Batten Disease: A Typical Neuronal Storage Disease or a Genetic Neurodegenerative Disorder Characterized by Excitotoxicity?

  • Steven U. Walkley
  • Donald A. Siegel
  • Kostantin Dobrenis
Part of the GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia book series (GWUN)


Batten disease (neuronal ceroid lipofuscinosis) is an inherited neurological disorder of humans and a variety of animal species including dogs, mice, and sheep. Affected individuals appear normal at birth but later exhibit progressive neurological deterioration and death. The spectrum of clinical disease includes retarded mental development and/or dementia, blindness, motor system dysfunction, and seizures, and in late disease the latter can be intractable. The age at which clinical symptoms appear varies and infantile, late infantile, juvenile and adult-onset disease subtypes are recognized. Disease course in individuals with early-onset disease generally is rapid, whereas late-onset disorders exhibit a more protracted course. On postmortem exam, atrophy of cerebral cortex and ballooning of surviving neurons are characteristic features. The latter finding has led to classification of Batten disease as a neuronal storage disorder along with Tay-Sachs, Hurler, and related lysosomal diseases. Although the primary metabolic defect(s) in Batten disease remain unknown, recent research has established that, with the exception of infantile disease variants, a substantial portion of the intracellular storage material is a single protein, subunit c of mitochondrial ATP synthase.1 Current findings suggest that this subunit, which is encoded by nuclear DNA, is synthesized correctly and undergoes normal trafficking to mitochondria; however, its subsequent removal from mitochondria and degradation appear to be delayed.2 Why this particular mitochondrial component accumulates in cells, and whether its accumulation signals the primary metabolic defect in Batten disease, are unknown.


GABAergic Neuron Neuronal Ceroid Lipofuscinosis Cortical Pyramidal Neuron GABAergic Cell Axon Hillock 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    D.N. Palmer, I.M. Fearnley, S.M. Medd, J.E. Walker, R.D. Martinus, S.L. Bayliss, N.A. Hall, B.D. Lake, L.S. Wolfe, and R.D. Jolly, Lysosomal storage of the DCCD reactive proteolipid subunit of mitochondrial ATP synthase in human and ovine ceroid lipofuscinosis, in “Lipofuscin and Ceroid Lipopigments,” E.A. Porta, ed., Plenum, New York (1990).Google Scholar
  2. 2.
    J. Ezaki, L.S. Wolfe, T. Higuti, K. Ishidoh, and E. Kominami, Specific delay of degradation of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid lipofuscinosis (Batten disease), J. Neuropathol. 64:733 (1995).Google Scholar
  3. 3.
    C.R. Houser, J.E. Vaughn, S.H.C. Hendry, E.G. Jones, and A. Peters, GABA neurons in the cerebral cortex, in “Cerebral Cortex: Functional Properties of Cortical Cells,” E.G. Jones and A. Peter, eds., Plenum, New York (1984).Google Scholar
  4. 4.
    S.U. Walkley and P. March, Biology of neuronal dysfunction in storage disorders, J. Inker. Metabol Dis. 16:284 (1993).CrossRefGoogle Scholar
  5. 5.
    S.U. Walkley, P.A. March, C.E. Schroeder, S. Wurzelmann, and R.D. Jolly, Pathogenesis of brain dysfunction in Batten disease, Am. J. Med. Gen. 56: (In press).Google Scholar
  6. 6.
    P.A. March, S.U. Walkley, and S. Wurzelmann, Morphological alterations in neocortical and cerebellar GABAergic neurons in a canine model of juvenile Batten’s disease. Am. J. Med. Gen. 56: (In press).Google Scholar
  7. 7.
    C. Stengel, Account of a singular illness among four siblings in the vicinity of Roraas, in “Ceroid Lipofuscinosis (Batten’s Disease), D. Armstrong, N. Koppang, and J.A. Rider, eds., Elsevier Biomedical Press, New York (1982).Google Scholar
  8. 8.
    F.E. Batten, Family cerebral degeneration with macular change (so-called juvenile form of family amaurotic idiocy). Quart. J. Med. 7:444–453 (1914).Google Scholar
  9. 9.
    B. Sachs, On arrested cerebral development with special reference to its cortical pathology, J. Nerv. Ment. Dis. 14:541 (1887).Google Scholar
  10. 10.
    B. Sachs and I. Strauss, The cell changes in amaurotic family idiocy, J. Exp. Med. 12:685 (1910).PubMedCrossRefGoogle Scholar
  11. 11.
    W. Zeman and S. Donahue, Fine structure of the lipid bodies in juvenile amaurotic idiocy. Acta Neuropath 3:144 (1963).PubMedCrossRefGoogle Scholar
  12. 12.
    R. Terry and M. Weiss, Studies in Tay-Sachs disease II. Ultrastructure of the cerebrum. J. Neuropathol. Exper. Neurol. 22:18 (1963).CrossRefGoogle Scholar
  13. 13.
    W. Zeman, and P. Dyken, Neuronal ceroid lipofuscinosis (Batten’s disease): Relationship to amaurotic family idiocy? Pediatrics 44:570 (1969).PubMedGoogle Scholar
  14. 14.
    R.D. Jolly, A. Shimada, I. Dopfmer, P.M. Slack, M.J. Birtles, and D.N. Palmer, Ceroid-lipofuscinosis (Batten’s disease): Pathogenesis and sequential neuropathological changes in the ovine model, Neuropathol. Appl Neurobiol. 15:371 (1989).PubMedCrossRefGoogle Scholar
  15. 15.
    G.O. Ivy, F. Schottler, J. Wenzel, M. Baudry, and G. Lynch, Inhibitors of lysosomal enzymes: Accumulation of lipofuscin-like dense bodies in the brain, Science 226:985 (1984).PubMedCrossRefGoogle Scholar
  16. 16.
    S.U. Walkley, Pathobiology of neuronal storage disease. Intern. Rev. Neurobiol. 29:191 (1988).CrossRefGoogle Scholar
  17. 17.
    D.A. Siegel and S.U. Walkley, Growth of ectopic dendrites on cortical pyramidal neurons in neuronal storage diseases correlates with abnormal accumulation of GM2 ganglioside. J. Neurochem. 62:1852 (1994).PubMedCrossRefGoogle Scholar
  18. 18.
    S.U. Walkley, Pyramidal neurons with ectopic dendrites in storage diseases exhibit increased GM2 ganglioside-immunoreactivity. Neuroscience (In press).Google Scholar
  19. 19.
    R.S. Williams, I.T. Lott, R.J. Ferrante and V.S. Caviness, The cellular pathology of neuronal ceroid lipofuscinosis, Arch. Neurol. 34:298 (1977).PubMedCrossRefGoogle Scholar
  20. 20.
    S.U. Walkley, H.J. Baker, M.C. Rattazzi, M.E. Haskins and J.-Y. Wu, Neuroaxonal dystrophy in neuronal storage disorders: Evidence for major GABAergic neuron involvement, J. Neurol. Sci. 104:1 (1991).PubMedCrossRefGoogle Scholar
  21. 21.
    W. Zeman, The ceroid lipofuscinoses, in H.M. Zimmerman, ed., “Progress in Neuropathology,” Grune & Straton, New York (1976).Google Scholar
  22. 22.
    H. Braak and H.H. Goebel, Pigmentoarchitectonic pathology of the isocortex in juvenile neuronal ceroid lipofuscinosis: Axonal enlargements in layer IIIab and cell loss in layer V, Acta Neuropathol. 46:79 (1979).PubMedCrossRefGoogle Scholar
  23. 23.
    M. Philippart, C. Messa, and H.T. Chugani, Spielmeyer-Vogt (Batten, Spielmeyer-Sjogren) disease. Distinctive patterns of cerebral glucose utilization, Brain 117:1085 (1994).PubMedCrossRefGoogle Scholar
  24. 24.
    P.S. Spencer, A.B. Sterman, D. Horoupian, and M.M. Foulds, Neurotoxic fragrance produces ceroid and myelin disease, Science 204:633 (1979).PubMedCrossRefGoogle Scholar
  25. 25.
    W. Cammer, Uncoupling of oxidative phosphorylation in vitro by the neurotoxic fragrance compound acetyl ethyl tetramethyl tetralin and its putative metabolite, Biochem. Pharm. 29:1531.Google Scholar
  26. 26.
    T. Miyagishi, N. Takahata, and R. Iizuka, Electron microscopic studies on the lipopigments in the cerebral cortex nerve cells of senile and vitamin E deficient rats. Acta Neuropathol 9:7 (1967).PubMedCrossRefGoogle Scholar
  27. 27.
    J. A. Rider, G. Dawson, and A. Siakotos, Perspective of biochemical research in the neuronal ceroid-lipofuscinosis, Am. J. Med. Gen. 42:519 (1992).CrossRefGoogle Scholar
  28. 28.
    M.F. Beal, Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative disease? Ann. Neurol. 31:119 (1992).PubMedCrossRefGoogle Scholar
  29. 29.
    C.W. Cotman, D.T. Monaghan, O.P. Ottersen, and J. Storm-Mathisen, Anatomical organization of excitatory amino acid receptors and their pathways, TINS 10:273 (1987).Google Scholar
  30. 30.
    R. Horowski, H. Wachtel, L. Turski, and P.-A. Löschmann, Glutamate excitotoxicity as a possible pathogenic mechanism in chronic neurodegeneration, in “Neurodegenerative Diseases,” D.B. Calne, ed., W.B. Saunders, Philadelphia (1994).Google Scholar
  31. 31.
    R.N. Boustany, S.C. Lane, and W. Quin, Apoptosis is the mechanism of neuronal cell death and retinal degeneration in Batten disease, Ann. Neurol 36:496 (1994).Google Scholar
  32. 32.
    E.D. Hall, Novel Inhibitors of iron-dependent lipid peroxidation for neurodegenerative disorders. Ann. Neurol 32:S137 (1992).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Steven U. Walkley
    • 1
  • Donald A. Siegel
    • 1
  • Kostantin Dobrenis
    • 1
  1. 1.Department of Neuroscience, Rose F. Kennedy Center for Research in Mental Retardation and Human DevelopmentAlbert Einstein College of MedicineBronxUSA

Personalised recommendations