Neurogenetics

, Volume 6, Issue 3, pp 107–126 | Cite as

Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses

  • Sara E. Mole
  • Ruth E. Williams
  • Hans H. Goebel
Review Article

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are a group of severe neurodegenerative diseases with onset usually in childhood and characterised by the intracellular accumulation of autofluorescent storage material. Within the last decade, mutations that cause NCL have been found in six human genes (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8). Mutations in two additional genes cause disease in animal models that share features with NCL-CTSD in sheep and mice and PPT2 in mice. Approximately 160 NCL disease-causing mutations have now been described (listed and fully cited in the NCL Mutation Database, http://www.ucl.ac.uk/ncl/). Most mutations result in a classic morphology and disease phenotype, but some mutations are associated with disease that is of later onset, less severe or protracted in its course, or with atypical morphology. Seven common mutations exist, some having a worldwide distribution and others associated with families originating from specific geographical regions. This review attempts to correlate the gene, disease-causing mutation, morphology and clinical phenotype for each type of NCL.

Keywords

Neuronal ceroid lipofuscinoses Batten disease Genotype Morphology Phenotype 

References

  1. 1.
    Santavuori P (1988) Neuronal ceroid lipofuscinosis in childhood. Brain Dev 10:80–83PubMedGoogle Scholar
  2. 2.
    Goebel HH, Mole SE, Lake BD (eds) (1999) The neuronal ceroid lipofuscinoses (Batten disease). Biomedical and health research. IOS, Amsterdam, pp 211Google Scholar
  3. 3.
    Mole SE (2004) The genetic spectrum of human neuronal ceroid-lipofuscinoses. Brain Pathol 14:70–76PubMedCrossRefGoogle Scholar
  4. 4.
    Mole S (2004) Neuronal ceroid lipofuscinoses (NCL). Eur J Paediatr Neurol 8:101–103CrossRefPubMedGoogle Scholar
  5. 5.
    Zeman W (1970) Historical development of the nosological concept of amaurotic familial idiocy. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, vol. 10. North-Holland, Amsterdam, pp 212–232Google Scholar
  6. 6.
    Goebel HH (1995) The neuronal ceroid-lipofuscinoses. J Child Neurol 10:424–437PubMedCrossRefGoogle Scholar
  7. 7.
    Goebel HH (2000) The new nosography of the neuronal ceroid-lipofuscinoses. Ann Pathol 20:479–491PubMedGoogle Scholar
  8. 8.
    Goebel HH, Wisniewski KE (2004) Current state of clinical and morphological features in human NCL. Brain Pathol 14:61–69PubMedCrossRefGoogle Scholar
  9. 9.
    Tyynelä J, Baumann M, Henseler M, Sandhoff K, Haltia M (1995) Sphingolipid activator proteins in the neuronal ceroid-lipofuscinoses: an immunological study. Acta Neuropathol 89:391–398PubMedGoogle Scholar
  10. 10.
    Tyynelä J, Suopanki J, Baumann M, Haltia M (1997) Sphingolipid activator proteins (SAPs) in neuronal ceroid-lipofuscinoses (NCL). Neuropediatrics 28:49–52PubMedGoogle Scholar
  11. 11.
    Tyynelä J, Palmer DN, Baumann M, Haltia M (1993) Storage of saposins A and D in infantile neuronal ceroid-lipofuscinosis. FEBS Lett 330:8–12CrossRefPubMedGoogle Scholar
  12. 12.
    Elleder M, Sokolova J, Hrebicek M (1997) Follow-up study of subunit c of mitochondrial ATP synthase (ASCMAS) in Batten disease and in unrelated lysosomal disorders. Acta Neuropathol 93:379–390CrossRefPubMedGoogle Scholar
  13. 13.
    Palmer DN, Martinus RD, Cooper SM, Midwinter GG, Reid JC, Jolly RD (1989) Ovine ceroid lipofuscinosis. The major lipopigment protein and the lipid-binding subunit of mitochondrial ATP synthase have the same NH2-terminal sequence. J Biol Chem 264:5736–5740PubMedGoogle Scholar
  14. 14.
    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 42:561–567CrossRefPubMedGoogle Scholar
  15. 15.
    Eiberg H, Gardiner RM, Mohr J (1989) Batten disease (Spielmeyer–Sjögren disease) and haptoglobins (HP): indication of linkage and assignment to chromosome 16. Clin Genet 36:217–218PubMedCrossRefGoogle Scholar
  16. 16.
    Zeman W, Rider JA (eds) (1975) The dissection of a degenerative disease. Elsevier, New YorkGoogle Scholar
  17. 17.
    Wisniewski KE, Kida E, Golabek A, Kaczmarski W, Connell F, Zhong N (2001) Neuronal ceroid lipofuscinoses: classification and diagnosis. In: Wisniewski KE, Zhong N (eds) Batten disease: diagnosis, treatment, and research. Academic, San Diego, pp 1–34Google Scholar
  18. 18.
    Hellsten E, Vesa J, Olkkonen VM, Jalanko A, Peltonen L (1996) Human palmitoyl protein thioesterase: evidence for lysosomal targeting of the enzyme and disturbed cellular routing in infantile neuronal ceroid lipofuscinosis. EMBO J 15:5240–5245PubMedGoogle Scholar
  19. 19.
    Verkruyse LA, Hofmann SL (1996) Lysosomal targeting of palmitoyl-protein thioesterase. J Biol Chem 271:15831–15836CrossRefPubMedGoogle Scholar
  20. 20.
    Ahtiainen L, Van Diggelen OP, Jalanko A, Kopra O (2003) Palmitoyl protein thioesterase 1 is targeted to the axons in neurons. J Comp Neurol 455:368–377CrossRefPubMedGoogle Scholar
  21. 21.
    Camp LA, Hofmann SL (1993) Purification and properties of a palmitoyl-protein thioesterase that cleaves palmitate from H-Ras. J Biol Chem 268:22566–22574PubMedGoogle Scholar
  22. 22.
    Camp LA, Verkruyse LA, Afendis SJ, Slaughter CA, Hofmann SL (1994) Molecular cloning and expression of palmitoyl-protein thioesterase. J Biol Chem 269:23212–23219PubMedGoogle Scholar
  23. 23.
    Chattopadhyay S, Pearce DA (2000) Neural and extraneural expression of the neuronal ceroid lipofuscinoses genes CLN1, CLN2, and CLN3: functional implications for CLN3. Mol Genet Metab 71:207–211CrossRefPubMedGoogle Scholar
  24. 24.
    Heinonen O, Salonen T, Jalanko A, Peltonen L, Copp A (2000) CLN-1 and CLN-5, genes for infantile and variant late infantile neuronal ceroid lipofuscinoses, are expressed in the embryonic human brain. J Comp Neurol 426:406–412CrossRefPubMedGoogle Scholar
  25. 25.
    Bellizzi JJ III, Widom J, Kemp C, Lu JY, Das AK, Hofmann SL, Clardy J (2000) The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A 97:4573–4578CrossRefPubMedGoogle Scholar
  26. 26.
    van Diggelen OP, Keulemans JL, Winchester B, Hofman IL, Vanhanen SL, Santavuori P, Voznyi YV (1999) A rapid fluorogenic palmitoyl-protein thioesterase assay: pre- and postnatal diagnosis of INCL. Mol Genet Metab 66:240–244CrossRefPubMedGoogle Scholar
  27. 27.
    Voznyi YV, Keulemans JL, Mancini GM, Catsman-Berrevoets CE, Young E, Winchester B, Kleijer WJ, van Diggelen OP (1999) A new simple enzyme assay for pre- and postnatal diagnosis of infantile neuronal ceroid lipofuscinosis (INCL) and its variants. J Med Genet 36:471–474PubMedGoogle Scholar
  28. 28.
    Halac IN, Kramer RD, Kohan R, Tapia V, Guelbert N, Oller-Ramírez AM, Ghio A, Cismondi IA, Depetris-Boldini C, Paschini-Capra A, Giner-Ayala A (2004) Evaluation of the screening of PPT1 and TPP-I in saliva in the infantile (INCL) and late infantile (LINCL) neuronal ceroid lipofuscinoses. In Proceedings of ‘Neuronal ceroid lipofuscinoses and other genetic lysosomal storage disorders: from the clinical to the molecular aspects’, Córdoba, Argentina, 18–20 September 2003. Rev Neurol 38:292–298Google Scholar
  29. 29.
    Das AK, Becerra CHR, Yi W, Lu J-Y, Siakotos AN, Wisniewski KE, Hofmann SL (1998) Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. J Clin Invest 102:361–370PubMedGoogle Scholar
  30. 30.
    Das AK, Lu JY, Hofmann SL (2001) Biochemical analysis of mutations in palmitoyl-protein thioesterase causing infantile and late-onset forms of neuronal ceroid lipofuscinosis. Hum Mol Genet 10:1431–1439CrossRefPubMedGoogle Scholar
  31. 31.
    Bach G (2001) Mucolipidosis type IV. Mol Genet Metab 73:197–203CrossRefPubMedGoogle Scholar
  32. 32.
    Lehtovirta M, Kyttälä A, Eskelinen E-L, Hess M, Heinonen O, Jalanko A (2001) Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL). Hum Mol Genet 10:69–75CrossRefPubMedGoogle Scholar
  33. 33.
    Salonen T, Heinonen-Kopra O, Vesa J, Jalanko A (2001) Neuronal trafficking of palmitoyl protein thioesterase provides an excellent model to study the effects of different mutations which cause infantile neuronal ceroid lipofuscinocis. Mol Cell Neurosci 18:131–140CrossRefPubMedGoogle Scholar
  34. 34.
    Vesa J, Hellsten E, Verkruyse LA, Camp LA, Rapola J, Santavuori P, Hofmann SL, Peltonen L (1995) Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376:584–587CrossRefPubMedGoogle Scholar
  35. 35.
    Hentze MW, Kulozik AE (1999) A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96:307–310CrossRefPubMedGoogle Scholar
  36. 36.
    Mitchison HM, Hofmann SL, Becerra CHR, Munroe PB, Lake BD, Crow YJ, Stephenson JBP, Williams RE, Hofman IL, Taschner PEM, Martin J-J, Philippart M, Andermann E, Andermann F, Mole SE, Gardiner RM, O’Rawe AM (1998) Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Hum Mol Genet 7:291–297CrossRefPubMedGoogle Scholar
  37. 37.
    Vanhanen SL, Puranen J, Autti T, Raininko R, Liewendahl K, Nikkinen P, Santavuori P, Suominen P, Vuori K, Hakkinen AM (2004) Neuroradiological findings (MRS, MRI, SPECT) in infantile neuronal ceroid-lipofuscinosis (infantile CLN1) at different stages of the disease. Neuropediatrics 35:27–35CrossRefPubMedGoogle Scholar
  38. 38.
    Santavuori P, Gottlob I, Haltia M, Rapola J, Lake BD, Tyynela J, Peltonen L (1999) CLN1—infantile and other types of NCL with GROD. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (Batten disease). IOS, Amsterdam, pp 16–36Google Scholar
  39. 39.
    Crow YJ, Tolmie JL, Howatson AG, Patrick WJA, Stephenson JBP (1997) Batten disease in the West of Scotland 1974–1995 including five cases of the juvenile form with granular osmiophilic deposits. Neuropediatrics 28:140–144PubMedGoogle Scholar
  40. 40.
    Santorelli FM, Bertini E, Petruzzella V, Di Capua M, Calvieri S, Gasparini P, Zeviani M (1998) A novel insertion mutation (A169i) in the CLN1 gene is associated with infantile neuronal ceroid lipofuscinosis in an Italian patient. Biochem Biophys Res Commun 245:519–522CrossRefPubMedGoogle Scholar
  41. 41.
    Stephenson JB, Greene ND, Leung KY, Munroe PB, Mole SE, Gardiner RM, Taschner PE, O’Regan M, Naismith K, Crow YJ, Mitchison HM (1999) The molecular basis of GROD-storing neuronal ceroid lipofuscinoses in Scotland. Mol Genet Metab 66:245–247CrossRefPubMedGoogle Scholar
  42. 42.
    Wisniewski KE, Connell F, Kaczmarski W, Kaczmarski A, Siakotos A, Becerra CR, Hofmann SL (1998) Palmitoyl-protein thioesterase deficiency in a novel granular variant of LINCL. Pediatr Neurol 18:119–123CrossRefPubMedGoogle Scholar
  43. 43.
    Mazzei R, Conforti FL, Magariello A, Bravaccio C, Militerni R, Gabriele AL, Sampaolo S, Patitucci A, Di Iorio G, Muglia M, Quattrone A (2002) A novel mutation in the CLN1 gene in a patient with juvenile neuronal ceroid lipofuscinosis. J Neurol 249:1398–1400CrossRefPubMedGoogle Scholar
  44. 44.
    van Diggelen OP, Thobois S, Tilikete C, Zabot MT, Keulemans JL, van Bunderen PA, Taschner PE, Losekoot M, Voznyi YV (2001) Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease. Ann Neurol 50:269–272CrossRefPubMedGoogle Scholar
  45. 45.
    Humphreys S, Lake BD, Scholtz CL (1985) Congenital amaurotic idiocy—a pathological, histochemical, biochemical and ultrastructural study. Neuropathol Appl Neurobiol 11:475–484PubMedGoogle Scholar
  46. 46.
    Garborg I, Torvik A, Hals J, Tangsrud SE, Lindemann R (1987) Congenital neuronal ceroid lipofuscinosis. A case report. Acta Pathol Microbiol Immunol Scand A 95:119–125PubMedGoogle Scholar
  47. 47.
    Rapola J, Salonen R, Ammala P, Santavuori P (1990) Prenatal diagnosis of the infantile type of neuronal ceroid lipofuscinosis by electron microscopic investigation of human chorionic villi. Prenat Diagn 10:553–559PubMedGoogle Scholar
  48. 48.
    Kohlschütter A, Lake BD (1999) NCL variants without genetic assignment. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (Batten disease). IOS, Amsterdam, pp 125–127Google Scholar
  49. 49.
    Burck U, Goebel HH, Kuhlendahl HD, Meier C, Goebel KM (1981) Neuromyopathy and vitamin E deficiency in man. Neuropediatrics 12:267–278PubMedGoogle Scholar
  50. 50.
    Wlodawer A, Li M, Dauter Z, Gustchina A, Uchida K, Oyama H, Dunn BM, Oda K (2001) Carboxyl proteinase from Pseudomonas defines a novel family of subtilisin-like enzymes. Nat Struct Biol 8:442–446CrossRefPubMedGoogle Scholar
  51. 51.
    Ezaki J, Takeda-Ezaki M, Kominami E (2000) Tripeptidyl peptidase I, the late infantile neuronal ceroid lipofuscinosis gene product, initiates the lysosomal degradation of subunit c of ATP synthase. J Biochem (Tokyo) 128:509–516Google Scholar
  52. 52.
    Junaid MA, Wu G, Pullarkat RK (2000) Purification and characterization of bovine brain lysosomal pepstatin-insensitive proteinase, the gene product deficient in the human late-infantile neuronal ceroid lipofuscinosis. J Neurochem 74:287–294CrossRefPubMedGoogle Scholar
  53. 53.
    Warburton MJ, Bernardini F (2001) The specificity of lysosomal tripeptidyl peptidase-I determined by its action on angiotensin-II analogues. FEBS Lett 500:145–148CrossRefPubMedGoogle Scholar
  54. 54.
    Bernardini F, Warburton MJ (2002) The lysosomal degradation of cholecystokinin-(29–33)-amide in mouse brain is dependent on tripeptidyl peptidase: I. Implications for the degradation and storage of peptides in classical late infantile neuronal ceroid lipofuscinosis. Biochem J 366:521–529CrossRefPubMedGoogle Scholar
  55. 55.
    Kopan S, Sivasubramaniam U, Warburton MJ (2004) The lysosomal degradation of neuromedin B is dependent on tripeptidyl peptidase: I. Evidence for the impairment of neuropeptide degradation in late-infantile neuronal ceroid lipofuscinosis. Biochem Biophys Res Commun 319:58–65CrossRefPubMedGoogle Scholar
  56. 56.
    Golabek AA, Kida E, Walus M, Wujek P, Mehta P, Wisniewski KE (2003) Biosynthesis, glycosylation, and enzymatic processing in vivo of human tripeptidyl-peptidase I. J Biol Chem 278:7135–7145CrossRefPubMedGoogle Scholar
  57. 57.
    Lin L, Sohar I, Lackland H, Lobel P (2001) The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH. J Biol Chem 276:2249–2255PubMedGoogle Scholar
  58. 58.
    Vesa J, Chin MH, Oelgeschlager K, Isosomppi J, DellAngelica EC, Jalanko A, Peltonen L (2002) Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. Mol Biol Cell 13:2410–2420CrossRefPubMedGoogle Scholar
  59. 59.
    Wlodawer A, Durell SR, Li M, Oyama H, Oda K, Dunn BM (2003) A model of tripeptidyl-peptidase I (CLN2), a ubiquitous and highly conserved member of the sedolisin family of serine-carboxyl peptidases. BMC Struct Biol 3:8CrossRefPubMedGoogle Scholar
  60. 60.
    Sleat DE, Donnelly RJ, Lackland H, Liu C-G, Sohar I, Pullarkat RK, Lobel P (1997) Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis. Science 277:1802–1805PubMedGoogle Scholar
  61. 61.
    Kurachi Y, Oka A, Itoh M, Mizuguchi M, Hayashi M, Takashima S (2001) Distribution and development of CLN2 protein, the late-infantile neuronal ceroid lipofuscinosis gene product. Acta Neuropathol (Berl) 102:20–26Google Scholar
  62. 62.
    Young EP, Worthington VC, Jackson M, Winchester BG (2001) Pre- and postnatal diagnosis of patients with CLN1 and CLN2 by assay of palmitoyl-protein thioesterase and tripeptidyl-peptidase I activities. Eur J Paediatr Neurol 5(Suppl A):193–196PubMedGoogle Scholar
  63. 63.
    Lukacs Z, Santavuori P, Keil A, Steinfeld R, Kohlschutter A (2003) Rapid and simple assay for the determination of tripeptidyl peptidase and palmitoyl protein thioesterase activities in dried blood spots. Clin Chem 49:509–511CrossRefPubMedGoogle Scholar
  64. 64.
    Tessa A, Simonati A, Tavoni A, Bertini E, Santorelli FM (2000) A novel nonsense mutation (Q509X) in three Italian late-infantile neuronal ceroid-lipofuscinosis children. Hum Mutat (online) 15:577CrossRefGoogle Scholar
  65. 65.
    Ju W, Zhong R, Moore S, Moroziewicz D, Currie JR, Parfrey P, Brown WT, Zhong N (2002) Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles. J Med Genet 39:822–825CrossRefPubMedGoogle Scholar
  66. 66.
    Claussen M, Heim P, Knispel J, Goebel HH, Kohlschutter A (1992) Incidence of neuronal ceroid lipofuscinosis in West Germany: variation of a method for studying autosomal recessive disorders. Am J Med Genet 42:536–538CrossRefPubMedGoogle Scholar
  67. 67.
    Zhong N, Wisniewski KE, Hartikainen J, Ju W, Moroziewicz DN, McLendon L, Brooks SS, Brown WT (1998) Two common mutations in the CLN2 gene underlie late infantile neuronal ceroid lipofuscinosis. Clin Genet 54:234–238PubMedCrossRefGoogle Scholar
  68. 68.
    Ko CH, Kong CK, Chow TC, Lee KC (2001) Classic late infantile neuronal ceroid lipofuscinosis in a Chinese patient. Hong Kong Med J 7:93–96PubMedGoogle Scholar
  69. 69.
    Lam CW, Poon PM, Tong SF, Ko CH (2001) Two novel CLN2 gene mutations in a Chinese patient with classical late-infantile neuronal ceroid lipofuscinosis. Am J Med Genet 99:161–163CrossRefPubMedGoogle Scholar
  70. 70.
    Lavrov AY, Ilyna ES, Zakharova EY, Boukina AM, Tishkanina SV (2002) The first three Russian cases of classical, late-infantile, neuronal ceroid lipofuscinosis. Eur J Paediatr Neurol 6:161–164CrossRefPubMedGoogle Scholar
  71. 71.
    Barisic N, Logan P, Pikija S, Skarpa D, Blau N (2003) R208X mutation in CLN2 gene associated with reduced cerebrospinal fluid pterins in a girl with classic late infantile neuronal ceroid lipofuscinosis. Croat Med J 44:489–493PubMedGoogle Scholar
  72. 72.
    Sleat DE, Gin RM, Sohar I, Wisniewski K, Sklower-Brooks S, Pullarkat RK, Palmer DN, Lerner TJ, Boustany R-M, Uldall P, Siakotos AN, Donnelly RJ, Lobel P (1999) Mutational analysis of the defective protease in classical late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. Am J Hum Genet 64:1511–1523CrossRefPubMedGoogle Scholar
  73. 73.
    Zhong N, Moroziewicz D, Jurkiewicz A, Ju W, Johnston L, Wisniewski KE, Brown WT (2000) Heterogeneity of late infantile neuronal ceroid lipofuscinoses. Genet Med 2:312–318PubMedCrossRefGoogle Scholar
  74. 74.
    Lin L, Lobel P (2001) Expression and analysis of CLN2 variants in CHO cells: Q100R represents a polymorphism, and G389E and R447H represent loss-of-function mutations. Hum Mutat 18:165Google Scholar
  75. 75.
    Steinfeld R, Heim P, Von Gregory H, Meyer K, Ullrich K, Goebel HH, Kohlschutter A (2002) Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet 112:347–354CrossRefPubMedGoogle Scholar
  76. 76.
    Wisniewski KE, Kida E, Connell F, Zhong N (2000) Neuronal ceroid lipofuscinoses: research update. Neurol Sci 21:S49–S56CrossRefPubMedGoogle Scholar
  77. 77.
    Chow CW, Borg J, Billson VR, Lake BD (1993) Fetal tissue involvement in the late infantile type of neuronal ceroid lipofuscinosis. Prenat Diagn 13:833–841PubMedGoogle Scholar
  78. 78.
    Williams RE, Gottlob I, Lake BD, Goebel HH, Winchester BG, Wheeler RB (1999) CLN2—classic late infantile NCL. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (Batten disease). IOS, Amsterdam, pp 37–54Google Scholar
  79. 79.
    Wisniewski KE, Kaczmarski A, Kida E, Connell F, Kaczmarski W, Michalewski MP, Moroziewicz DN, Zhong N, Das AM, Jolly RD, Kohlschutter A (1999) Reevaluation of neuronal ceroid lipofuscinoses: atypical juvenile onset may be the result of CLN2 mutations. Mol Genet Metab 66:248–252CrossRefPubMedGoogle Scholar
  80. 80.
    Goebel HH, Kominami E, Neuen-Jacob E, Wheeler RB (2001) Morphological studies on CLN2. Eur J Paediatr Neurol 5(Suppl A):203–207CrossRefPubMedGoogle Scholar
  81. 81.
    Rowan SA, Lake BD (1995) Tissue and cellular distribution of subunit c of ATP synthase in Batten disease (neuronal ceroid-lipofuscinosis). Am J Med Genet 57:172–176CrossRefPubMedGoogle Scholar
  82. 82.
    Caillaud C, Manicom J, Puech JP, Lobel P, Poenaru L (1999) Enzymatic and molecular pre natal and postnatal diagnosis of ceroid lipofuscinoses. Am J Hum Genet 65(Suppl):A232Google Scholar
  83. 83.
    Hartikainen JM, Ju W, Wisniewski KE, Moroziewicz DN, Kaczmarski AL, McLendon L, Zhong D, Suarez CT, Brown WT, Zhong N (1999) Late infantile neuronal ceroid lipofuscinosis is due to splicing mutations in the CLN2 gene. Mol Genet Metab 67:162–168CrossRefPubMedGoogle Scholar
  84. 84.
    Tsiakas K, Steinfeld R, Storch S, Ezaki J, Lukacs Z, Kominami E, Kohlschutter A, Ullrich K, Braulke T (2004) Mutation of the glycosylated asparagine residue 286 in human CLN2 protein results in loss of enzymatic activity. Glycobiology 14:1C–5CCrossRefPubMedGoogle Scholar
  85. 85.
    Wujek P, Kida E, Walus M, Wisniewski KE, Golabek AA (2004) N-Glycosylation is crucial for folding, trafficking, and stability of human tripeptidyl-peptidase I. J Biol Chem 279:12827–12839CrossRefPubMedGoogle Scholar
  86. 86.
    Simonati A, Santorum E, Tessa A, Polo A, Simonetti F, Bernardina BD, Santorelli FM, Rizzuto N (2000) A CLN2 gene nonsense mutation is associated with severe caudate atrophy and dystonia in LINCL. Neuropediatrics 31:199–201CrossRefPubMedGoogle Scholar
  87. 87.
    Ezaki J, Takeda-Ezaki M, Koike M, Ohsawa Y, Taka H, Mineki R, Murayama K, Uchiyama Y, Ueno T, Kominami E (2003) Characterization of Cln3p, the gene product responsible for juvenile neuronal ceroid lipofuscinosis, as a lysosomal integral membrane glycoprotein. J Neurochem 87:1296–1308CrossRefPubMedGoogle Scholar
  88. 88.
    Haskell RE, Carr CJ, Pearce DA, Bennett MJ, Davidson BL (2000) Batten disease: evaluation of CLN3 mutations on protein localization and function. Hum Mol Genet 9:735–744CrossRefPubMedGoogle Scholar
  89. 89.
    Järvelä I, Sainio M, Rantamaki T, Olkkonen VM, Carpén O, Peltonen L, Jalanko A (1998) Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Hum Mol Genet 7:85–90CrossRefPubMedGoogle Scholar
  90. 90.
    Järvelä I, Lehtovirta M, Tikkanen R, Kyttälä A, Jalanko A (1999) Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL). Hum Mol Genet 8:1091–1098CrossRefPubMedGoogle Scholar
  91. 91.
    Luiro K, Kopra O, Lehtovirta M, Jalanko A (2001) CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: new clues to Batten disease. Hum Mol Genet 10:2123–2131CrossRefPubMedGoogle Scholar
  92. 92.
    Janes RW, Munroe PB, Mitchsion HM, Gardiner RM, Mole SE, Wallace BA (1996) A model for Batten disease protein CLN3: functional implications from homology and mutations. FEBS Lett 399:75–77CrossRefPubMedGoogle Scholar
  93. 93.
    Mao Q, Foster BJ, Xia H, Davidson BL (2003) Membrane topology of CLN3, the protein underlying Batten disease. FEBS Lett 541:40–46CrossRefPubMedGoogle Scholar
  94. 94.
    Kyttälä A, Ihrke G, Vesa J, Schell MJ, Luzio JP (2003) Two motifs target Batten disease protein CLN3 to lysosomes in transfected non-neuronal and neuronal cells. Mol Biol CellGoogle Scholar
  95. 95.
    Rakheja D, Narayan SB, Pastor JV, Bennett MJ (2004) CLN3P, the Batten disease protein, localizes to membrane lipid rafts (detergent-resistant membranes). Biochem Biophys Res Commun 317:988–991CrossRefPubMedGoogle Scholar
  96. 96.
    Pearce DA, Ferea T, Nosel SA, Das B, Sherman F (1999) Action of BTN1, the yeast orthologue of the gene mutated in Batten disease. Nat Genet 22:55–58CrossRefPubMedGoogle Scholar
  97. 97.
    Chattopadhyay S, Muzaffar NE, Sherman F, Pearce DA (2000) The yeast model for Batten disease: mutations in BTN1, BTN2, and HSP30 alter pH homeostasis. J Bacteriol 182:6418–6423CrossRefPubMedGoogle Scholar
  98. 98.
    The International Batten Disease Consortium (1995) Isolation of a novel gene underlying Batten disease, CLN3. Cell 82:949–957Google Scholar
  99. 99.
    Mitchison HM, O’Rawe AM, Taschner PEM, Santavuori P, de Vos N, Breuning MH, Mole SE, Gardiner RM, Järvelä IE (1995) Batten disease (CLN3): linkage disequilibrium mapping in the Finnish population and analysis of European haplotypes. Am J Hum Genet 56:654–662PubMedGoogle Scholar
  100. 100.
    Munroe PB, Mitchison HM, O’Rawe AM, Anderson JW, Boustany R-M, Lerner TJ, Taschner PEM, de Vos N, Breuning MH, Gardiner RM, Mole SE (1997) Spectrum of mutations in the Batten disease gene, CLN3. Am J Hum Genet 61:310–316PubMedGoogle Scholar
  101. 101.
    Munroe PB, O’Rawe AM, Mitchison HM, Järvelä IE, Santavuouri P, Lerner TJ, Taschner PEM, Gardiner RM, Mole SE (1997) Strategy for mutation detection in CLN3: characterisation of two Finnish mutations. Neuropediatrics 28:15–17PubMedGoogle Scholar
  102. 102.
    Järvelä I, Autti T, Lamminranta S, Åberg L, Raininko R, Santavuori P (1997) Clinical and magnetic resonance imaging findings in Batten disease: analysis of the major mutation (1.02-kb deletion). Ann Neurol 42:799–802CrossRefPubMedGoogle Scholar
  103. 103.
    Lauronen L, Munroe PB, Järvelä I, Autti T, Mitchison HM, O’Rawe AM, Gardiner RM, Mole SE, Puranen J, Häkkinen A-M, Kirveskari E, Santavuori P (1999) Delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis. Neurology 52:360–365PubMedGoogle Scholar
  104. 104.
    Goebel HH, Pilz H, Gullotta F (1976) The protracted form of juvenile neuronal ceroid-lipofuscinosis. Acta Neuropathol (Berl) 36:393–396CrossRefGoogle Scholar
  105. 105.
    Elleder M, Lake BD, Goebel HH, Rapola J, Haltia M, Carpenter S (1999) Definitions of the ultrastructural patterns found in NCL. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (Batten disease). IOS, Amsterdam, pp 5–15Google Scholar
  106. 106.
    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: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (Batten disease). IOS, Amsterdam, pp 55–70Google Scholar
  107. 107.
    Goebel HH (2004) Introduction. Symposium: the neuronal ceroid lipofuscinopses (NCL)—a group of lysosomal storage diseases come of age. Brain Pathol 14:59–60CrossRefGoogle Scholar
  108. 108.
    Goebel HH, Zeman W, Pilz H (1975) Significance of muscle biopsies in neuronal ceroid-lipofuscinoses. J Neurol Neurosurg Psychiatry 38:985–993PubMedGoogle Scholar
  109. 109.
    Munroe PB, Rapola J, Mitchison HM, Mole SE, Gardiner RM, Järvelä IE (1996) Prenatal diagnosis of Batten disease. Lancet 347:1014–1015CrossRefPubMedGoogle Scholar
  110. 110.
    Lake BD, Young EP, Winchester BG (1998) Prenatal diagnosis of lysosomal storage diseases. Brain Pathol 8:133–149PubMedCrossRefGoogle Scholar
  111. 111.
    Goebel HH, Zeman W, Patel VK, Pullarkat RK, Lenard HG (1979) On the ultrastructural diversity and essence of residual bodies in neuronal ceroid-lipofuscinosis. Mech Ageing Dev 10:53–70CrossRefPubMedGoogle Scholar
  112. 112.
    Goebel HH, Kohlschutter A, Lenard HG (1982) Morphologic and chemical biopsy findings in mucolipidosis IV. Clin Neuropathol 1:73–82PubMedGoogle Scholar
  113. 113.
    Bargal R, Goebel HH, Latta E, Bach G (2002) Mucolipidosis IV: novel mutation and diverse ultrastructural spectrum in the skin. Neuropediatrics 33:199–202CrossRefPubMedGoogle Scholar
  114. 114.
    Goebel HH (1993) Protracted juvenile neuronal ceroid-lipofuscinosis. J Inherit Metab Dis 16:233–236CrossRefPubMedGoogle Scholar
  115. 115.
    Wisniewski KE, Zhong N, Kaczmarski W, Kaczmarski A, Sklower-Brooks S, Brown WT (1998) Studies of atypical JNCL suggest overlapping with other NCL forms. Pediatr Neurol 18:36–40CrossRefPubMedGoogle Scholar
  116. 116.
    Wisniewski KE, Zhong N, Kaczmarski W, Kaczmarski A, Kida E, Brown WT, Schwarz KO, Lazzarini AM, Rubin AJ, Stenroos ES, Johnson WG, Wisniewski TM (1998) Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis. Ann Neurol 43:106–110CrossRefPubMedGoogle Scholar
  117. 117.
    Åberg L, Järvelä I, Rapola J, Autti T, Kirveskari E, Lappi M, Sipilä L, Santavuori P (1998) Atypical juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposit-like inclusions in the autonomic nerve cells of the gut wall. Acta Neuropathol 95:306–312CrossRefPubMedGoogle Scholar
  118. 118.
    de los Reyes E, Dyken PR, Phillips P, Brodsky M, Bates S, Glasier C, Mrak RE (2004) Profound infantile neuroretinal dysfunction in a heterozygote for the CLN3 genetic defect. J Child Neurol 19:42–46PubMedGoogle Scholar
  119. 119.
    Boehme DH, Cottrell JC, Leonberg SC, Zeman W (1971) A dominant form of neuronal ceroid-lipofuscinosis. Brain 94:745–760PubMedGoogle Scholar
  120. 120.
    Nijssen PC, Ceuterick C, van Diggelen OP, Elleder M, Martin JJ, Teepen JL, Tyynela J, Roos RA (2003) Autosomal dominant adult neuronal ceroid lipofuscinosis: a novel form of NCL with granular osmiophilic deposits without palmitoyl protein thioesterase 1 deficiency. Brain Pathol 13:574–581PubMedCrossRefGoogle Scholar
  121. 121.
    Ferrer I, Arbizu T, Pena J, Serra JP (1980) A Golgi and ultrastructural study of a dominant form of Kufs’ disease. J Neurol 222:183–190CrossRefPubMedGoogle Scholar
  122. 122.
    Dyken P, Wisniewski K (1995) Classification of the neuronal ceroid-lipofuscinoses: expansion of the atypical forms. Am J Med Genet 57:150–154CrossRefPubMedGoogle Scholar
  123. 123.
    Josephson SA, Schmidt RE, Millsap P, McManus DQ, Morris JC (2001) Autosomal dominant Kufs’ disease: a cause of early onset dementia. J Neurol Sci 188:51–60CrossRefPubMedGoogle Scholar
  124. 124.
    Berkovic SF, Carpenter S, Andermann F, Andermann E, Wolfe LS (1988) Kufs’ disease: a critical reappraisal. Brain 111:27–62PubMedGoogle Scholar
  125. 125.
    Sadzot B, Reznik M, Arrese-Estrada JE, Franck G (2000) Familial Kufs’ disease presenting as a progressive myoclonic epilepsy. J Neurol 247:447–454CrossRefPubMedGoogle Scholar
  126. 126.
    Constantinidis J, Wisniewski KE, Wisniewski TM (1992) The adult and a new late adult forms of neuronal ceroid lipofuscinosis. Acta Neuropathol (Berl) 83:461–468CrossRefGoogle Scholar
  127. 127.
    Dom R, Brucher JM, Ceuterick C, Carton H, Martin JJ (1979) Adult ceroid-lipofuscinosis (Kufs’ disease) in two brothers. Retinal and visceral storage in one; diagnostic muscle biopsy in the other. Acta Neuropathol (Berl) 45:67–72CrossRefGoogle Scholar
  128. 128.
    Vercruyssen A, Martin JJ, Ceuterick C, Jacobs K, Swerts L (1982) Adult ceroid-lipofuscinosis: diagnostic value of biopsies and of neurophysiological investigations. J Neurol Neurosurg Psychiatry 45:1056–1059PubMedCrossRefGoogle Scholar
  129. 129.
    Martin JJ, Libert J, Ceuterick C (1987) Ultrastructure of brain and retina in Kufs’ disease (adult type-ceroid-lipofuscinosis). Clin Neuropathol 6:231–235PubMedGoogle Scholar
  130. 130.
    Isosomppi J, Vesa J, Jalanko A, Peltonen L (2002) Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein. Hum Mol Genet 11:885–891CrossRefPubMedGoogle Scholar
  131. 131.
    Savukoski M, Klockars T, Holmberg V, Santavuori P, Lander ES, Peltonen L (1998) CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis. Nat Genet 19:286–288CrossRefPubMedGoogle Scholar
  132. 132.
    Holmberg V, Lauronen L, Autti T, Santavuori P, Savukoski M, Uvebrant P, Hofman I, Peltonen L, Järvelä I (2000) Phenotype–genotype correlation in eight patients with Finnish variant late infantile NCL (CLN5). Neurology 55:579–581PubMedGoogle Scholar
  133. 133.
    Pineda-Trujillo N, Cornejo W, Wheeler RB, Múnera S, Valencia A, Agudelo-Arango J, Cogollo A, Anderson G, Bedoya G, Mole SE, Ruíz-Linares A (2004) A novel mutation in CLN5 underlying juvenile onset neuronal ceroid lipofuscinosis in South America. Neurology (in press)Google Scholar
  134. 134.
    Santavuori P, Rapola J, Nuutila A, Raininko R, Lappi M, Launes J, Herva R, Saino K (1991) The spectrum of Jansky–Bielschowsky disease. Neuropediatrics 22:92–96PubMedGoogle Scholar
  135. 135.
    Autti T, Raininko R, Launes J, Nuutila A, Santavuori P (1992) Jansky–Bielschowsky variant disease: CT, MRI, and SPECT findings. Paediatric Neurol 8:121–126CrossRefGoogle Scholar
  136. 136.
    Lauronen L, Huttunen J, Kirveskari E, Wikstrom H, Sainio K, Autti T, Santavuori P (2002) Enlarged SI and SII somatosensory evoked responses in the CLN5 form of neuronal ceroid lipofuscinosis. Clin Neurophysiol 113:1491–1500CrossRefPubMedGoogle Scholar
  137. 137.
    Santavuori P, Rapola J, Saino K, Raitta C (1982) A variant of Jansky–Bielschowsky disease. Neuropediatrics 13:135–141PubMedGoogle Scholar
  138. 138.
    Tyynelä J, Suopanki J, Santavuori P, Baumann M, Haltia M (1997) Variant late infantile neuronal ceroid-lipofuscinosis: pathology and biochemistry. J Neuropathol Exp Neurol 56:369–375PubMedGoogle Scholar
  139. 139.
    Rapola J, Lake BD (2000) Lymphocyte inclusions in Finnish-variant late infantile neuronal ceroid lipofuscinosis (CLN5). Neuropediatrics 31:33–34CrossRefPubMedGoogle Scholar
  140. 140.
    Gao H, Boustany RM, Espinola JA, Cotman SL, Srinidhi L, Antonellis KA, Gillis T, Qin X, Liu S, Donahue LR, Bronson RT, Faust JR, Stout D, Haines JL, Lerner TJ, MacDonald ME (2002) Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet 70:324–335CrossRefPubMedGoogle Scholar
  141. 141.
    Wheeler RB, Sharp JD, Schultz RA, Joslin JM, Williams RE, Mole SE (2002) The gene mutated in variant late infantile neuronal ceroid lipofuscinosis (CLN6) and nclf mutant mice encodes a novel predicted transmembrane protein. Am J Hum Genet 70:537–542CrossRefPubMedGoogle Scholar
  142. 142.
    Mole SE, Michaux G, Codlin S, Wheeler RB, Sharp JD, Cutler DF (2004) CLN6, which is associated with a lysosomal storage disease, is an endoplasmic reticulum protein. Exp Cell Res 298:399–406CrossRefPubMedGoogle Scholar
  143. 143.
    Heine C, Koch B, Storch S, Kohlschutter A, Palmer DN, Braulke T (2004) Defective ER-resident membrane protein CLN6 affects lysosomal degradation of endocytosed arylsulfatase A. J Biol Chem 279:22347–22352CrossRefPubMedGoogle Scholar
  144. 144.
    Sharp JD, Wheeler RB, Parker KA, Gardiner RM, Williams RE, Mole SE (2003) Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat 22:35–42CrossRefPubMedGoogle Scholar
  145. 145.
    Lake BD, Cavanagh NPC (1978) Early-juvenile Batten’s disease—a recognisable subgroup distinct from other forms of Batten’s disease. J Neurol Sci 36:265–271CrossRefPubMedGoogle Scholar
  146. 146.
    Kimura S, Goebel HH (1987) Electron microscopic studies on skin and lymphocytes in early juvenile neuronal ceroid lipofuscinosis. Brain Dev 9:576–580PubMedGoogle Scholar
  147. 147.
    Andermann E, Jacob JC, Andermann F, Carpenter S, Wolfe L, Berkovic SF (1988) The Newfoundland aggregate of neuronal ceroid lipofuscinosis. Am J Med Genet Suppl 5:111–116CrossRefPubMedGoogle Scholar
  148. 148.
    Wheeler RB, Sharp JD, Mitchell WA, Bate SL, Williams RE, Lake BD, Gardiner RM (1999) A new locus for variant late infantile neuronal ceroid lipofuscinosis (LINCL)—CLN7. Mol Genet Metab 66:337–338CrossRefPubMedGoogle Scholar
  149. 149.
    Peña JA, Cardozo JJ, Montiel CM, Molina OM, Boustany R (2001) Serial MRI findings in the Costa Rican variant of neuronal ceroid-lipofuscinosis. Pediatr Neurol 25:78–80CrossRefPubMedGoogle Scholar
  150. 150.
    Elleder M, Franc J, Kraus J, Nevsímalová S, Sixtová K, Zeman J (1997) Neuronal ceroid lipofuscinosis in the Czech Republic: analysis of 57 cases. Report of the ‘Prague NCL Group’. Eur J Paediatr Neurol 4:109–114CrossRefGoogle Scholar
  151. 151.
    Teixeira C, Guimaraes A, Bessa C, Ferreira MJ, Lopes L, Pinto E, Pinto R, Boustany RM, Sa Miranda MC, Ribeiro MG (2003) Clinicopathological and molecular characterization of neuronal ceroid lipofuscinosis in the Portuguese population. J Neurol 250:661–667CrossRefPubMedGoogle Scholar
  152. 152.
    Teixeira CA, Espinola JA, Huo L, Kohlschütter J, Persaud Sawin D-A, Minassian B, Bessa CJP, Guimarães A, Stephan AA, Clara Sà Miranda M, MacDonald ME, Gil Ribeiro M, Boustany R-M (2003) Novel mutations in the CLN6 gene causing a variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat 21:502–508CrossRefPubMedGoogle Scholar
  153. 153.
    Nardocci N, Morbin M, Bugiani M, Lamantea E, Bugiani O (2000) Neuronal ceroid lipofuscinosis: detection of atypical forms. Neurol Sci 21:S57–S61CrossRefPubMedGoogle Scholar
  154. 154.
    Binelli S, Canafoglia L, Panzica F, Pozzi A, Franceschetti S (2000) Electroencephalographic features in a series of patients with neuronal ceroid lipofuscinoses. Neurol Sci 21:S83–S87CrossRefPubMedGoogle Scholar
  155. 155.
    Scaioli V, Nardocci N (2000) A pathophysiological study of neuronal ceroid lipofuscinoses in 17 patients: critical review and methodological proposal. Neurol Sci 21:S89–S92CrossRefPubMedGoogle Scholar
  156. 156.
    Veneselli E, Biancheri R, Perrone MV, Buoni S, Fois A (2000) Neuronal ceroid lipofuscinoses: clinical and EEG findings in a large study of Italian cases. Neurol Sci 21:S75–S81CrossRefPubMedGoogle Scholar
  157. 157.
    Iannetti P, Messa C, Spalice A, Lucignani G, Fazio F (1994) Positron emission tomography in neuronal ceroid lipofuscinosis (Jansky–Bielschowsky disease): a case report. Brain Dev 16:459–462CrossRefPubMedGoogle Scholar
  158. 158.
    Williams RE, Lake BD, Elleder M, Sharp J (1999) CLN6—variant late infantile/early juvenile NCL. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (Batten disease). IOS, Amsterdam, pp 102–113Google Scholar
  159. 159.
    Heine C, Tyynela J, Cooper JD, Palmer DN, Elleder M, Kohlschutter A, Braulke T (2003) Enhanced expression of manganese-dependent superoxide dismutase in human and sheep CLN6 tissues. Biochem J 376:369–376CrossRefPubMedGoogle Scholar
  160. 160.
    Mitchell WA, Wheeler RB, Sharp JD, Bate SL, Gardiner RM, Ranta US, Lonka L, Williams RE, Lehesjoki AE, Mole SE (2001) Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8. Eur J Paediatr Neurol 5(Suppl A):21–27CrossRefPubMedGoogle Scholar
  161. 161.
    Ranta S, Topçu M, Tegelberg S, Tan H, Üstübütün A, Saatci I, Dufke A, Enders H, Pohl K, Alembik Y, Mitchell WA, Mole SE, Lehesjoki A-E (2004) Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients is allelic to Northern epilepsy. Hum Mutat 23:300–305CrossRefPubMedGoogle Scholar
  162. 162.
    Williams RE, Topçu M, Lake BD, Mitchell WA, Mole SE (1999) CLN7—Turkish variant late infantile NCL. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (Batten disease). IOS, Amsterdam, pp 114–116Google Scholar
  163. 163.
    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 AE (1999) The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nat Genet 23:233–236CrossRefPubMedGoogle Scholar
  164. 164.
    Lonka L, Kyttälä A, Ranta S, Jalanko A, Lehesjoki AE (2000) The neuronal ceroid lipofuscinosis CLN8 membrane protein is a resident of the endoplasmic reticulum. Hum Mol Genet 9:1691–1697CrossRefPubMedGoogle Scholar
  165. 165.
    Lonka L, Salonen T, Siintola E, Kopra O, Lehesjoki AE, Jalanko A (2004) Localization of wild-type and mutant neuronal ceroid lipofuscinosis CLN8 proteins in non-neuronal and neuronal cells. J Neurosci Res 76:862–871CrossRefPubMedGoogle Scholar
  166. 166.
    Winter E, Ponting CP (2002) TRAM, LAG1 and CLN8: members of a novel family of lipid-sensing domains? Trends Biochem Sci 27:381–383CrossRefPubMedGoogle Scholar
  167. 167.
    Katz ML, Khan S, Awano T, Shahid SA, Siakotos AN, Johnson GS (2005) A mutation in the CLN8 gene in English setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun 327:541–547CrossRefPubMedGoogle Scholar
  168. 168.
    Hirvasniemi A, Lang H, Lehesjoki AE, Leisti J (1994) Northern epilepsy syndrome: an inherited childhood onset epilepsy with associated mental deterioration. J Med Genet 31:177–182PubMedGoogle Scholar
  169. 169.
    Topçu M, Tan H, Yalnizoglu D, Usubutun A, Saatci I, Aynaci M, Anlar B, Topaloglu H, Turanli G, Kose G, Aysun S (2004) Evaluation of 36 patients from Turkey with neuronal ceroid lipofuscinosis: clinical, neurophysiological, neuroradiological and histopathologic studies. Turk J Pediatr 46:1–10PubMedGoogle Scholar
  170. 170.
    Herva R, Tyynela J, Hirvasniemi A, Syrjakallio-Ylitalo M, Haltia M (2000) Northern epilepsy: a novel form of neuronal ceroid-lipofuscinosis. Brain Pathol 10:215–222PubMedCrossRefGoogle Scholar
  171. 171.
    Haltia M, Tyynelä J, Hirvasniemi A, Herva R, Ranta US, Lehesjoki A-E (1999) CLN8—Northern epilepsy. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (Batten disease). IOS, Amsterdam, pp 117–124Google Scholar
  172. 172.
    Stengel OC (1826) Account of a singular illness among four siblings in the vicinity of RØraas. Ceroid-lipofuscinosis (Batten’s disease). Elsevier/North Holland Biomedical Press, 1982, Amsterdam, pp 17–19Google Scholar
  173. 173.
    Zeman W, Dyken P (1969) Neuronal ceroid-lipofuscinosis (Batten’s disease): relationship to amaurotic familial idiocy? Pediatrics 44:570–583PubMedGoogle Scholar
  174. 174.
    Zeman W (1971) Morphological approaches to the nosology of nervous system defects. Birth Defects Orig Artic Ser 3:23–30Google Scholar
  175. 175.
    Tyynelä J, Sohar I, Sleat DE, Gin RM, Donnelly RJ, Baumann M, Haltia M, Lobel P (2000) A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration. EMBO J 19:2786–2792CrossRefPubMedGoogle Scholar
  176. 176.
    Koike M, Nakanishi H, Saftig P, Ezaki J, Isahara K, Ohsawa Y, Schulz-Schaeffer W, Watanabe T, Waguri S, Kametaka S, Shibata M, Yamamoto K, Kominami E, Peters C, von Figura K, Uchiyama Y (2000) Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci 20:6898–6906PubMedGoogle Scholar
  177. 177.
    Gupta P, Soyombo AA, Atashband A, Wisniewski KE, Shelton JM, Richardson JA, Hammer RE, Hofmann SL (2001) Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc Natl Acad Sci U S A 98:13566–13571CrossRefPubMedGoogle Scholar
  178. 178.
    Gupta P, Soyombo AA, Shelton JM, Wilkofsky IG, Wisniewski KE, Richardson JA, Hofmann SL (2003) Disruption of PPT2 in mice causes an unusual lysosomal storage disorder with neurovisceral features. Proc Natl Acad Sci U S A 100:12325–12330CrossRefPubMedGoogle Scholar
  179. 179.
    Jolly RD, Martinus RD, Palmer DN (1992) Sheep and other animals with ceroid lipofuscinoses: their relevance to Batten disease. Am J Med Genet 42:609–614CrossRefPubMedGoogle Scholar
  180. 180.
    Lingaas F, Aarskaug T, Sletten M, Bjerkas I, Grimholt U, Moe L, Juneja RK, Wilton AN, Galibert F, Holmes NG, Dolf G (1998) Genetic markers linked to neuronal ceroid lipofuscinosis in English setter dogs. Anim Genet 29:371–376CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Sara E. Mole
    • 1
  • Ruth E. Williams
    • 2
  • Hans H. Goebel
    • 3
    • 4
  1. 1.MRC Laboratory for Molecular Cell Biology and Department of Paediatrics and Child HealthUniversity College LondonLondonUK
  2. 2.Department of Paediatric NeurologyGuy’s HospitalLondonUK
  3. 3.Department of NeuropathologyJohannes Gutenberg UniversityMainzGermany
  4. 4.Medical CenterMainzGermany

Personalised recommendations