Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;10(2):215–222. doi: 10.1111/j.1750-3639.2000.tb00255.x

Northern Epilepsy: A Novel Form of Neuronal Ceroid‐Lipofuscinosis

Riitta Herva 1, Jaana Tyynelä 2,3, Aune Hirvasniemi 4, Marja Syrjäkallio‐Ylitalo 1, Matti Haltia 2,✉
PMCID: PMC8098134  PMID: 10764041

Abstract

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic‐clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid‐Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane‐bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N‐terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid‐lipofuscinosis with an exceptionally protracted course.

Full Text

The Full Text of this article is available as a PDF (141.5 KB).

References

  • 1. Berkovic SF , Carpenter S , Andermann F , Andermann E , Wolfe LS ( 1988. ) Kufs' disease: a critical reappraisal . Brain 111 : 27 – 62 . [DOI] [PubMed] [Google Scholar]
  • 2. Braak H ( 1979. ) Spindle‐shaped appendages of IIIab‐pyramids filled with lipofuscin: a striking pathological change of the senescent human isocortex . Acta Neuropathol 46 : 197 – 202 . [DOI] [PubMed] [Google Scholar]
  • 3. Braak H , Braak E ( 1993. ) Pathoarchitectonic pattern of iso‐ and allocortical lesions in juvenile and adult neuronal ceroid‐lipofuscinosis . J Inher Metab Dis 16 : 259 – 262 . [DOI] [PubMed] [Google Scholar]
  • 4. Elleder M , Lake BD , Goebel HH , Rapola J , Haltia M , Carpenter S ( 1999. ) Definitions of the ultrastructural patterns found in NCL In : Biomedical and Health Research vol. 33: The Neuronal Ceroid Lipofuscinoses . Goebel HH , Mole SE , Lake BD ( eds. ), pp. 5 – 7 , IOS press; ; Amsterdam . [Google Scholar]
  • 5. Ezakij Tanida I , Kanehagi N , Kominami E ( 1999. ) A lysosomal proteinase, the late infantile neuronal ceroid lipofuscinosis gene (CLN2) product, is essential for degradation of a hydrophobic protein, the subunit c of ATP synthase . J Neurochem 72 : 2573 – 2582 . [DOI] [PubMed] [Google Scholar]
  • 6. Fearnley IM , Walker JE , Martinus RD , Jolly RD , Kirkland KB , Shaw GJ , Palmer DN ( 1990. ) The sequence of the major protein stored in ovine ceroid lipofuscinosis is identical with that of the dicyclohexylcardodiimide reactive proteolipid of mitochondrial ATP synthase . Biochem J 268 : 751 – 758 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Goebel HH , Mole SE , Lake BD ( 1999. ) Introduction In : Biomedical and Health Research vol. 33: The Neuronal Ceroid Lipofuscinoses . Goebel HH , Mole SE , Lake BD ( eds. ), pp. 1 – 4 , IOS press; ; Amsterdam . [Google Scholar]
  • 8. Hirvasniemi A , Lang H , Lehesjoki A‐E , Leisti J ( 1994. ) Northern epilepsy syndrome: an inherited childhood onset epilepsy with associated mental retardation . J Med Genet 31 : 177 – 182 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Hirvasniemi A , Herrala P , Leisti J ( 1995. ) Northern epilepsy syndrome: clinical course and the effect of medication on seizures . Epilepsia 36 : 792 – 797 . [DOI] [PubMed] [Google Scholar]
  • 10. Hofman I , Kohlschütter A , Santavuori P , Gottlob I , Goebel HH , Lake BD , Schutgens RBH , Greene NDE , Leung K‐Y , Mitchison HM , Munroe PB , Taschner PEM ( 1999. ) CLN3. Juvenile NCL In : Biomedical and Health Research vol. 33: The Neuronal Ceroid Lipofuscinoses . Goebel HH , Mole SE , Lake BD ( eds. ), pp. 55 – 76 , IOS Press; ; Amsterdam . [Google Scholar]
  • 11. The international Batten's disease consortium ( 1995. ) Isolation of a novel gene underlying Batten disease, CLN3 . Cell 82 : 949 – 957 . [DOI] [PubMed] [Google Scholar]
  • 12. Laemmli UK ( 1970. ) Cleavage of structural proteins during the assembly of the head of bacteriophage T4 . Nature 227 : 680 – 685 . [DOI] [PubMed] [Google Scholar]
  • 13. Lingaas F , Mitchison HM , Mole SE , Koppang N , Goebel HH , Lake BD ( 1999. ) Animal models of NCL In : Biomedical and Health Research vol. 33: The Neuronal Ceroid Lipofuscinoses . Goebel HH , Mole SE , Lake BD ( eds. ), pp. 152 – 167 , IOS Press; ; Amsterdam . [Google Scholar]
  • 14. Martin J‐J , Gottlob I , Goebel HH , Mole SE ( 1999. ) CLN4 ‐ Adult NCL In : Biomedical and Health Research vol. 33: The Neuronal Ceroid Lipofuscinoses . Goebel HH , Mole SE , Lake BD ( eds. ), pp. 77 – 90 , IOS Press; ; Amsterdam . [Google Scholar]
  • 15. Palmer DN , Fearnley IM , Walker JE , Hall NA , Lake BD , Wolfe LS , Haltia M , Martinus RD , Jolly RD ( 1992. ) Mitochondrial ATP‐synthase subunit c storage in the ceroid‐lipofuscinoses (Batten disease) . Am J Med Genet 42 : 561 – 567 . [DOI] [PubMed] [Google Scholar]
  • 16. Ranta S , Zhang Y , Ross B , Lonka L , Takkunen E , Messer A , Sharp J , Wheeler R , Kusumi K , Mole S , Liu W , Soares MB , de Fatima Bonaldo M , Hirvasniemi A , de la Chapelle A , Gilliam TC , Lehesjoki A‐E ( 1999. ) The neuronal ceroid lipofuscinoses in human EPMR and mnd‐mutant mice are associated with mutations in CLN8 . Nature Genet 23 : 233 – 237 . [DOI] [PubMed] [Google Scholar]
  • 17. Rapola J ( 1993. ) Neuronal ceroid‐lipofuscinoses of childhood In : Perspectives in Pediatric Pathology, Vol. 17: Genetic Metabolic Diseases . Landing BH , Haust MD , Bernstein J , Rosenberg HS ( eds. ) pp 7 – 44 . Karger; ; Basel . [PubMed] [Google Scholar]
  • 18. Rosenblum WI ( 1999. ) The presence, origin, and significance of A‐beta peptide in the cell bodies of neurons . J Neuropathol Exp Neurol 58 : 575 – 581 . [DOI] [PubMed] [Google Scholar]
  • 19. Santavuori P ( 1988. ) Neuronal ceroid‐lipofuscinoses in childhood . Brain Dev 10 : 80 – 83 . [DOI] [PubMed] [Google Scholar]
  • 20. Savukoski M , ( 1998. ) CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid‐lipofuscinosis . Nature Genetics 19 : 286 – 288 . [DOI] [PubMed] [Google Scholar]
  • 21. Sleat DE , Donnelly RJ , Lackland H , Liu CG , Sohar I , Pullarkat RK , Lobel P ( 1997. ) Association of mutations in a lysosomal protein with classical late‐infantile neuronal ceroid lipofuscinosis . Science 277 : 1802 – 1805 . [DOI] [PubMed] [Google Scholar]
  • 22. Towbin H , Staehelin T , Gordon J ( 1979. ) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications . Proc Natl Acad Sci USA 76 : 4350 – 4354 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Tyynelä J , Baumann M , Henseler M , Sandhoff K , Haltia M ( 1995. ) Sphingolipid activator proteins in the neuronal ceroid‐lipofuscinoses: an immunological study . Acta Neuropathol 89 : 391 – 398 . [DOI] [PubMed] [Google Scholar]
  • 24. Tyynelä J , Suopanki J , Santavuori P , Baumann M , Haltia M ( 1997. ) Variant late infantile neuronal ceroid lipofuscinosis: Pathology and biochemistry . J Neuropathol Experiment Neurol 56 : 369 – 375 . [DOI] [PubMed] [Google Scholar]
  • 25. Vesa J , Hellsten E , Verkruyse LA , Camp LA , Rapola J , Santavuori P , Hofmann SL , Peltonen L ( 1995. ) Mutations in palmitoyl‐protein thioesterase gene causing infantile neuronal ceroid lipofusinosis . Nature 376 : 584 – 547 . [DOI] [PubMed] [Google Scholar]
  • 26. Villanova M , Ceuterick C , Dotti MT , Santorelli FM , Casali C , Malandrini A , De Stefano N , Lübke U , Martin JJ , Guazzi GC , Federico A ( 1999. ) Detection of beta‐A4 amyloid and its precursor protein in the muscle of a patient with juvenile neuronal ceroid lipofuscinosis (Spielmeyer‐Vogt‐Sjögren) . Acta Neuropathol 98 : 78 – 84 . [DOI] [PubMed] [Google Scholar]
  • 27. Wisniewski KE , Maslinska D , Kitaguchi T , Kim KS , Goebel HH , Haltia M ( 1990. ) Topographic heterogeneity of amyloid β‐protein epitopes in brains with various forms of neuronal ceroid‐lipofuscinoses suggesting deficient processing of amyloid precursor protein . Acta Neuropathol 80 : 26 – 34 . [DOI] [PubMed] [Google Scholar]
  • 28. Zeman W , Dyken P ( 1969. ) Neuronal ceroid lipofuscinosis (Batten's disease): Relationship to amaurotic family idiocy ? Pediatrics 44 : 570 – 583 . [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES