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. 2006 Apr 5;13(4):574–581. doi: 10.1111/j.1750-3639.2003.tb00486.x

Autosomal Dominant Adult Neuronal Ceroid Lipofuscinosis: a Novel Form of NCL with Granular Osmiophilic Deposits without Palmitoyl Protein Thioesterase 1 Deficiency

Peter C G Nijssen 1,✉, Chantal Ceuterick 2, Otto P van Diggelen 3, Milan Elleder 4, Jean‐Jacques Martin 2, Johannes L J M Teepen 5, Jaana Tyynelä 6, Raymund A C Roos 7
PMCID: PMC8095852  PMID: 14655761

Abstract

We describe the neuropathological and biochemical autopsy findings in 3 patients with autosomal dominant adult neuronal ceroid lipofuscinosis (ANCL, Parry type; MIM 162350), from a family with 6 affected individuals in 3 generations. Throughout the brain of these patients, there was abundant intraneuronal lysosomal storage of autofluorescent lipopigment granules. Striking loss of neurons in the substantia nigra was found. In contrast, little neuronal cell loss occurred in other cerebral areas, despite massive neuronal inclusions. Visceral storage was present in gut, liver, cardiomyocytes, skeletal muscle, and in the skin eccrine glands. The storage material showed highly variable immunoreactivity with antiserum against subunit c of mitochondrial ATP synthase, but uniform strong immunoreactivity for saposin D (sphingolipid activating protein D). Protein electrophoresis of isolated storage material revealed a major protein band of about 14 kDa, recognized in Western blotting by saposin D antiserum (but not subunit c of mitochondrial ATPase (SCMAS) antiserum).

Electron microscopy showed ample intraneuronal granular osmiophilic deposits (GRODs), as occurs in CLN1 and congenital ovine NCL. These forms of NCL are caused by the deficiencies of palmitoyl protein thioesterase 1 and cathepsin D, respectively. However, activities of these enzymes were within normal range in our patients. Thus we propose that a gene distinct from the cathepsin D and CLN1‐CLN8 genes is responsible for this autosomal dominant form of ANCL.

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References

  • 1. Arpa Gutierrez J, Gutierrez Molina M, Barreiro Tella P, Fernandez Balaños R, Morales Bastos MC, Amcosta Varo J, Sebastian de la Cruz F, Diaz Tejedor E (1978) El tipo dominante de ceroide lipofuscinosis del adulto. Soc Español Neurol XXX Ann Meet Proc. .
  • 2. Boehme DH, Cottrell JC, Leonberg SC, Zeman W (1971) A dominant form of neuronal ceroid‐lipofuscinosis. Brain 94:745–760. [DOI] [PubMed] [Google Scholar]
  • 3. Das AK, Becerra CH, Yi W, Lu JY, Siakotos AN, Wisniewski KE, Hofmann SL (1998) Molecular genetics of palmitoyl‐protein thioesterase deficiency in the U.S. J Clin Invest 102:361–370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Dyken P, Wisniewski K (1995) Classification of the neuronal ceroid‐lipofuscinoses: expansion of the atypical forms. Am J Med Genet 57:150–154. [DOI] [PubMed] [Google Scholar]
  • 5. Elleder M (1978) A histochemical and ultrastructural study of stored material in neuronal ceroid lipofuscinosis. Virchows Arch B Cell Pathol 28:167–178. [DOI] [PubMed] [Google Scholar]
  • 6. Elleder M, Lake BD, Goebel HH, Rapola J, Haltia M, Carpenter S (1999) Definitions of the ultrastructural patterns found in NCL In: The neuronal ceroid lipofuscinoses (Batten disease). Goebel HH, Mole SE, Lake BD (eds.), pp. 5–7, IOS press, Amsterdam :. [Google Scholar]
  • 7. Elleder M, Sokolova J, Hrebicek M (1997) Follow‐up study of subunit c of mitochondrial ATP synthase (SCMAS) in Batten disease and in unrelated lysosomal disorders. Acta Neuropathol (Berl) 93:379–390. [DOI] [PubMed] [Google Scholar]
  • 8. Elleder M, Tyynela J (1998) Incidence of neuronal perikaryal spheroids in neuronal ceroid lipofuscinoses (Batten disease). Clin Neuropathol 17:184–189. [PubMed] [Google Scholar]
  • 9. Ferrer I, Arbizu T, Pena J, Serra JP (1980) A Golgi and ultrastructural study of a dominant form of Kufs' disease. J Neurol 222:183–190. [DOI] [PubMed] [Google Scholar]
  • 10. Goebel HH (1995) The neuronal ceroid‐lipofuscinoses. J Child Neurol 10:424–437. [DOI] [PubMed] [Google Scholar]
  • 11. Neuronal ceroid lipofuscinoses NCL mutations database. University College London web site. Available at http://www.ucl.ac.uk/ncl. Last modified on 16 October 2002.
  • 12. Josephson SA, Schmidt RE, Millsap P, McManus DQ, Morris JC (2001) Autosomal dominant Kufs' disease: a cause of early onset dementia. J Neurol Sci 188:51–60. [DOI] [PubMed] [Google Scholar]
  • 13. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685. [DOI] [PubMed] [Google Scholar]
  • 14. Leonberg SC, Armstrong D, Boehme D (1982) A century of Kufs' disease in an American family In: Ceroid‐lipofuscinosis (Batten's disease), Armstrong D, Koppang N, Rider JA (eds.) pp. 87–93, Elsevier biomedical press, Amsterdam . [Google Scholar]
  • 15. Markwell MA, Haas SM, Bieber LL, Tolbert NE (1978) A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem 87:206–210. [DOI] [PubMed] [Google Scholar]
  • 16. Martin JJ, Gottlob I, Goebel HH, Mole SE (1999) CLN4: Adult NCL In: The neuronal ceroid lipofuscinoses (Batten disease). Goebel HH, Mole SE, Lake BD (eds.), pp. 77–90, IOS press, Amsterdam . [Google Scholar]
  • 17. Mole SE (1999) Batten's disease: eight genes and still counting Lancet 354:443–445. [DOI] [PubMed] [Google Scholar]
  • 18. Nijssen PCG, Brusse E, Leyten ACM, Martin JJ, Teepen JLJM, Roos RAC (2002) Autosomal dominant adult neuronal ceroid lipofuscinosis: Parkinsonism due to both striatal and nigral dysfunction. Mov Disord 17:482–487. [DOI] [PubMed] [Google Scholar]
  • 19. Santavuori P, Gottlob I, Haltia M, Rapola J, Lake BD, Tyynelä J, Peltonen L (1999) CLN1: Infantile and other types of NCL with GROD In: The neuronal ceroid lipofuscinoses (Batten disease). Goebel HH, Mole SE, Lake BD (eds.), pp. 16–36, IOS press, Amsterdam . [Google Scholar]
  • 20. Sohar I, Sleat DE, Jadot M, Lobel P (1999) Biochemical characterization of a lysosomal protease deficient in classical late infantile neuronal ceroid lipofuscinosis (LINCL) and development of an enzyme‐based assay for diagnosis and exclusion of LINCL in human specimens and animal models. J Neurochem 73:700–711. [DOI] [PubMed] [Google Scholar]
  • 21. Tyynelä J, Palmer DN, Baumann M, Haltia M (1993) Storage of saposins A and D in infantile neuronal ceroid‐lipofuscinosis. FEBS Lett 330:8–12. [DOI] [PubMed] [Google Scholar]
  • 22. Tyynelä J, Sohar I, Sleat DE, Gin RM, Donnelly RJ, Baumann M, Haltia M, Lobel P (2000) A mutation in cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration. EMBO J 19:2786–2792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Palmer DN, Tyynela J, Van Mil HC, Westlake VJ, Jolly RD (1997) Accumulation of sphingolipid activator proteins (SAPs) Aand D in granular osmiophilic deposits in miniature Schnauzer dogs with ceroid‐lipofuscinosis. J Inherit Metab Dis 20:74–84. [DOI] [PubMed] [Google Scholar]
  • 24. Van Diggelen OP, Keulemans JL, Winchester B, Hofman IL, Vanhanen SL, Santavuori P, Voznyi YV (1999) A rapid fluorogenic palmitoyl‐protein thioesterase assay: preand postnatal diagnosis of I NCL. Mol Genet Metab 66:240–244. [DOI] [PubMed] [Google Scholar]
  • 25. 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 adultonset patients of a childhood disease. Ann Neurol 50:269–272. [DOI] [PubMed] [Google Scholar]
  • 26. Wolozin B, Behl C (2000) Mechanisms of neurodegenerative disorders: part 1: protein aggregates. Arch Neurol 57:793–796. [DOI] [PubMed] [Google Scholar]
  • 27. Wolozin B, Behl C (2000) Mechanisms of neurodegenerative disorders: part 2: control of cell death. Arch Neurol 57:801–804. [DOI] [PubMed] [Google Scholar]
  • 28. Young EP, Winchester BG, Peter LW, Wheeler RB, Lake BD (2000) Exclusion of late infantile neuronal ceroid lipofuscinosis (LINCL) in a fetus by assay of tripeptidyl peptidase I in chorionic villi. Prenat Diagn 20:337–339. [PubMed] [Google Scholar]

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