title: Autosomal dominant adult neuronal ceroid lipofuscinosis: a novel form of NCL with granular osmiophilic deposits without palmitoyl protein thioesterase 1 deficiency.
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.
authors.affiliation: Department of Neurology, St Elisabeth Hospital, Tilburg, The Netherlands. p.nijssen@elisabeth.nl
authors.forename: Peter C G
authors.initials: PC
authors.lastname: Nijssen
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick
authors.forename: Otto P
authors.initials: OP
authors.lastname: van Diggelen
authors.forename: Milan
authors.initials: M
authors.lastname: Elleder
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Johannes L J M
authors.initials: JL
authors.lastname: Teepen
authors.forename: Jaana
authors.initials: J
authors.lastname: Tyynelä
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002402:Cathepsin D / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005192:Family Health; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008055:Lipids; D016464:Lysosomal Storage Diseases / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D010170:Palmitoyl-CoA Hydrolase / Q000172:deficiency / Q000378:metabolism*; D010375:Pedigree; D010447:Peptide Hydrolases / Q000378:metabolism; D010860:Pigments, Biological / Q000378:metabolism; D049231:Saposins
chemical_list: D006023:Glycoproteins; D008055:Lipids; D010860:Pigments, Biological; D049231:Saposins; C051596:lipopigments; D010170:Palmitoyl-CoA Hydrolase; D010447:Peptide Hydrolases; D002402:Cathepsin D; D025261:Mitochondrial Proton-Translocating ATPases