Journal of Inherited Metabolic Disease

, Volume 36, Issue 5, pp 859–868 | Cite as

Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review

  • Rabab Debs
  • Roseline Froissart
  • Patrick Aubourg
  • Caroline Papeix
  • Claire Douillard
  • Bertrand Degos
  • Bertrand Fontaine
  • Bertrand Audoin
  • Arnaud Lacour
  • Gérard Said
  • Marie T. Vanier
  • Frédéric Sedel
Original Article


Krabbe disease usually presents as a severe leukodystrophy in early infancy and childhood. From a series of 11 patients and 30 cases previously reported in the literature we describe the clinical, radiological, electrophysiological and genetic features of adult Krabbe disease. Patients diagnosed after the age of 16 years were included in this study. They were further divided into three groups depending on age at symptoms onset: (1) childhood onset cases (n = 7); (2) adolescence onset cases (n = 6) and adult onset cases (n = 28). Overall, 96 % of patients in the adult-onset group presented with signs of pyramidal tracts dysfunction. Spastic paraparesis or tetraparesis became prominent in all cases. A peripheral neuropathy was present in 59 % of cases and was most often demyelinating (80 %). Other clinical signs encompassed dysarthria (31 %), cerebellar ataxia (27 %), pes cavus (27 %), deep sensory signs (23 %), tongue atrophy (15 %), optic neuropathy (12 %), cognitive decline (12 %). Cerebrospinal fluid protein concentration was moderately increased in 54 % of patients. Patients in the adolescent- and childhood-onset groups had similar presentations but were more likely to display optic neuropathy (33 % and 57 %) and cerebellar ataxia (50 % and 57 %). In the adult-onset group, the disease progressed slowly over more than 10 years, but a rapid course was observed in two patients. Abnormalities of brain MRI was similar in the three groups and included high signals of cortico-spinal tracts (94 % of cases), hyper-intensities of optic radiations (89 %) and hyper-intensities or atrophy of the posterior part of the corpus callosum (60 %). No clear genotype-phenotype relationship could be demonstrated.


Cerebellar Ataxia Spastic Paraparesis Charcot Marie Tooth Disease Charcot Marie Tooth Infantile Form 
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.


Conflict of interest



  1. Bajaj NP, Waldman A, Orrell R, Wood NW, Bhatia KP (2002) Familial adult onset of Krabbe’s disease resembling hereditary spastic paraplegia with normal neuroimaging. J Neurol Neurosurg Psychiatry 72:635–638CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bataillard M, Richard P, Rumbach L, Vanier MT, Truttmann M (1997) Isolated spastic paraparesis disclosing Krabbe disease in adult age. Rev Neurol (Paris) 153:347–350Google Scholar
  3. Bernardini GL, Herrera DG, Carson D et al (1997) Adult-onset Krabbe’s disease in siblings with novel mutations in the galactocerebrosidase gene. Ann Neurol 41:111–114CrossRefPubMedGoogle Scholar
  4. 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
  5. De Gasperi R, Gama Sosa MA, Sartorato E, Battistini S, Raghavan S, Kolodny EH (1999) Molecular basis of late-life globoid cell leukodystrophy. Hum Mutat 14:256–262CrossRefPubMedGoogle Scholar
  6. De Jesus VR, Zhang XK, Keutzer J et al (2009) Development and evaluation of quality control dried blood spot materials in newborn screening for lysosomal storage disorders. Clin Chem 55:158–164CrossRefPubMedGoogle Scholar
  7. De Stefano N, Dotti MT, Mortilla M et al (2000) Evidence of diffuse brain pathology and unspecific genetic characterization in a patient with an atypical form of adult-onset Krabbe disease. J Neurol 247:226–228CrossRefPubMedGoogle Scholar
  8. Duffner PK, Barczykowski A, Kay DM et al (2012) Later onset phenotypes of Krabbe Disease: results of the world-wide registry. Pediatr Neurol 46:298–306CrossRefPubMedGoogle Scholar
  9. Escolar ML, Poe MD, Provenzale JM et al (2005) Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. N Engl J Med 352:2069–2081CrossRefPubMedGoogle Scholar
  10. Farina L, Bizzi A, Finocchiaro G (2000) MR imaging and proton MR spectroscopy in adult Krabbe disease. AJNR Am J Neuroradiol 21:1478–1482PubMedGoogle Scholar
  11. Fontaine B, Thenin JP, Viader F (2003) Gait disorders with insidious progression in a 60-year old woman. Rev Neurol (Paris) 159:695–699Google Scholar
  12. Grewal RP, Petronas N, Barton NW (1991) Late onset globoid cell leukodystrophy. J Neurol Neurosurg Psychiatry 54:1011–1012CrossRefPubMedPubMedCentralGoogle Scholar
  13. Hagberg B, Sourander P, Svennerholm L (1963) Diagnosis of Krabbe’s infantile leucodystrophy. J Neurol Neurosurg Psychiatry 26:195–198CrossRefPubMedPubMedCentralGoogle Scholar
  14. Hagberg B, Kollberg H, Sourander P, Akesson H (1969) Infantile globoid cell leukodystrophy (Krabbe’s disease). A clinical and genetic study of 32 Swedish cases 1953–1967. Neuropadiatrie 1:74–88CrossRefPubMedGoogle Scholar
  15. Harzer K, Knoblich R, Rolfs A, Bauer P, 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
  16. Henderson RD, MacMillan JC, Bradfield JM (2003) Adult onset Krabbe disease may mimic motor neurone disease. J Clin Neurosci 10:638–639CrossRefPubMedGoogle Scholar
  17. Husain AM, Altuwaijri M, Aldosari M (2004) Krabbe disease: neurophysiologic studies and MRI correlations. Neurology 63:617–620CrossRefPubMedGoogle Scholar
  18. Jardim LB, Giugliani R, Pires RF et al (1999) Protracted course of Krabbe disease in an adult patient bearing a novel mutation. Arch Neurol 56:1014–1017CrossRefPubMedGoogle Scholar
  19. Kapoor R, McDonald WI, Crockard A, Moseley IF (1992) Clinical onset and MRI features of Krabbe’s disease in adolescence. J Neurol Neurosurg Psychiatry 55:331–332CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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
  21. Korn-Lubetzki I, Dor-Wollman T, Soffer D, Raas-Rothschild A, Hurvitz H, Nevo Y (2003) Early peripheral nervous system manifestations of infantile Krabbe disease. Pediatr Neurol 28:115–118CrossRefPubMedGoogle Scholar
  22. 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
  23. 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
  24. Lyon G, Hagberg B, Evrard P, Allaire C, Pavone L, Vanier M (1991) Symptomatology of late onset Krabbe’s leukodystrophy: the European experience. Dev Neurosci 13:240–244CrossRefPubMedGoogle Scholar
  25. Malandrini A, D’Eramo C, Palmeri S et al (2012) Peripheral neuropathy in late-onset Krabbe disease: report of three cases. Neurol Sci doi:10.1007/s10072-012-0956-6Google Scholar
  26. Morana G, Biancheri R, Dirocco M et al (2009) Enhancing cranial nerves and cauda equina: an emerging magnetic resonance imaging pattern in metachromatic leukodystrophy and krabbe disease. Neuropediatrics 40:291–294CrossRefPubMedGoogle Scholar
  27. Phelps M, Aicardi J, Vanier MT (1991) Late onset Krabbe’s leukodystrophy: a report of four cases. J Neurol Neurosurg Psychiatry 54:293–296CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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
  29. Sabatelli M, Quaranta L, Madia F et al (2002) Peripheral neuropathy with hypomyelinating features in adult-onset Krabbe’s disease. Neuromuscul Disord 12:386–391CrossRefPubMedGoogle Scholar
  30. Satoh JI, Tokumoto H, Kurohara K et al (1997) Adult-onset Krabbe disease with homozygous T1853C mutation in the galactocerebrosidase gene. Unusual MRI findings of corticospinal tract demyelination. Neurology 49:1392–1399CrossRefPubMedGoogle Scholar
  31. Sedel F, Tourbah A, Fontaine B, Lubetzki C, Baumann N, Saudubray JM, Lyon-Caen O (2008) Leukoencephalopathies associated with Inborn Errors of Metabolism in adults: a diagnostic approach. J Inherit Metab Dis 31:295–307CrossRefPubMedGoogle Scholar
  32. Siddiqi ZA, Sanders DB, Massey JM (2006) Peripheral neuropathy in Krabbe disease: effect of hematopoietic stem cell transplantation. Neurology 67:268–272CrossRefPubMedGoogle Scholar
  33. Suzuki K (1998) Twenty five years of the “psychosine hypothesis”: a personal perspective of its history and present status. Neurochem Res 23:251–259CrossRefPubMedGoogle Scholar
  34. Suzuki K, Suzuki Y (1970) Globoid cell leucodystrophy (Krabbe’s disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci U S A 66:302–309CrossRefPubMedPubMedCentralGoogle Scholar
  35. Svennerholm L, Vanier MT, Mansson JE (1980) Krabbe disease: a galactosylsphingosine (psychosine) lipidosis. J Lipid Res 21:53–64PubMedGoogle Scholar
  36. Thomas PK, Halpern JP, King RH, Patrick D (1984) Galactosylceramide lipidosis: novel presentation as a slowly progressive spinocerebellar degeneration. Ann Neurol 16:618–620CrossRefPubMedGoogle Scholar
  37. Turazzini M, Beltramello A, Bassi R, Del Colle R, Silvestri M (1997) Adult onset Krabbe’s leukodystrophy: a report of 2 cases. Acta Neurol Scand 96:413–415CrossRefPubMedGoogle Scholar
  38. Vanier MT, Svennerholm L, Månsson JE, Håkansson G, Boué A, Lindsten J (1981) Prenatal diagnosis of Krabbe disease. Clin Genet 20:79–89CrossRefPubMedGoogle Scholar
  39. Verdru P, Lammens M, Dom R, Van Elsen A, Carton H (1991) Globoid cell leukodystrophy: a family with both late-infantile and adult type. Neurology 41:1382–1384CrossRefPubMedGoogle Scholar
  40. Wang C, Melberg A, Weis J, Månsson JE, Raininko R (2007) The earliest MR imaging and proton MR spectroscopy abnormalities in adult-onset Krabbe disease. Acta Neurol Scand 116:268–272CrossRefPubMedGoogle Scholar
  41. Wenger DA (2000) Krabbe disease. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (eds) GeneReviews™ [Internet]. University of Washington, SeattleGoogle Scholar
  42. Wenger DA, Suzuki K, Suzuki Y (2001) Galctosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds) The metabolic and molecular bases of inherited disease. McGraw Hill, New York, pp 3669–3694Google Scholar
  43. Zhang XK, Elbin CS, Turecek F et al (2010) Multiplex lysosomal enzyme activity assay on dried blood spots using tandem mass spectrometry. Methods Mol Biol 603:339–350CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Rabab Debs
    • 1
  • Roseline Froissart
    • 2
  • Patrick Aubourg
    • 3
  • Caroline Papeix
    • 1
  • Claire Douillard
    • 4
  • Bertrand Degos
    • 1
  • Bertrand Fontaine
    • 1
    • 5
  • Bertrand Audoin
    • 6
  • Arnaud Lacour
    • 7
  • Gérard Said
    • 1
  • Marie T. Vanier
    • 2
    • 8
  • Frédéric Sedel
    • 1
    • 9
    • 10
  1. 1.Department of Neurology, Pitié-Salpêtrière HospitalAssistance Publique-Hôpitaux de Paris and University Pierre&Marie CurieParisFrance
  2. 2.Laboratoire des Maladies Héréditaires du Métabolisme et Laboratoire Gillet-Mérieux, Groupe Hospitalier EstHospices Civils de LyonBronFrance
  3. 3.Department of Pediatric Neurology, CHU Kremlin Bicêtre, Assistance Publique–Hôpitaux de Paris, France and INSERM UMR745University Paris-DescartesParisFrance
  4. 4.Service d’endocrinologie et maladies métaboliquesClinique endocrinologique Marc LinquetteCHU de LilleFrance
  5. 5.Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, INSERM, UMR 546ParisFrance
  6. 6.Department of NeurologyCHU de la TimoneMarseilleFrance
  7. 7.Service de Neurologie D et Centre de réference des maladies rares neuromusculairesLilleFrance
  8. 8.INSERM, Unité 820, Faculté de Médecine Lyon EstUniversité Lyon-1LyonFrance
  9. 9.Neurometabolic unit, reference center for lysosomal diseases, GRC13-UPMCParisFrance
  10. 10.Department of NeurologyHôpital de la SalpêtrièreParis cedex 13France

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