Acta Neuropathol (2008) 116:119–124 DOI 10.1007/s00401-008-0349-3 C A S E R E P O R T Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing diVerent sensitivity of neuronal subpopulations to TPP1 deWciency Milan Elleder · Lenka Dvoláková · Larisa Stolnaja · Hana Vlánková · Helena H4lková · Rastislav Druga · Helena Poup5tová · Eva Konpálová · Josef Mikulántík Received: 12 December 2007 / Revised: 28 January 2008 / Accepted: 31 January 2008 / Published online: 19 February 2008 © Springer-Verlag 2008 Abstract This is the Wrst neuropathology report of a male patient (born 1960–died 1975) with an extremely rare, atyp- ical variant of CLN2 that has been diagnosed only in Wve families so far. The clinical history started during his pre- school years with relatively mild motor and psychological diYculties, but with normal intellect and vision. Since age six there were progressive cerebellar and extrapyramidal symptomatology, amaurosis, and mental deterioration. Epi- leptic seizures were absent. The child died aged 15 years in extreme cachexy. Neuropathology revealed neurolysoso- mal storage of autoXuorescent, curvilinear and subunit c of mitochondrial ATP synthase (SCMAS) rich material. The neuronal storage led to laminar neuronal depopulation in the cerebral cortex and to a practically total eradication of the cerebellar cortical neurons. The other areas of the cen- tral nervous system including hippocampus, which are usu- ally heavily aVected in classical forms of CLN2, displayed either a lesser degree or absence of neuronal storage, or storage without signiWcant neuronal loss. Transformation of the stored material to the spheroid like perikaryal inclusions was rudimentary. The follow-up, after 30 years, showed heterozygous values of TPP1 (tripeptidylpeptidase 1) M. Elleder (&) · L. Dvoláková · L. Stolnaja · H. Vlánková · H. H4lková · H. Poup5tová · E. Konpálová Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Division B, Bldg.D, Ke Karlovu 2, 128 08 Prague 2, Czech Republic e-mail: melleder@cesnet.cz R. Druga Institute of Anatomy, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic J. Mikulántík Department of Pathology, Hospital Liberec, Liberec, Czech Republic activity in the white blood cells of both parents and the sis- ter. DNA analysis of CLN2 gene identiWed a paternal fre- quent mutation c.622C > T (p.Arg208 X) in the 6th exon and a maternal novel mutation c.1439 T > G in exon 12 (p.Val480Gly). TPP1 immunohistochemistry using a speciWc antibody gave negative results in the brain and other organs. Our report supports the notion that the spec- trum of CLN2 phenotypes may be surprisingly broad. The study revealed variable sensitivities in neuronal subpopula- tions to the metabolic defect which may be responsible for the variant’s serious course. Keywords CLN 2 · Atypical course · Neuropathology · Storage pattern Introduction The family of neuronal ceroid lipofuscinoses (NCL) con- sists, to date, of ten entities [13], two of which still resist exact deWnition at the molecular level, while the others have been well deWned. Three are caused by mutations of genes coding for enzymes: cathepsin D [17, 20], palmitoyl- protein thioesterase [23] and tripeptidylpeptidase 1 (TPP1) [18]; in Wve the mutated gene codes for transmembrane proteins or for soluble lysosomal proteins with unknown functions. All the relevant information concerning the responsible genes, mutated proteins, their structural and functional relationship to the lysosomal system, and the nature of the stored compounds, which are mainly proteins, has been reviewed [9, 13, 15]. A molecular classiWcation has replaced the former phenotype based one and uniWed the diverse phenotypes under a single precisely deWned dis- order [16, 22, 26]. The CLN2 phenotype is generally con- sidered to be repetitive and uniform, well deWned by age of 123