherit Metab Dis. Jun 2008;31(3):295-307. [Medline].

  21. Nyhan WL, Ozand PT. Krabbe disease/galactosylceramide lipidosis/globoid cell leukodystrophy. In: Atlas of Metabolic Disease. New York, NY: Chapman & Hall Medical; 1998:581-5.

  22. Luzi P, Rafi MA, Wenger DA. Structure and organization of the human galactocerebrosidase (GALC) gene. Genomics. Mar 20 1995;26(2):407-9. [Medline].

  23. Oehlmann R, Zlotogora J, Wenger DA, Knowlton RG. Localization of the Krabbe disease gene (GALC) on chromosome 14 by multipoint linkage analysis. Am J Hum Genet. Dec 1993;53(6):1250-5. [Medline].

  24. Farrell DF, Percy AK, Kaback MM, McKhann GM. Globoid cell (Krabbe's) leukodystrophy: heterozygote detection in cultured skin fibroblasts. Am J Hum Genet. Nov 1973;25(6):604-9. [Medline].

  25. Wenger DA, Sattler M, Clark C, McKelvey H. An improved method for the identification of patients and carriers of Krabbe's disease. Clin Chim Acta. Oct 30 1974;56(2):199-206. [Medline].

  26. Bowen DM, Radin NS. Cerebroside galactosidase: a method for determination and a comparison with other lysosomal enzymes in developing rat brain. J Neurochem. Apr 1969;16(4):501-11. [Medline].

  27. Lane B, Carroll BA, Pedley TA. Computerized cranial tomography in cerebral diseases of white matter. Neurology. Jun 1978;28(6):534-44. [Medline].

  28. Brockmann K, Dechent P, Wilken B, et al. Proton MRS profile of cerebral metabolic abnormalities in Krabbe disease. Neurology. Mar 11 2003;60(5):819-25. [Medline].

  29. Provenzale JM, Escolar M, Kurtzberg J. Quantitative analysis of diffusion tensor imaging data in serial assessment of krabbe disease. Ann N Y Acad Sci. Dec 2005;1064:220-9. [Medline].

  30. Austin JH, Lehfeldt D. Studies in globoid (Krabbe) leucodystrophy. 3. Significance of experimentally produced globoid-like elements in rat white matter and spleen. J Neuropathol Exp Neurol. Apr 1965;24:265-89. [Medline].

  31. Tokimasa S, Ohta H, Takizawa S, et al. Umbilical cord-blood transplantations from unrelated donors in patients with inherited metabolic diseases: Single-institute experience. Pediatr Transplant. Sep 2008;12(6):672-6. [Medline].

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Further Reading

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Keywords

Krabbe disease, galactocerebrosidase deficiency, galactosylceramide beta-galactosidase deficiency, GALC deficiency, globoid cell leukodystrophy, Krabbe's disease, infantile irritability, hypertonia, hyperesthesia, psychomotor arrest, galactosylceramide lipidosis, diffuse infantile familial sclerosis, myelin sheath disorders, sphingolipidosis, hematopoietic stem cell transplantation, respiratory failure, gastroesophageal reflux, GERD

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Contributor Information and Disclosures

Author

David H Tegay, DO, FACMG, Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Stony Brook University Medical Center
David H Tegay, DO, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association, American Society of Human Genetics, and Federation of American Societies for Experimental Biology
Disclosure: Nothing to disclose.

Medical Editor

Erawati V Bawle, MD, FAAP, FACMG, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, Wayne State University School of Medicine
Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
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 broker recommendation; Avanir Pharma Stock Investment from broker recommendation

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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