Acta Neuropathol (2008) 116:119–124 admixture of other proWles was also seen. No autopsy reports have been made available. Our case shared both basic features of the NCL2 storage process, i.e. the ultrastructural appearance with the uniform curvilinear proWle pattern of the stored material [6] and the extracerebral SCMAS storage pattern [7]. Therefore, the original pathology report, in the late 1970s, concluded ceroid lipofuscinosis, supposedly of the late infantile type. The case was mentioned as atypical CLN2 in the national report [5] due to the notably atypical clinical manifestation, relative to classical CLN2, which is characterized by an early, full blown onset, rapidly progressive course with Wts, frequently of the myoclonic type, early amaurosis and ERG extinction, EEG with a spike response to photic stimula- tion, and death within the Wrst decade. The crucial contem- porary electrophysiological tests were not available at that time. The Wnal conWrmation had to wait as only recently it has been possible to contact the family and oVer diagnosis veriWcation using diagnostic criteria at the molecular level [18]. The neuropathology of this variant case, published for the Wrst time, showed signiWcant sparing and survival of neurons in regions extensively aVected in classical CLN2 such as large striatal neurons, neurons in the medulla oblongata and spinal alpha motor neurons [1, 3, 10] as well as our unpublished observations (see inserts to Fig. 2a, e). Sparing of the hippocampal neuronal population contrasted with its complete eradication in full blown CLN2 [21]. This indicates that brain cortical neuronal damage is more severe in the six-layered neocortex than in the developmentally older cortical formations which have reduced lamination (hippocampal formation, entorhinal cortex). The described case diVered from the typical phenotype by the complete absence of epileptic paroxysms of any type. Our report strengthens the evidence that the spectrum of CLN2 phenotypes may be surprisingly broad, not only with regard to the rate of progression but also the variability of neurological manifestations. This in turn makes an intra- vital diagnosis and eVective genetic counseling, based on established clinical criteria only, extremely diYcult if even possible. The genotype phenotype correlation is diYcult. In our case, the frequent mutation (p.Arg208X) was com- bined with the novel one (p.Val480Gly) which might be responsible for the variant phenotype. However, the posi- tion of the valine residue near the active center and its high phylogenetic conservation [27] does not suggest a mutation of a mild type. Mutation in the vicinity (p.Phe481Cys) was described [12] without any details of the clinical phenotype. The suggestion that the variant course described in two patients is caused by the p.Arg447His exchange at the highly conserved and protein stabilizing arginine residue [27], could not be conWrmed experimentally [14]. The 123 genotype in the other published variant cases was also char- acterized by mutations with heavy impact on the enzyme at the structural level [11, 23]. These data suggest that the explanation of the variant course, at the genotype level, is hardly possible. We would like to emphasize that only when this case was studied at the cellular and tissue levels, it was possible to unravel the signiWcantly diVerent sensi- tivity of various neuronal populations to TPP1 deWciency in the described genotype. We, therefore, suggest that diVer- ent degrees of aVection of brain neuronal populations may be responsible for the variant’s serious course. We would like to stress that neuropathology should be performed in other variant cases as well as this approach seems to be eVective in evaluating the given genotype/phenotype corre- lation in individual neuronal populations. Acknowledgments The diagnostic studies were supported by the grant agency of the Ministry of Health of the Czech Republic (IGA MZ CR NR/8351-3). There was also institutional support from a research project of the Ministry of Education Youth and Sports (Grant No. MSM 0021620806). We would like to express our gratitude to the pa- tient’s parents and to the aunt of the patient a pediatrician. They all helped signiWcantly by providing essential information on the clinical history of the patient. Access to archived clinical records of the patient was kindly provided by K.Sixtová, MD, Thomayer Teaching Hospital, Prague. Our laboratory is a member of the Rare NCL Gene Consortium (http://www.ucl.ac.uk/ncl/RNGC.shtml). References 1. Bednar B, Dittrich J, Jirasek A, Smid F, Vacek R (1967) Juvenile familiar amaurotic idiocy and myoclonic forms of cerebral lipido- ses (in Czech). Cs patol 3:141–149 2. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate- phenol-chloroform extraction. Anal Biochem 162:156–159 3. de Baecque CM, Pollack MA, Suzuki K (1976) Late infantile neuronal storage disease with curvilinear bodies. Arch Pathol Lab Med 100:139–144 4. Elleder M (1978) A histochemical and ultrastructural study of stored material in neuronal ceroid lipofuscinosis. Virchows Arch B Cell Pathol 28:167–178 5. Elleder M, Kraus J, Nevsimalova S, Sixtova K, Zeman J (1999) NCL in DiVerent European Countries. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lipofuscinoses (batten dis- ease). IOS Press, Amsterdam, pp 129 6. Elleder M, Lake BD, Goebel HH, Rapola J, Haltia M, Carpenter S (1999) DeWnitions of the Ultrastructural Patterns found in NCL. In: Goebel HH, Mole SE, Lake BD (eds) The neuronal ceroid lip- ofuscinoses (batten disease). IOS Press, Amsterdam, pp 5–15 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 93:379–390 8. Elleder M, Tyynela J (1998) Incidence of neuronal perikaryal spheroids in neuronal ceroid lipofuscinoses (batten disease). Clin Neuropathol 17:184–189 9. Ezaki J, Kominami E (2004) The intracellular location and func- tion of proteins of neuronal ceroid lipofuscinoses. Brain Pathol 14:77–85 123