Degenerative and Metabolic Brain Diseases

  • Casper JansenEmail author


Neurodegenerative diseases are rare in childhood. Most of them result from disturbances in the metabolism of energy, lipids, amino acids, or metals. Symptoms may not appear before childhood or adolescence, but some are fatal in utero or in the neonatal period; they form the core of this overview. Before starting a postmortem examination, clinical and radiological findings should be obtained, because they may yield important diagnostic clues. Neuropathologically, a useful starting point is to establish whether the gray or the white matter is primarily affected. Microscopically, the neuropathological features can be diagnostic for a certain disease, but in most cases additional biochemical, genetic, and molecular studies are required to come to a final diagnosis.


Neurodegeneration Neurometabolic disease Leukodystrophy Poliodystrophy Neuronal storage disease Mitochondrial disease Lysosomal disease Peroxisomal disease 


  1. 1.
    Wong V. Neurodegenerative diseases in children. Hong Kong Med J. 1997;3:89–95.PubMedGoogle Scholar
  2. 2.
    Pierre G. Neurodegenerative disorders and metabolic disease. Arch Dis Child. 2013;98:618–24.CrossRefGoogle Scholar
  3. 3.
    Volpe JJ. Neurology of the newborn. 5th ed. Philadelphia: Saunders Elsevier; 2008.Google Scholar
  4. 4.
    Verity C, Winstone AM, Stellitano L, Will R, Nicoll A. The epidemiology of progressive intellectual and neurological deterioration in childhood. Arch Dis Child. 2010;95:361–4.CrossRefGoogle Scholar
  5. 5.
    Maroun LL, Graem N. Autopsy standards of body parameters and fresh organ weights in nonmacerated and macerated human fetuses. Pediatr Dev Pathol. 2005;8:204–17.CrossRefGoogle Scholar
  6. 6.
    Friede RL. Developmental neuropathology. 2nd ed. Berlin: Springer-Verlag; 1989.CrossRefGoogle Scholar
  7. 7.
    Folkerth RD, Lidov HGW. Congenital malformations, perinatal diseases, and phacomatoses. In: Prayson RA, editor. Neuropathology. 2nd ed. Philadelphia: Elsevier Saunders; 2012. p. 96–182.Google Scholar
  8. 8.
    Dawson TP, Neal JW, Llewellyn L, Thomas C. Neuropathology techniques. London: Arnold; 2003.Google Scholar
  9. 9.
    Suzuki K, Suzuki K. Lysosomal diseases. In: Love S, Louis DN, Ellison DW, editors. Greenfield’s neuropathology. 8th ed. London: Hodder Arnold; 2008. p. 515–99.Google Scholar
  10. 10.
    Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–54.CrossRefGoogle Scholar
  11. 11.
    Lloyd JB, Mason RW. Biology of the lysosome: subcellular biochemistry. New York: Plenum Press; 1996.CrossRefGoogle Scholar
  12. 12.
    Okada S, O’Brien JS. Tay-Sachs disease: generalized absence of a beta-D-N-acetylhexosaminidase component. Science. 1969;165:698–700.CrossRefGoogle Scholar
  13. 13.
    Charrow J. Ashkenazi Jewish genetic disorders. Fam Cancer. 2004;3:201–6.CrossRefGoogle Scholar
  14. 14.
    Smith NJ, Winstone AM, Stellitano L, Cox TM, Verity CM. GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed. Dev Med Child Neurol. 2012;54:176–82.CrossRefGoogle Scholar
  15. 15.
    Purpura DP, Suzuki K. Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease. Brain Res. 1976;116:1–21.CrossRefGoogle Scholar
  16. 16.
    Purpura DP. Ectopic dendritic growth in mature pyramidal neurones in human ganglioside storage disease. Nature. 1978;276:520–1.CrossRefGoogle Scholar
  17. 17.
    Walkley SU, Pierok AL. Ferric ion-ferrocyanide staining in ganglioside storage disease establishes that meganeurites are of axon hillock origin and distinct from axonal spheroids. Brain Res. 1986;382:379–86.CrossRefGoogle Scholar
  18. 18.
    Haltia M. The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol. 2003;62:1–13.CrossRefGoogle Scholar
  19. 19.
    Haltia M. The neuronal ceroid-lipofuscinoses: from past to present. Biochim Biophys Acta. 1762;2006:850–6.Google Scholar
  20. 20.
    Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, et al. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain. 2006;129:1438–45.CrossRefGoogle Scholar
  21. 21.
    Anderson GW, Goebel HH, Simonati A. Human pathology in NCL. Biochim Biophys Acta. 1832;2013:1807–26.Google Scholar
  22. 22.
    Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis. 2007;30:654–63.CrossRefGoogle Scholar
  23. 23.
    Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, et al. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997;277:228–31.CrossRefGoogle Scholar
  24. 24.
    Stone DL, van Diggelen OP, de Klerk JB, Gaillard JL, Niermeijer MF, Willemsen R, et al. Is the perinatal lethal form of Gaucher disease more common than classic type 2 Gaucher disease? Eur J Hum Genet. 1999;7:505–9.CrossRefGoogle Scholar
  25. 25.
    Stone DL, Carey WF, Christodoulou J, Sillence D, Nelson P, Callahan M, et al. Type 2 Gaucher disease: the collodion baby phenotype revisited. Arch Dis Child Fetal Neonatal Ed. 2000;82:F163–6.CrossRefGoogle Scholar
  26. 26.
    Sidransky E, Tayebi N, Stubblefield BK, Eliason W, Klineburgess A, Pizzolato GP, et al. The clinical, molecular, and pathological characterisation of a family with two cases of lethal perinatal type 2 Gaucher disease. J Med Genet. 1996;33:132–6.CrossRefGoogle Scholar
  27. 27.
    Harding BN, Egger J, Portmann B, Erdohazi M. Progressive neuronal degeneration of childhood with liver disease. A pathological study. Brain. 1986;109:181–206.CrossRefGoogle Scholar
  28. 28.
    Harding BN. Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review. J Child Neurol. 1990;5:273–87.CrossRefGoogle Scholar
  29. 29.
    Naviaux RK, Nguyen KV. POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol. 2004;55:706–12.CrossRefGoogle Scholar
  30. 30.
    Harding BN, Surtees RAH. Metabolic and neurodegenerative diseases of childhood. In: Love S, Louis DN, Ellison DW, editors. Greenfield’s neuropathology. 8th ed. London: Hodder Arnold; 2008. p. 481–514.Google Scholar
  31. 31.
    Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat Genet. 1993;3:7–13.CrossRefGoogle Scholar
  32. 32.
    Menkes JH. Kinky hair disease: twenty five years later. Brain Dev. 1988;10:77–9.CrossRefGoogle Scholar
  33. 33.
    Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15:319–28.CrossRefGoogle Scholar
  34. 34.
    Cheon JE, Kim IO, Hwang YS, Kim KJ, Wang KC, Cho BK, et al. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics. 2002;22:461–76.CrossRefGoogle Scholar
  35. 35.
    Kinney HC, Brody BA, Kloman AS, Gilles FH. Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants. J Neuropathol Exp Neurol. 1988;47:217–34.CrossRefGoogle Scholar
  36. 36.
    Matalon R, Michals K, Kaul R. Canavan disease: from spongy degeneration to molecular analysis. J Pediatr. 1995;127:511–7.CrossRefGoogle Scholar
  37. 37.
    Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M, N’guyen S, et al. Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. Am J Hum Genet. 2001;69:1134–40.CrossRefGoogle Scholar
  38. 38.
    Kobayashi T, Goto I, Yamanaka T, Suzuki Y, Nakano T, Suzuki K. Infantile and fetal globoid cell leukodystrophy: analysis of galactosylceramide and galactosylsphingosine. Ann Neurol. 1988;24:517–22.CrossRefGoogle Scholar
  39. 39.
    Sahai I, Baris H, Kimonis V, Levy HL. Krabbe disease: severe neonatal presentation with a family history of multiple sclerosis. J Child Neurol. 2005;20:826–8.CrossRefGoogle Scholar
  40. 40.
    Wolf NI, Sistermans EA, Cundall M, Hobson GM, Davis-Williams AP, Palmer R, et al. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain. 2005;128:743–51.CrossRefGoogle Scholar
  41. 41.
    Koeppen AH, Robitaille Y. Pelizaeus-Merzbacher disease. J Neuropathol Exp Neurol. 2002;61:747–59.CrossRefGoogle Scholar
  42. 42.
    Scheffer IE, Baraitser M, Wilson J, Harding B, Kendall B, Brett EM. Pelizaeus-Merzbacher disease: classical or connatal? Neuropediatrics. 1991;22:71–8.CrossRefGoogle Scholar
  43. 43.
    DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003;348:2656–68.CrossRefGoogle Scholar
  44. 44.
    Zeviani M, Di DS. Mitochondrial disorders. Brain. 2004;127:2153–72.CrossRefGoogle Scholar
  45. 45.
    Chinnery PF, Betts J, Jaros E, Turnbull D, Dimauro S, Perry RH. Mitochondrial disorders. In: Love S, Louis DN, Ellison DW, editors. Greenfield’s neuropathology. 8th ed. London: Hodder Arnold; 2008. p. 601–42.Google Scholar
  46. 46.
    Brown GK, Squier MV. Neuropathology and pathogenesis of mitochondrial diseases. J Inherit Metab Dis. 1996;19:553–72.CrossRefGoogle Scholar
  47. 47.
    Volpe JJ, Adams RD. Cerebro-hepato-renal syndrome of Zellweger: an inherited disorder of neuronal migration. Acta Neuropathol. 1972;20:175–98.CrossRefGoogle Scholar
  48. 48.
    Evrard P, Caviness Jr VS, Prats-Vinas J, Lyon G. The mechanism of arrest of neuronal migration in the Zellweger malformation: an hypothesis based upon cytoarchitectonic analysis. Acta Neuropathol. 1978;41:109–17.CrossRefGoogle Scholar
  49. 49.
    Feigin I, Kim HS. Subacute necrotizing encephalomyelopathy in a neonatal infant. J Neuropathol Exp Neurol. 1977;36:364–72.CrossRefGoogle Scholar
  50. 50.
    Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol. 2008;39:223–35.CrossRefGoogle Scholar
  51. 51.
    Zhu Z, Yao J, Johns T, Fu K, De BI, Macmillan C, et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet. 1998;20:337–43.CrossRefGoogle Scholar
  52. 52.
    Grunewald S, Matthijs G, Jaeken J. Congenital disorders of glycosylation: a review. Pediatr Res. 2002;52:618–24.CrossRefGoogle Scholar
  53. 53.
    Marquardt T, Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr. 2003;162:359–79.PubMedGoogle Scholar
  54. 54.
    Martin JJ, Schlote W. Central nervous system lesions in disorders of amino-acid metabolism. A neuropathological study. J Neurol Sci. 1972;15:49–76.CrossRefGoogle Scholar
  55. 55.
    Kolodny EH. Agenesis of the corpus callosum: a marker for inherited metabolic disease? Neurology. 1989;39:847–8.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2015

Authors and Affiliations

  1. 1.Laboratory for Pathology Eastern NetherlandsHengeloThe Netherlands

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