Annotated Bibliography

Beutler, E. (2004). Enzyme Replacement in Gaucher Disease. PLOS Medicine, 1(2): e21. DOI: 10.1371/journal.pmed.0010021

  • This review summarized the successful use of enzyme replacement therapy to treat the lysosomal storage disorder Gaucher Disease. This will help me as i attempt to apply the concepts of enzyme replacement therapy to Krabbe Disease.

Castelvetri, L.C., Givogri, M.I., Zhu, H., Smith, B., Lopez-Rosas, A., Qiu, X., van Breemen, R., & Bongarzone, E.R. (2011). Axonopathy is a compounding factor in the pathogenesis of Krabbe disease. Acta neuropathologica, 122(1), 35-48doi:10.1007/s00401-011-0814-2

  • This source explores the contributing factors to axonopathy and the pathologic consequences of axonopathy in vivo using the Krabbe Disease mouse model. The authors report that the galactocerebrocidase deficiency alone caused axonal swelling within a week of birth. The authors tracked the spread of axonal swelling and subsequent demyelination and death throughout the nervous system; the authors also demonstrate that adding pyschosine to healthy neurons was sufficient to induce axonal swelling and cell death.

Castelvetri, L. C.,Givogri M. I., Hebert, A., Smith, B., Yuyu, S., Kaminska, A., Lopez-Rosas, A., Morfini, G., Pigino, G., Sands, M., Brady, S.T., & Bongarzone, E.R. (2013). The sphingolipid psychosine inhibits fast axonal transport in Krabbe Disease by activation of GSK3 and deregulation of molecular motors. Society for Neuroscience, 33(4), 10048-10056. DOI:10.1523/JNEUROSCI.0217-13.2013

  • This is a landmark study as it is the first to identify a molecular mechanism by which psychosine causes dying-back degeneration (disintegration of the axonal skeleton and membrane followed by demyelination) in vivo and in vitro. Psychosine activates PP1, PP2, and GSK3β—these enzymes hyperphosphorylate kinesin light chains (KLCs) which subsequently block fast axonal transport. Inhibition of fast axonal transport has known physiological consequences such as dying-back degeneration.

Contreras, M. A., Ries, W. L., Shanmugarajan, S., Arboleda, G., Singh, I., & Singh, A. K. (2010). Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease1802(7), 601-608. doi:10.1016/j.bbadis.2010.04.006

  • The authors propose a molecular mechanism for the lack of growth in patients with infant onset of Krabbe disease. This mechanism suggests that psychosine accumulation decreases IGF-1 mRNA  levels, which decreases somatic growth.

Debs, R., Froissart, R., Aubourg, P., Papeix, C., Douillard, C., Degos, B., Fontaine, B., Audoin, B., Lacour, A., Said, G., Vanier, M.T., & Sedel, F. (2012). Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review. Journal of Inherited Metabolic Disease, 36(5), 859-68 doi: 10.1007/s10545-012-9560-4

  • The authors reviewed 11 cases of patients with Krabbe Disease and 30 literature cases in attempt to correlate clinical symptoms with genotype or age of onset as part of the molecular pathogenesis of Krabbe Disease. These 41 studies represented a variety of genotypic mutations and ages of onset including infant, child, adolescent, and adult onset. While the authors were able to correlate rate of disease progression and symptoms such as cerebellar ataxia and optic neuropathy with age of onset, no correlations between mutation type and symptoms were observed. This helps provide metabolic context for Krabbe disease in addition to molecular information.

Duchen, L.W, Eicher, E.M., Jacobs, J.M., Scaravilli, F., & Teixeira F. (1980).  Hereditary leucodystrophy in the mouse: the new mutant twitcher.Brain. 103(3):695-710. doi: 10.1093/brain/103.3.695

  • This is a landmark paper as it establishes a murine disease model for Krabbe Disease to facilitate future studies regarding disease pathogenesis and therapeutic intervention.

Duffner, P. K., Caggana, M., Orsini, J. J., Wenger, D. A., Patterson, M. C., Crosley, C. J., Kurtzberg, J., Arnold, G.L., Escolar, M.L., Adams, D.J., Andriola, M.R., Aron, A.M., Ciafaloni, M.,  Djukic, A., Erbe, R.W., Galvin-Parton, P., Helton, L.E., Kolodney, E.H., Kosofsky, B.E., Kronn, D.F., Kwon, J.M., Levy, P.A., Miller-Horn, J., Naidich, T. P., Pellegrino, J.E., Provenzale, J.M., Rothman, S.J., & Wasserstein, M. P. (2009). Newborn screening for Krabbe disease: the New York State model. Pediatric neurology40(4), 245-252. Link to article

  • This article provides all of the parameters and procedures involved in testing for Krabbe Disease, including the normal and abnormal ranges.

Duffner, P.K., Barczykowski, A., Kay, D.M., Jalal, K., Yan, L., Abdelhalim, A., Gill, S., Gill, A.L., & Carter, R.(2012) Later onset phenotypes of Krabbe Disease: results of the world-wide registry. Pediatr Neurol 46:298–306 doi:10.1016/j.pediatrneurol.2012.02.023

  • The authors established a worldwide registry for all patients with Krabbe disease in order to more effectively consolidate and organize information regarding symptoms, biochemical features (such as remaining enzymatic activity), responses to treatments, genotypes, biomarker levels, test results, and survival rates. This helps provide metabolic context for Krabbe disease in addition to molecular information.

Gelinas, J., Liao, P., Lehman, A., Stockler, S., & Sirrs, S. (2012). Child Neurology: Krabbe disease A potentially treatable white matter disorder. Neurology79(19), e170-e172. DOI 10.1212/WNL.0b013e3182735c8b

  • The authors present a case study of two siblings with infant-onset with Krabbe Disease. One sibling was not treated due to a late diagnosis—the other was diagnosed through prenatal genetic screen and treated with hematopoietic stem cell transplantation (HCST). This study describes the successful treatment of this patient at the biochemical level (as of 2012, the patient was five years old and attending kindergarten classes with an aide) and comments on the advantages and disadvantages of HCST as a therapy for Krabbe Disease.

Gentner, B., Visigalli, I., Hiramatsu, H., Lechman, E., Ungari, S., Giustacchini, A., Schira, G., Amendola, M., Quattrini, A., Martino, S., Orlacchio, A., Dick, J.E., Biffi, A., & Naldini, L.(2010). Identification of hematopoietic stem cell–specific miRNAs enables gene therapy of globoid cell leukodystrophy. Science translational medicine 2(58), 58ra84-58ra84. DOI: 10.1126/scitranslmed.3001522

  • Hematopoietic stem cell (HSC) transplantation is a currently utilized treatment for patients with Krabbe disease. HSCs are also the subject of gene therapy development as a therapeutic intervention for several diseases including Krabbe disease. High levels of galactocerebrosidase in HSCs (versus mature hematopoietic cells), however, is toxic. The authors present a method of suppressing and then rescuing galactocerebrosidase in HSCs in vivo until they mature by designing a vector containing the gene for galactocerebrosidase and for a miR-126 target sequence, a HSC-specific miRNA. This miRNA expression level decreases as the HSC matures, thus allowing the level of galactocerebrocidase to increase as the cells mature.

Giri, S., Khan, M., Rattan, R., Singh, I., & Singh, A. K. (2006). Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death. Journal of lipid research, 47(7), 1478-1492. doi: 10.1194/jlr.M600084

  • The authors further develop an understanding of Krabbe pathogenesis by establishing a molecular mechanism by which psychosine accumulation leads to oligodendrocyte death, leading to a decrease in myelination of neurons. Psychosine activates secretory phospholipase A2, which stimulates the overexpression of lycophosphatidylcholine (LPC) and arachadonic acid (AA). Metabolism of AA results in the generation  of reactive oxygen species, which can accumulate and trigger oligodendrocyte death. Small molecule inhibition of secretory phospholipase A2 blocks AA and LPC release, decreases reactive oxygen species, and promotes cell survival in vitro and in vivo, thus identifying a potential avenue for therapy development.

Greenfieldboyce, N. (2013). Screening Newborns For Disease Can Leave Families In Limbo. NPR Podcast and Transcript. 

  • This podcast was only used to confirm which states currently mandate newborn screening for Krabbe Disease.

Hartline, D.K.  (2008). What is myelin?. Neuron Glia Biology, 4, pp 153-163 doi:10.1017/S1740925X09990263

  • This source provided helpful background the importance of myelin to action potential propagation.

Hill, C.H., Graham, S.C., Read, R.J., & Deane, J.E. (2013). Structural snapshots illustrate the catalytic cycle of β-galactocerebrosidase, the defective enzyme in Krabbe disease. PNAS, 110(51), 20479-20484. doi: 10.1073/pnas.1311990110

  • The authors present the first crystal structures of wild-type human β-galactocerebrosidase in complex with its substrate, covalently intermediate, and product; from these structures, the authors confirm the previously hypothesized catalytic mechanism and identify additional critical active site residues. This structural and catalytic information will be useful in understanding Krabbe Disease enzymopathy and identifying future avenues of therapy development.

Igisu, H., & Suzuki, K. (1984). Progressive accumulation of toxic metabolite in a genetic leukodystrophy. Science224(4650), 753-755. DOI: 10.1126/science.6719111

  • This is a landmark paper in which Igisu and Suzuki identified the psychosine as the previously unknown toxic metabolite causing the majority of Krabbe Disease pathology.

Kemper, A. R., Knapp, A. A., Green, N. S., Comeau, A. M., Metterville, D. R., & Perrin, J. M. (2010). Weighing the evidence for newborn screening for early-infantile Krabbe disease. Genetics in Medicine12(9), 539-543. DOI: 10.1097/GIM.0b013e3181e85721

  • The authors analyze the advantages and disadvantages of early screening, diagnosis, and treatment of Krabbe Disease in infants. Early treatment with HSCT is correlated with decreased childhood mortality, although the consequences of such an invasive treatmetnt are not yet fully understood.

Krabbe K. 1916. A new familial, infantile form of diffuse brain sclerosis. Brain 39:74–114 Available through an E-book that contains the original article

  • This paper is a landmark paper as it is the first paper on Krabbe Disease and its discovery.

Loes, D. J., Peters, C., & Krivit, W. (1999). Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method. American journal of neuroradiology20(2), 316-323. Link to Article

  • This paper compiled Krabbe Disease patient MRIs from both early onset and late onset patients and compared them in order to draw broader conclusions on brain imaging results based on type of Krabbe Disease.

Lyon, G., Hagberg, B., Evrard, P., Allaire, C., Pavone, L., & Vanier, M. (1991). Symptomatology of late onset Krabbe’s leukodystrophy: the European experience. Developmental neuroscience13(4-5), 240-244. DOI:10.1159/000112167

  • This article summarizes the symptoms of late infantile, juvenile, and adult/adolescent onset Krabbe Disease

Miyatake, T., & Suzuki, K. (1972). Globoid cell leukodystrophy: additional deficiency of psychosine galactosidase. Biochemical and biophysical research communications48(3), 538-543. DOI: 10.1016/0006-291X(72)90381-6

  • The authors identify that pyschosine galactosidase is also deficient in Krabbe Disease,  thus contributing to the accumulation of psychosine and the pathology of the disease.

Norton, W.T., and Cammer, W. (1984). Isolation and characterization of myelin. In Myelin. P. Morell, ed. (New York: Plenum Press), pp. 147–195.

  • This source was provided helpful information on myelin composition and metabolism.

Puckett, R. L., Orsini, J. J., Pastores, G. M., Wang, R. Y., Chang, R., Saavedra-Matiz, C. A., … & Abdenur, J. E. (2012). Krabbe disease: clinical, biochemical and molecular information on six new patients and successful retrospective diagnosis using stored newborn screening cards. Molecular genetics and metabolism105(1), 126-131. doi:10.1016/j.ymgme.2011.10.010

  • This article identifies six novel mutations in the GALC gene, and also identifies the risk for Krabbe patients of death due to aspiration pneumonia and infection.

Rafi, M.A., Rao, H.Z., Luzi, P., Curtis, M.T., & Wenger, D.A. (July 2012). Extended normal life after AAVrh10-mediated gene therapy in the mouse model of Krabbe Disease Nature: Molecular Therapy 20(11):2031–2042. doi:10.1038/mt.2012.153

  • The authors develop an adenovirus to deliver the gene for wild-type galactocerebrosidase to Twitcher mice (the Krabbe Disease animal model). Treated mice showed elevated galactocerebrosidase in the brain and CNS. Normal disease pathology in the mice was significantly reduced—the mice maintained a healthy weight, lived up to 8 months, and hardly twitched. Gene therapy via viral infection is an appealing avenue to explore for treatment of Krabbe disease.

Ribbens, J., Whiteley, G., Furuya, H., Southall, N., Hu, X., Marugan, J., Ferrer, M., & Gustavo, H.B.M. (2013). A high-throughput screening assay using Krabbe disease patient cells. Analytical biochemistry 434(1), 15-25.

  • The authors design an assay that screens small molecules for therapuetic potential as enhancers of galactocerebrosidase that can also cross the blood brain barrier.

Sharp, M. E., Laule, C., Nantel, S., Mädler, B., Aul, R. B., Yip, S., & Sirrs, S. (2013). Stem Cell Transplantation for Adult-Onset Krabbe Disease: Report of a Case. In JIMD Reports-Volume 10 (pp. 57-59). Springer Berlin Heidelberg.

  • This is a case report of an individual with adult-onset Krabbe disease ( very rare) who was treated with HCST. Though long term follow-up care needed to fully assess the efficacy of the treatment, the patient’s symptoms have not progressed in 24 months.

Sly, W. S., & Vogler, C. (2013). The final frontier–crossing the blood‐brain barrier. EMBO molecular medicine5(5), 655-657. DOI: 10.1002/emmm.201302668

  • This article discussed effective strategies such as tagging proteins with ApoB in order to help molecules cross the blood-brain barrier.

Smith, B.R., Santos, M.B., Marshall, M.S., Cantuti-Castelvetri, L., Lopez-Rosas, A., Li, G., Van Breemen, R., Claycomb, K.I., Gallea, J.I., Celej, M.S., Crocker, S.J., Givogri, M.I., & Bongarzone, E.R. (February 2014). Neuronal inclusions of α-synuclein contribute to the pathogenesis of Krabbe disease. The Journal of Pathology 232(5), 509-521. DOI: 10.1002/path.4328

  • This study identifies a pathologic feature of Krabbe disease: fibrillized deposits of proteins including α-synuclein. α-synuclein deposition  appears to be psychosine-mediated.

Suzuki, K., & Suzuki, Y. (1970) Globoid cell leucodystrophy (Krabbe’s disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci U S A 66:302–309  PDF format

  • This is a landmark paper—the authors identify that galactocerebrosidase deficiency is the primary player in Krabbe disease rather than the previously implicated cerebroside-sulfatide sulfotransferase.

Svennerholm, L., Vanier, M. T., & Månsson, J. E. (1980). Krabbe disease: a galactosylsphingosine (psychosine) lipidosis. Journal of lipid research21(1), 53-64. PDF format

  • The authors identified high concentrations of psychosine in post-mortem brains of Krabbe Disease patients.

Taylor, R.M., Lee, J.P., Palacino, J.J., Bower, K.A., Li, J., Vanier, M.T., Wenger, D.A., Sidman, R.L., & Snyder, E.Y. (2006). Intrinsic resistance of neural stem cells to toxic metabolites may make them well suited for cell non-autonomous disorders: evidence from a mouse model of Krabbe leukodystrophy. Journal of Neurochemistry 97,1585-1599. doi:10.1111/j.1471-4159.2006.03986.x.

  • These authors identify neural stem cell therapy as a means of attenuating Krabbe disease pathology in mice. Neonatal, juvenile, and adult Twitcher mice were injected with neural stems cells that ended up being resistant to toxic accumulation of psychosine.

Thomas, P.K., Halpern, J.P., King, R.H., & Patrick, D. (1984). Galactosylceramide lipidosis: novel presentation as a slowly progressive spinocerebellar degeneration. Ann Neurol 16:618–620 DOI: 10.1002/ana.410160515

  • This paper contributes to the historical and metabolic understanding of Krabbe disease as the physicians identify that Krabbe disease may present in adults as progressive disease of CNS decomposition.

Uchida, N., Chen, K., Dohse, M., Hansen, K. D., Dean, J., Buser, J. R., Riddle, A.,Beardsley, D.J.,Wan, Y.,Gong, X.,Nguyen, T.,Cummings, B.J.,Anderson, A.J.,Tamaki, S.J.,Tsukamoto, A.,Wiessman, I.L.,Matsumoto, S.G.,Sherman, L.S.,Kroenke, C.D., & Back, S. A. (2012). Human neural stem cells induce functional myelination in mice with severe dysmyelination. Science translational medicine, 4(155), 155ra136-155ra136. DOI: 10.1126/scitranslmed.3004371

  • The authors demonstrate that neural stem cells injected into the brains of mice suffering from demyelination were able to rescue oligodendrocytes and restore CNS myelination. These results have significant implications for therapeutic intervention in Krabbe Disease as one of the primary pathological concerns is demyelination.

Wicks, S.E., Heaven, L, Zhang, B., Dowden,J., Klopf-Eiermann, J., Fisher-Perkins, J.M., Trygg C.B., Scruggs, B.A., Zhang, X., Gimble, J.M., Bunnell, B.A., & Pistell, P.J. (2011). Effect of intrastriatal mesenchymal stromal cell injection on progression of a murine model of Krabbe disease. Behavioural brain research 225(2),  415-425.

  • The authors demonstrate that treatment of both neonatal and adult Twitcher mice with bone marrow-derived mesenchymal stromal cells (MSCs) improves the mice’s gait, twitching, and rotarod performance (ability to cling to a rotating rod)—this may be another viable treatment option to assess in humans.

Wiederschain, G., (2011). Assays and kits to determine galactocerebrosidase activity on solid support. Patent number WO2012058625 A2. 

  • This patent application explains the methodology by which the galactocerebrosidase activity assay is used to diagnose Krabbe Disease.

Won, J.S., Kim, J., Paintlia, M.K., Singh, I., & Singh, A.K. (2013). Role of endogenous psychosine accumulation in oligodendrocyte differentiation and survival: implication for Krabbe disease. Brain Research 1508(1): 44 -52

  • The authors specifically implicate psychosine as an inhibitor of oligodendrocyte differentiation in vitro under galactocerebrosidase-deficient conditions.

Yagasaki, H., Kato, M., Ishige, M., Shichino, H., Chin, M., & Mugishima, H. (2011). Successful cord blood transplantation in a 42-day-old boy with infantile Krabbe disease. International journal of hematology93(4), 566-568. DOI:10.1007/s12185-011-0835-6

  • This article details the successful umbilical cord transplant of the youngest patient with Krabbe disease ever to receive this treatment.

Yang, Y., Ren, X., Xu, Q., Wang, Z., Liu, H., & Hu, X. (2013) Four novel GALC gene mutations in two Chinese patients with Krabbe disease Gene 519(2):381-384

  • The authors identify four new mutations of the gene coding for galactocerebrosidase, thus adding furhther molecular understanding to Krabbe Disease. These are also the first galactocerebrosidase mutations observed in Chinese individuals.

Yeager, A.M., Brennan, S., Tiffany, C., Moser, H.W., Santos, G.W., (1984). Prolonged survival and remyelination after hematopoietic cell transplantation in the twitcher mouse. Science, 225, 1053–1054 DOI: 10.1126/science.6382609

  • This is a landmark paper—it is the paper that demonstrated successful HCST in vivo (Twitcher mice) as means of treating Krabbe disease. This is currently the predominant therapy for Krabbe patients.

Zlotogora, J., Levy-Lahad, E., Legum C., Iancu, T.C., Ziegler, M., & Bach G. (2011). Krabbe Disease in Israel. Israel Journal of Medical Sciences, 27(4):196-198. PMID:2010272

  • This paper indicates that the incidence rate of Krabbe Disease for the Druze population in Northern Israel and for the Arab-Muslim populatin surrounding Jerusalem is 1/130.