The Spectrum of Krabbe Disease in Greece: Biochemical and Molecular Findings

  • Evangelia Dimitriou
  • Monica Cozar
  • Irene Mavridou
  • Daniel Grinberg
  • Lluïsa Vilageliu
  • Helen MichelakakisEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 25)


Krabbe disease is an autosomal recessive neurodegenerative lysosomal storage disease caused by the deficiency of β-galactocerebrosidase. This deficiency results in the impaired degradation of β-galactocerebroside, a major myelin lipid, and of galactosylsphingosine. Based on the age of onset of neurological symptoms, an infantile form (90% patients) and late-onset forms (10% patients) of the disease are recognized. Over 130 disease-causing mutations have been identified in the β-galactocerebrosidase gene. We present the biochemical and molecular findings in 19 cases of Krabbe disease, 17 of them unrelated, diagnosed in Greece over the last 30 years. β-Galactocerebrosidase activity assayed in leukocyte homogenates using either the tritium-labeled or the fluorescent substrate was diagnostic for all. Increased plasma chitotriosidase activity was found in 11/15 patients.

Mutational analysis, carried out in 11 unrelated cases, identified seven different mutations, four previously described (p.I250T, c.1161+6532_polyA+9kbdel, p.K139del, p.D187V) and three novel mutations (p.D610A, c.583-1 G>C, p.W132X), and seven distinct genotypes. The most prevalent mutation was mutation p.I250T, first described in a patient of Greek origin. It accounted for 36.4% (8/22) of the mutant alleles. The second most frequent mutation was c.1161+6532_polyA+9kbdel that accounted for 22.7% (5/22) of the mutant alleles. The observed frequency was lower than that described in Northern European countries and closer to that described in Italian patients.


Lysosomal Storage Disorder Lysosomal Storage Disease Infantile Form Chitotriosidase Activity Plasma Chitotriosidase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are grateful to Prof. Zafeiriou, Dr. Garoufi, Dr. Skiadas, Dr. Lourbopoulos, and all the clinicians that collaborated with us in the diagnosis of the Krabbe patients. We are also grateful to A. Bayona for technical help. This work was partially supported by grants SAF2011-25431 from the Spanish Ministry of Science and Innovation and 2009SGR971 and 2014SGR932, from the Catalan Government.


  1. Boot RG, Renkema GH, Verhoek M et al (1998) The human chitotriosidase gene. Nature of inherited enzyme deficiency. J Biol Chem 273:25680–25685CrossRefPubMedGoogle Scholar
  2. Chen YQ, Wenger DA (1993) Galactocerebrosidase from human urine: purification and partial characterization. Biochim Biophys Acta 1170:53–61CrossRefPubMedGoogle Scholar
  3. De Gasperi R, Gama Sosa MA, Sartorato EL et al (1996) Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. Am J Hum Genet 59:1233–1242PubMedPubMedCentralGoogle Scholar
  4. Debs R, Froissart R, Aubourg P et al (2013) Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review. J Inherit Metab Dis 36:859–868CrossRefPubMedGoogle Scholar
  5. Duffner PK, Barczykowski A, Kay DM et al (2012) Later onset phenotypes of Krabbe disease: results of the worldwide registry. Pediatr Neurol 46:298–306CrossRefPubMedGoogle Scholar
  6. Formici P, Radi E, Battisti C et al (2007) Psychosine induced apoptosis and cytokine activation in immune peripheral cells of Krabbe patients. J Cell Physiol 212:737–743CrossRefGoogle Scholar
  7. Foss AH, Duffner PK, Carter RL (2013) Lifetime risk estimators in epidemiological studies of Krabbe disease: review and Monte Carlo comparison. Rare Dis 1:e25212Google Scholar
  8. Graziano ACE, Cardile V (2015) History, genetic, and recent advances on Krabbe disease. Gene 555:2–13CrossRefPubMedGoogle Scholar
  9. Harzer K, Knoblich R, Rolfs BP, Eggers J (2002) Residual galactosylsphingosine (psychosine) beta-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease. Clin Chim Acta 317:77–84CrossRefPubMedGoogle Scholar
  10. Hollak CE, van Weely S, van Oers MH, Aerts JM (1994) Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 93:1288–1292CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hult M, Darin N, von Doblen MJE (2014) Epidemiology of lysosomal storage diseases in Sweden. Acta Paediatr 103:1258–1263CrossRefPubMedGoogle Scholar
  12. Kleijer WJ, Keulemans JLM, van Der Kraan M et al (1997) Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin. JInher Metab Dis 20:587–594CrossRefGoogle Scholar
  13. Kolodny EH, Raghavan S, Krivit W (1991) Late-onset Krabbe disease (globoid cell leukodystrophy): clinical and biochemical features of 15 cases. Dev Neurosci 13:232–239CrossRefPubMedGoogle Scholar
  14. Lee WC, Kang D, Causevic E, Herdt AR, Eckman EA, Ekman CB (2010) Molecular characterization of mutations that cause globoid cell leukodystrophy and pharmacological rescue using small molecule chemical chaperones. J Neurosci 30:5489–5497CrossRefPubMedPubMedCentralGoogle Scholar
  15. Luzi P, Rafi MA, Wenger DA (1995) Characterization of the large deletion in the GALC gene found in patients with Krabbe disease. Hum Mol Genet 4:2335–2338CrossRefPubMedGoogle Scholar
  16. Luzi P, Rafi MA, Wenger DA (1996) Multiple mutations in the GALC gene in a patient with adult-onset Krabbe disease. Ann Neurol 40:116–119CrossRefPubMedGoogle Scholar
  17. Michelakakis H, Dimitriou E, Labadaridis I (2004) The expanding spectrum of disorders with elevated plasma chitotriosidase activity: an update. J Inher Metab Dis 27:705–706CrossRefPubMedGoogle Scholar
  18. Parsqui AL, Di Renzo M, Auteri A, Federico G, Puccelti L (2007) Increased TNF-alpha production by peripheral blood mononuclear cells in patients with Krabbe’s disease: effect of psychosine. Eur J Clin Invest 37:742–745CrossRefGoogle Scholar
  19. Rafi MA, Luzi P, Chen YQ, Wenger DA (1995) A large deletion together with a point mutation in the GALC gene is a common mutant allele in patients with infantile Krabbe disease. Hum Mol Genet 4:1285–1289CrossRefPubMedGoogle Scholar
  20. Rafi MA, Luzi P, Zlotogora J, Wenger DA (1996) Two different mutations are responsible for Krabbe disease in Druze and Moslem Arab populations in Israel. Hum Genet 97:304–308CrossRefPubMedGoogle Scholar
  21. Rodriguez-Pascau L, Gort L, Schuchman EH, Vilageliu L, Gringberg D, Chabas A (2009) Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients. Hum Mutat 30:1117–1122CrossRefPubMedPubMedCentralGoogle Scholar
  22. Sakai N, Inui K, Fujii N et al (1994) Krabbe disease: isolation and characterization of a full-length cDNA for human galactocerebrosidase. Biochem Biophys Res Commun 198:485–491CrossRefPubMedGoogle Scholar
  23. Suzuki K (1998) Twenty five years of the “psychosine hypothesis”: a personal perspective of its history and present status. Neurochem Res 23:251–272CrossRefPubMedGoogle Scholar
  24. Svennerholm L, Vanier MT, Mansson JE (1980) Krabbe disease: a galactosylsphingosine (psychosine) lipidosis. J Lipid Res 21:53–64PubMedGoogle Scholar
  25. Tanaka K, Nagara H, Kobayashi T, Goto I (1989) The twitcher mouse: accumulation of galactosylsphingosine and pathology of the central nervous system. Brain Res 482:347–450CrossRefPubMedGoogle Scholar
  26. Tappino B, Biancheri R, Mort M et al (2010) Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease. Hum Mutat 31:E1894–E1914CrossRefPubMedPubMedCentralGoogle Scholar
  27. Wajner A, Michelin K, Burin MG et al (2006) Comparison between the biochemical properties of plasma chitotriosidase from normal individuals and from patients with Gaucher disease, GM1-gangliosidosis, Krabbe disease and heterozygotes for Gaucher disease. Clin Biochem 40:365–369CrossRefGoogle Scholar
  28. Wenger DA (2008) Krabbe disease. In: Gene reviews and gene tests: medical genetics information resource (database on line). Copyright, University Washington, Seattle. 1997–2010.
  29. Wenger DA, Rafi MA, Luzi P (1997) Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications. Hum Mutat 10:268–279CrossRefPubMedGoogle Scholar
  30. Wenger DA, Suzuki K, Suzuki Y (2001) Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Chilids B, Vogelstein D (eds) The metabolic and molecular bases of inherited disease. McGraw Hill, New York, pp 3669–3694Google Scholar
  31. Wenger DA, Escolar MI, Luzi P, Rafi MA (2013) Krabbe disease (globoid cell leukodystrophy). In: Valle D, Beaudet AL, Vogelstein D, Kinzler KW, Antonarakis SE, Ballabio A (eds) The online metabolic and molecular bases of inherited disease. McGraw Hill, New YorkGoogle Scholar
  32. Wenger DA, Luzi P, Rafi AM (2014) Krabbe disease: are certain mutations disease-causing only when specific polymorphisms are present or when inherited in trans with specific second mutations? Mol Genet Metab 111:307–308CrossRefPubMedGoogle Scholar
  33. Wiederschain G, Raghavan S, Kolodny E (1992) Characterization of 6-hexadecanoylamino-4-methylumbelliferyl-beta-D-galactopyranoside as fluorogenic substrate of galactocerebrosidase for the diagnosis of Krabbe disease. Clin Chim Acta 205:87–96CrossRefPubMedGoogle Scholar
  34. Xu C, Sakai N, Taniike M, Inui K, Ozono K (2006) Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype-phenotype correlation. J Hum Genet 15:548–554CrossRefGoogle Scholar
  35. Young E, Wilson J, Patrick AD, Chrome L (1972) Galactocerebrosidase deficiency in globoid cell leukodystrophy of late onset. Arch Dis Child 47:449–450CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Evangelia Dimitriou
    • 1
  • Monica Cozar
    • 2
  • Irene Mavridou
    • 1
  • Daniel Grinberg
    • 2
  • Lluïsa Vilageliu
    • 2
  • Helen Michelakakis
    • 1
    Email author
  1. 1.Department Enzymology and Cellular FunctionInstitute of Child HealthAthensGreece
  2. 2.Department of Genetics, Faculty of BiologyUniversitat de Barcelona, IBUB, CIBERERBarcelonaSpain

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