- Author: David H Tegay, DO, FACMG; Chief Editor: Luis O Rohena, MD more...
Krabbe disease is an autosomal recessive sphingolipidosis caused by deficient activity of the lysosomal hydrolase galactosylceramide beta-galactosidase (GALC). GALC degrades galactosylceramide, a major component of myelin, and other terminal beta-galactose–containing sphingolipids, including psychosine (galactosylsphingosine). Increased psychosine levels are believed to lead to widespread destruction of oligodendroglia in the CNS and to subsequent demyelination.[1, 2, 3]
Krabbe originally described a condition with infantile onset that was characterized by spasticity and a rapidly progressive neurologic degeneration leading to death. Since the original description, numerous cases have been documented that show a wide distribution in age of onset.
Krabbe disease has the following 4 clinical subtypes, distinguished by age of onset:
Type 1 - Infantile
Type 2 - Late infantile
Type 3 - Juvenile
Type 4 - Adult
Hallmarks of the classic infantile form include irritability, hypertonia, hyperesthesia, and psychomotor arrest, followed by rapid deterioration, elevated protein levels in cerebrospinal fluid (CSF), neuroradiologic evidence of white matter disease, optic atrophy, and early death.
Studies indicate that early unrelated hematopoietic stem cell transplantation in both the infantile and late-onset forms is associated with at least short-term benefits on neurocognitive parameters, lifespan, and quality of life.[7, 8, 9, 10] Because of this evidence of success, the addition of Krabbe disease to newborn screening panels has occurred in some states and is under consideration in others.
Galactosylceramide (galactocerebroside) is biosynthesized via galactosylation of ceramide (N- acyl-sphingosine). Galactosylceramide is highly concentrated in the myelin sheath, where it is synthesized in oligodendroglia and Schwann cells; it is practically absent in systemic organs with the exception of the kidneys. Galactosylceramide can be converted to sulfatide by adding a sulfate group. Galactosylceramide degradation is catalyzed by GALC, a lysosomal hydrolase. Psychosine (galactosylsphingosine) is synthesized by direct galactosylation of sphingosine and is also degraded by GALC.[2, 12] (Other compounds, such as monogalactosyldiglyceride and lactosylceramide, also are degraded by GALC but are not believed to be involved in the pathogenesis of Krabbe disease.)
Peak synthesis and turnover of galactosylceramide coincides with the peak period of myelin formation and turnover during the first 18 months of life. Myelination continues, albeit at a slower rate, through the first 2 decades of life before reaching a stable state with minimal turnover. GALC activity also increases in relation to this peak.
In Krabbe disease, myelin composition is not qualitatively abnormal. However, because of deficient GALC activity (0-5% reference value), galactosylceramide accumulation occurs, particularly during the early period of rapid myelin turnover. This accumulation causes formation of globoid cells (hematogenous often-multinucleated macrophages containing undigested galactosylceramide), which is the histologic hallmark of Krabbe disease. Psychosine also accumulates and is thought to be a highly cytotoxic substance and responsible for the widespread destruction of myelin-producing oligodendroglia.[2, 12, 13]
A study by White et al found that psychosine's cytotoxic effects on oligodendroglia and Schwann cells was mediated through disruption of the architecture and composition of lipid rafts (cell membrane regions characterized by high cholesterol and sphingolipid concentration), followed by altered protein kinase C (PKC) function. Psychosine was found to accumulate preferentially in white matter, with associated regional cholesterol increases causing alterations of lipid raft (LR) markers flotillin-2 and caveolin-1. PKC is an important signaling molecule in numerous cell pathways, including cell differentiation, proliferation and apoptosis. PKC isozymes are LR-dependent molecules that link psychosine-induced LR disruption to reduced PKC function and altered cell signaling activity, possibly driving demyelination and apoptosis in oligodendrocytes and Schwann cells.
The rapid destruction of oligodendroglia leads to myelin breakdown, and further myelin production diminishes, causing the following:
Severe depletion of oligodendroglia
Globoid cell formation
Qualitatively normal myelin
Severely reduced levels of myelin production
Lack of increased total galactosylceramide content in the brain 
The role of various inflammatory molecules, including prostaglandin D and AMP-activated protein kinase (AMPK), in Krabbe disease progression has been explored in animal models. Upregulation of hematopoietic prostaglandin D synthase (HPGDS) causes increased prostaglandin D (PGD2) levels in microglial cells in response to progressive demyelination and is thought to be involved in inducing astrocytic gliosis through astrocytic PGD2 receptors (DP1). Blockage of HPGDS signaling pathways in the mouse twitcher model of Krabbe disease resulted in downregulation of astrocytic gliosis and demyelination, reduction in symptomatology, and decreased oligodendrocyte death.
AMPK plays a role in regulation of energy homeostasis and response to metabolic stress and is believed to possess anti-inflammatory properties. Psychosine has been shown to down-regulate AMPK activity in oligodendrocytes and astrocytes. Activation of AMPK, in animal models, resulted in restoration of lipid metabolism and decreased inflammation.
Calculated incidence of Krabbe disease is 1 case per 100,000 population.
Overall calculated European incidence is 1 case per 100,000 population, with a higher reported incidence in Sweden of 1.9 cases per 100,000 population. An unusually high incidence, 6 cases per 1000 live births, is reported in the Druze community in Israel.[6, 17]
Morbidity in patients with all subtypes arises from the primary progressive neurodegeneration of the central and peripheral nervous systems and secondary effects of the disease (ie, weakness, seizure, loss of protective reflexes, immobility). The sequelae, including infection and respiratory failure, cause most deaths.
Krabbe disease is panethnic, although most reported cases have been among people of European ancestry. Late-onset Krabbe disease may be more common in southern Europe.
Krabbe disease is inherited as an autosomal recessive trait and equally affects both sexes.
Typical age of onset is 3-6 months for the infantile form of Krabbe disease (type 1), 6 months to 3 years for the late infantile form (type 2), 3-8 years for the juvenile form (type 3), and older than 8 years for the adult form (type 4).[5, 6, 20, 21]
Suzuki K, Suzuki Y. Globoid cell leucodystrophy (Krabbe's disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci U S A. 1970 Jun. 66(2):302-9. [Medline].
Graziano AC, Cardile V. History, genetic, and recent advances on Krabbe disease. Gene. 2015 Jan 15. 555(1):2-13. [Medline].
Krabbe K. A new familial, infantile form of diffuse brain sclerosis. Brain. 1916. 39:74.
Suzuki K. Globoid cell leukodystrophy (Krabbe's disease): update. J Child Neurol. 2003 Sep. 18(9):595-603. [Medline].
Wenger DA, Suzuki K, Suzuki Y, Suzuki K. 147. 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.
Caniglia M, Rana I, Pinto RM, et al. Allogeneic bone marrow transplantation for infantile globoid-cell leukodystrophy (Krabbe's disease). Pediatr Transplant. 2002 Oct. 6(5):427-31. [Medline].
Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med. 2005 May 19. 352(20):2069-81. [Medline].
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. 2006 Feb. 12(2):184-94. [Medline].
Igisu H, Suzuki K. Progressive accumulation of toxic metabolite in a genetic leukodystrophy. Science. 1984 May 18. 224(4650):753-5. [Medline].
Miyatake T, Suzuki K. Globoid cell leukodystrophy: additional deficiency of psychosine galactosidase. Biochem Biophys Res Commun. 1972 Aug 7. 48(3):539-43. [Medline].
White AB, Givogri MI, Lopez-Rosas A, Cao H, van Breemen R, Thinakaran G. Psychosine accumulates in membrane microdomains in the brain of krabbe patients, disrupting the raft architecture. J Neurosci. 2009 May 13. 29(19):6068-77. [Medline].
Mohri I, Taniike M, Taniguchi H, Kanekiyo T, Aritake K, Inui T. Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher. J Neurosci. 2006 Apr 19. 26(16):4383-93. [Medline].
Giri S, Khan M, Nath N, Singh I, Singh AK. The role of AMPK in psychosine mediated effects on oligodendrocytes and astrocytes: implication for Krabbe disease. J Neurochem. 2008 Jun. 105(5):1820-33. [Medline].
Zlotogora J, Regev R, Zeigler M, et al. Krabbe disease: increased incidence in a highly inbred community. Am J Med Genet. 1985 Aug. 21(4):765-70. [Medline].
Barczykowski AL, Foss AH, Duffner PK, Yan L, Carter RL. Death rates in the U.S. due to Krabbe disease and related leukodystrophy and lysosomal storage diseases. Am J Med Genet A. 2012 Nov. 158A(11):2835-42. [Medline].
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].
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. 1985 Aug. 16(3):137-42. [Medline].
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].
Hagberg B. The clinical diagnosis of Krabbe's infantile leucodystrophy. Acta Paediatr Scand. 1963. 52:213.
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].
Korn-Lubetzki I, Dor-Wollman T, Soffer D, et al. Early peripheral nervous system manifestations of infantile Krabbe disease. Pediatr Neurol. 2003 Feb. 28(2):115-8. [Medline].
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. 2008 Jun. 31(3):295-307. [Medline].
Duffner PK, Barczykowski A, Kay DM, Jalal K, Yan L, Abdelhalim A, et al. Later onset phenotypes of Krabbe disease: results of the world-wide registry. Pediatr Neurol. 2012 May. 46(5):298-306. [Medline].
Nyhan WL, Ozand PT. Krabbe disease/galactosylceramide lipidosis/globoid cell leukodystrophy. Atlas of Metabolic Disease. New York, NY: Chapman & Hall Medical; 1998. 581-5.
Luzi P, Rafi MA, Wenger DA. Structure and organization of the human galactocerebrosidase (GALC) gene. Genomics. 1995 Mar 20. 26(2):407-9. [Medline].
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. 1993 Dec. 53(6):1250-5. [Medline].
Farrell DF, Percy AK, Kaback MM, McKhann GM. Globoid cell (Krabbe's) leukodystrophy: heterozygote detection in cultured skin fibroblasts. Am J Hum Genet. 1973 Nov. 25(6):604-9. [Medline].
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. 1974 Oct 30. 56(2):199-206. [Medline].
Bowen DM, Radin NS. Cerebroside galactosidase: a method for determination and a comparison with other lysosomal enzymes in developing rat brain. J Neurochem. 1969 Apr. 16(4):501-11. [Medline].
Tokushige SI, Sonoo T, Maekawa R, Shirota Y, Hanajima R, Terao Y, et al. Isolated pyramidal tract impairment in the central nervous system of adult-onset Krabbe disease with novel mutations in the GALC gene. Brain Dev. 2012 Sep 5. [Medline].
Camelier M, Civallero G, De Mari J, Burin M, Giugliani R. Galactocerebrosidase assay on dried-leukocytes impregnated in filter paper for the detection of Krabbe disease. Clin Chim Acta. 2015 Jan 1. 438:178-80. [Medline].
Duffner PK, Caggana M, Orsini JJ, et al. Newborn screening for Krabbe disease: the New York State model. Pediatr Neurol. 2009 Apr. 40(4):245-52; discussion 253-5. [Medline].
Lane B, Carroll BA, Pedley TA. Computerized cranial tomography in cerebral diseases of white matter. Neurology. 1978 Jun. 28(6):534-44. [Medline].
Brockmann K, Dechent P, Wilken B, et al. Proton MRS profile of cerebral metabolic abnormalities in Krabbe disease. Neurology. 2003 Mar 11. 60(5):819-25. [Medline].
Provenzale JM, Peddi S, Kurtzberg J, Poe MD, Mukundan S, Escolar M. Correlation of neurodevelopmental features and MRI findings in infantile Krabbe's disease. AJR Am J Roentgenol. 2009 Jan. 192(1):59-65. [Medline].
Udow S, Bunge M, Ryner L, Mhanni AA, Salman MS. Prolonged survival and serial magnetic resonance imaging/magnetic resonance spectroscopy changes in infantile Krabbe disease. Pediatr Neurol. 2012 Oct. 47(4):299-302. [Medline].
Provenzale JM, Escolar M, Kurtzberg J. Quantitative analysis of diffusion tensor imaging data in serial assessment of krabbe disease. Ann N Y Acad Sci. 2005 Dec. 1064:220-9. [Medline].
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. 1965 Apr. 24:265-89. [Medline].
Duffner PK, Caviness VS Jr, Erbe RW, Patterson MC, Schultz KR, Wenger DA. The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York. Genet Med. 2009 Jun. 11(6):450-4. [Medline].
Luzi P, Abraham RM, Rafi MA, Curtis M, Hooper DC, Wenger DA. Effects of treatments on inflammatory and apoptotic markers in the CNS of mice with globoid cell leukodystrophy. Brain Res. 2009 Dec 1. 1300:146-58. [Medline].
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. 2008 Sep. 12(6):672-6. [Medline].