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Pathway Description
Globoid Cell Leukodystrophy
Homo sapiens
Disease Pathway
Globoid Cell Leukodistrophy (GLD), also called Krabbe disease and galactosylceramide lipidosis, is an extremely rare inherited inborn error of metabolism (IEM). It is a degenerative disorder that affects the nervous system. It has an estimated prevalence of 1/100,000 in the Northern European population and a worldwide incidence of 1/100,000-1/250,000 live births. GLD is an autosomal recessive disorder that is caused by a deficiency of an enzyme called galactosylceramidase. Galactosylceramidase is a lysosomal protein that hydrolyzes the galactose ester bonds of ceramides and ceramide derivatives including galactocerebroside, galactosylsphingosine (psychosine), lactosylceramide, and monogalactosyldiglyceride. More specifically, galactosylceramidase is an enzyme that is involved in the catabolism (via the removal of galactose) of galactosylceramide, a major lipid in myelin, kidney, and epithelial cells of the small intestine and colon. Defects in galactosylceramidase lead to the accumulation of cytotoxic psychosine, which ultimately leads to apoptosis of oligodendrocytes and demyelination. As a result, this enzyme deficiency impairs the growth and maintenance of myelin, the protective sheath around nerve cell axons that ensures that electrical impulses are rapidly transmitted. GLD is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). GLD is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that often have multiple nuclei. There are three different phenotypes for GLD: infantile, juvenile, and late-onset. Neurodegeneration and early death (at age 2-3) occur in most infantile cases. In juvenile patients, the disease is often fatal 2-7 years after the symptoms begin. Adult-onset patients can survive many years after symptoms first manifest. The symptoms of infantile GLD usually begin during the first year of life. Typically, the initial signs and symptoms include feeding difficulties, episodes of fever without any sign of infection, irritability, stiff posture, muscle weakness, and slowed mental and physical development. Muscles continue to weaken as the disease progresses which decreases the infant's ability to move, chew, swallow, and breathe. It is also common for affected infants to experience vision loss and seizures. Treatment is limited to hematopoietic stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients. Stem cell transplants have been shown to slow the progression of the disease.
References
Globoid Cell Leukodystrophy References
[Uniprot: P54803](http://www.uniprot.org/uniprot/P54803)
[OMIM: Entry 245200](http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=245200)
Arroyo HA, Grippo J, Taratuto A, Duffau J, Chamoles N: Krabbe disease in monozygotic triplets. Dev Med Child Neurol. 1991 Dec;33(12):1101-3.
Pubmed: 1778346
De Gasperi R, Gama Sosa MA, Sartorato EL, Battistini S, MacFarlane H, Gusella JF, Krivit W, Kolodny EH: Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. Am J Hum Genet. 1996 Dec;59(6):1233-42.
Pubmed: 8940268
Duchen LW, Eicher EM, Jacobs JM, Scaravilli F, Teixeira F: Hereditary leucodystrophy in the mouse: the new mutant twitcher. Brain. 1980 Sep;103(3):695-710.
Pubmed: 7417782
Furuya H, Kukita Y, Nagano S, Sakai Y, Yamashita Y, Fukuyama H, Inatomi Y, Saito Y, Koike R, Tsuji S, Fukumaki Y, Hayashi K, Kobayashi T: Adult onset globoid cell leukodystrophy (Krabbe disease): analysis of galactosylceramidase cDNA from four Japanese patients. Hum Genet. 1997 Sep;100(3-4):450-6.
Pubmed: 9272171
Husain AM, Altuwaijri M, Aldosari M: Krabbe disease: neurophysiologic studies and MRI correlations. Neurology. 2004 Aug 24;63(4):617-20.
Pubmed: 15326231
Kolodny EH, Raghavan S, Krivit W: Late-onset Krabbe disease (globoid cell leukodystrophy): clinical and biochemical features of 15 cases. Dev Neurosci. 1991;13(4-5):232-9. doi: 10.1159/000112166.
Pubmed: 1817026
Xu C, Sakai N, Taniike M, Inui K, Ozono K: Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype-phenotype correlation. J Hum Genet. 2006;51(6):548-54. doi: 10.1007/s10038-006-0396-3. Epub 2006 Apr 11.
Pubmed: 16607461
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. doi: 10.1002/(SICI)1098-1004(1997)10:4<268::AID-HUMU2>3.0.CO;2-D.
Pubmed: 9338580
Li Y, Sands MS: Experimental therapies in the murine model of globoid cell leukodystrophy. Pediatr Neurol. 2014 Nov;51(5):600-6. doi: 10.1016/j.pediatrneurol.2014.08.003. Epub 2014 Aug 8.
Pubmed: 25240259
Sphingolipid Metabolism References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Vance, D.E., and Vance, J.E. Biochemistry of lipids, lipoproteins, and membranes (4th ed.) (2002) Amsterdam; Boston: Elsevier.
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