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From: TSS ()
LETTER TO THE EDITOR John Woulfe Ć Andrew Kertesz Ć Inge Frohn Sharon Bauer Ć Peter St. George-Hyslop Catherine Bergeron Gerstmann-Straussler-Scheinker disease with the Q217R mutation mimicking frontotemporal dementia Received: 14 March 2005 / Revised: 2 June 2005 / Accepted: 3 June 2005 / Published online: 16 July 2005 Springer-Verlag 2005 Keywords Frontotemporal dementia Ć Gerstmann- Stra¨ ussler-Scheinker disease Ć Inherited prion disease Ć Prion protein Ć tau Gerstmann-Stra¨ ussler-Scheinker disease (GSS) is a dominantly inherited neurodegenerative disorder caused by mutations in the prion protein (PrP) gene. Pathologically, GSS is characterized by the presence of numerous amyloid plaques throughout the brain, especially the cerebellum [5]. The clinical phenotype typically features cerebellar ataxia, akinetic parkinsonism, pyramidal signs, and cognitive decline. The term frontotemporal dementia (FTD) encompasses several clinically and histopathologically distinct entities [1, 5, 8]. We present a case of pathologically and genetically con- .rmed GSS (with the Q217R mutation in the PrP gene) that presented clinically as FTD. The patient was 45 years old when she .rst complained of poor memory and a sensation of ‘‘numbness’’ in her head. Her concentration was impaired and her speech became perseverative. Initially, memory function was well preserved, but attention and concentration were severely impaired. Subsequently, she developed slurred speech, and bizarre, stereotypic behavior. Detailed neuropsychological examination revealed visuospatial abnormality and an EEG showed only periodic frontal slowing. A diagnosis of Pick’s disease was made 8 years after onset. The patient’s father had a similar illness with ‘‘personality alterations’’. However, additional family history was not available and a clear pattern of inheritance for the patient’s disease could not be established. Ten years after disease onset, at the age of 55, the patient was still fully oriented and her autobiographical and episodic memory were relatively preserved. Her MMSE was 26/30, but she had word .nding di.culty as well as de.cits in calculation, drawing, and visual scanning. She elicited paraphasic responses on naming. She displayed ideomotor, ideational and limb-kinetic apraxia. Her right hand was hypokinetic and appeared to be .xed at her side. She had jerky tremulousness and increased tone, more on the right than the left. She also displayed a sti. gait with absent arm swing on the right side. Notably, cerebellar ataxia was not present. In light of the development of these extrapyramidal motor features, a diagnosis of corticobasal degeneration was entertained. Bilateral grasp and persisting glabellar tap, snout, and palmomental re.exes were elicited. Her language capacity continued to diminish and a year later she was almost mute. An MRI scan was unremarkable. She died approximately 13 years after the onset of her illness. Consent for autopsy restricted to examination of the brain was provided by the patient’s husband. The brain weighed 1,220 g (normal; 1,250 g). There was mild cortical atrophy a.ecting the frontal, temporal, and parietal lobes in a bilaterally symmetric fashion as well as de-pigmentation of the substantia nigra bilaterally. The cerebellum appeared normal. Microscopically (Fig. 1), all areas of neocortex sampled revealed abundant, large amyloid plaques with single or multicentric .brillary cores. This was associated with neuronal loss and astrocytic gliosis. Spongiform change was present, but inconspicuous and focal. PrP immunostaining with the monoclonal 6H4 (Prionics) labeled the di.use component of the plaques, while an N-terminal antibody (1:2,000, Chemicon) stained the cores. The monoclonal 3F4 antibody (1:200, Signet) labeled both components. The peripheral regions of the di.use component of some plaques exhibited b-amyloid immunoreactivity (mouse monoclonal, 1:100, Dako). Smaller multicentric plaques and astrocytic gliosis were also encountered in the striatum, globus pallidus, basal nucleus of Meynert, thalamus, hippocampus, and cerebellar dentate nucleus and cerebellar cortex. In the substantia nigra, abundant compact plaques were associated with a profound loss of J. Woulfe (&) Ć A. Kertesz Ć I. Frohn Ć S. Bauer P. St. George-Hyslop Ć C. Bergeron Department of Pathology, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, K1Y 4E9, Canada E-mail: jwoulfe@ottawahospital.on.ca Acta Neuropathol (2005) 110: 317–319 DOI 10.1007/s00401-005-1054-0 pigmented neurons and astrocytic gliosis. Tau immunostaining (using rabbit polyclonal antibody, 1:300, Dako) and Bielschowsky silver staining revealed a poorly developed neuritic component surrounding the plaques as well as abundant intraneuronal neuro.brillary tangles. These were identi.ed in all areas of neocortex examined where they were concentrated in layers III and V. Neuro.brillary tangles were also present in the hippocampus, striatum, thalamus, substantia nigra, and locus coeruleus. Immunoblotting was performed on proteinase K-treated brain tissue using anti-PrP antibody 3F4 (Senetek 1:10,000, 1 h, room temperature). The signal was detected with the enhanced chemiluminescence plus detection system (ECL Plus, Amersham) and visualized with the Storm 860 (Molecular Dynamics). The immunoblot showed prominent bands in the ranges 18–19 and 27–29 kDa, a truncated fragment at 8 kDa and higher molecular mass fragments (Fig. 2). Notably, the 21- to 30-kDa isoforms described in sporadic Creutzfeldt- Jakob disease (CJD) and in GSS variants lacking spongiform change were absent, as reported previously [12]. The entire PrP gene open reading frame was ampli- .ed from genomic DNA by PCR. The resultant PCR fragments were then sequenced using dideoxy cycle sequencing with dye-labeled primers on an ABI377 automated sequencer. This revealed homozygosity for valine at codon 129 (PrP:Val129/Val1129) and a missense substitution of adenosine to guanosine in the second nucleotide of codon 217 was observed, resulting in an amino acid substitution of arginine for glutamine at this site (Q217R). Fig. 1 Microscopic pathology. a, b Multicentric plaques in a hematoxylin and eosin-stained section of the frontal cortex (a) and in the cerebellar cortex immunostained for PrP using monoclonal antibody 3F4 (b). c, d Frequent PrPimmunoreactive plaques in the frontal neocortex (c) and the molecular layer of the cerebellar cortex (d). e, f Tauimmunoreactive neuronal neuro.brillary tangles and neuropil threads (e) and plaqueassociated dystrophic neurites (f) in the frontal cortex (PrP prion protein). Bars a, f 50 lm; b 125 lm; c, d 0.5 mm; e 30 lm 318 The clinical diagnosis in this patient was FTD. At di.erent times in the clinical evolution of her disease, Pick’s disease and corticobasal degeneration were entertained as diagnoses in our patient. However, the neuropathological diagnosis in this case was GSS. There is precedence for clinical overlap between inherited prion disease and FTD. Nitrini et al. [11] described the clinical features of 12 patients from a family with CJD associated with a point mutation (T183A). The clinical features were consistent with FTD and parkinsonism linked to chromosome 17 (FTDP-17). The point mutation described in the present case (Q217R) has been described previously in a single Swedish pedigree [6]. The present case displays several similarities, both clinically and pathologically to the Swedish cohort. Pathologically, the Swedish patients displayed profound tau-positive neuro.brillary pathology as well as b-amyloid deposition at the periphery of many of the PrP plaques. Neuro.brillary tangles have been described in GSS patients with the Y145Stop [9], F198S [2], P105L [10, 14] and A117V [13] mutations. The mechanisms underlying neuro.- brillary degeneration in these forms of GSS remain to be elucidated. It has been suggested that the Ab deposited in association with the PrP plaques contributes to the development of neuro.brillary pathology is these forms of GSS [4, 7]. In summary, this case of neuropathologically con- .rmed GSS caused by a Q217R mutation in the PrP gene expands the pathological spectrum of FTD as well as the clinical spectrum of prion diseases. It is tempting to speculate that the formidable cortical neuro.brillary burden in our case is relevant with respect to the predominantly cognitive clinical manifestations, leading to the clinical diagnosis of FTD. Acknowledgements The authors wish to acknowledge the assistance and contributions of the Canadian CJD Surveillance System. References 1. Bergeron C, Lowe J (2003) Frontotemporal degeneration. In: Dickson D (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 340–341 2. Ghetti B, Tagliavini F, Masters CL, Beyreuther K, Giaccone G, Verga L, Farlow MR, Conneally PM, Dlouhy SR, Azzarelli B, Bugiani O (1989) Gerstmann-Stra¨ ussler-Scheinker disease. II. Neuro.brillary tangles and plaques with PrP-amyloid coexist in an a.ected family. Neurology 39:1453–1461 3. Ghetti B, Piccardo P, Frangione B, Bugiani O, Giaccone G, Young K, Prelli F, Farlow MR, Dlouhy SR, Tagliavani F (1996) Prion protein amyloidosis. Brain Pathol 6:127–145 4. Hardy J, Allsop D (1991) Amyloid deposition as the central event in the etiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388 5. Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, Kril JJ, Halliday GM (2004) Clinicopathological correlates in frontotemporal dementia. Ann Neurol 56:399–406 6. Hsiao K, Dlouhy SR, Farlow MR, Cass C, DaCosta M, Conneally PM, Hodes ME, Ghetti B, Prusiner SB (1992) Mutant prion proteins in Gerstmann-Stra¨ ussler-Scheinker disease with neuro.brillary tangles. Nat Genet 1:68–71 7. Ikeda S-I, Yanagisawa N, Glenner GG, Allsop D (1992) Gerstmann-Stra¨ ussler-Scheinker disease showing b-protein amyloid deposits in the peripheral regions of PrP-immunoreactive amyloid plaques. Neurodegeneration 1:281–288 8. Josephs KA, Holton JL, Rossor MN, Godbolt AK, Ozawa T, Strand K, Khan N, Al-Sarraj S, Revesz T (2004) Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 30:369–373 9. Kitamoto T, Iizuka R, Tateishi J (1993) An amber mutation of prion protein in Gerstmann-Stra¨ ussler syndrome with mutant PrP plaques. Biochem Biophys Res Commun 192:525–531 10. Kitamoto T, Amano N, Terao Y, Nakazato Y, Ishiki T, Mizutani T, Tateishi J (1993) A new inherited prion disease (PrP-P105L mutation) showing spastic paraparesis. Ann Neurol 34:808–813 11. Nitrini R, Da Silva LST, Rosemberg S, Caramelli P, Carrilho PEM, Lughetti P, Passos-Bueno MR, Zatz M, Albrecht S, LeBlanc A (2001) Prion disease resembling frontotemporal dementia and parkinsonism linked to chromosome 17. Arq Neuropsiquiatr 59:161–164 12. Piccardo P, Dlouhy SR, Lievens PM, Young K, Bird TD, Nochlin D, Dickson DW, Vinters HV, Zimmerman TR, Mackenzie IR, Kish SJ, Ang LC, De Carli C, Pocchiari M, Brown P, Gibbs CJ Jr, Gajdusek DC, Bugiani O, Ironside J, Tagliavini F, Ghetti B (1998) Phenotypic variability of Gerstmann- Straussler-Scheinker disease is associated with prion protein heterogeneity. J Neuropathol Exp Neurol 57:979–988 13. Tranchant C, Sergeant N, Wattez A, Mohr M, Warter JM, Delacourte A (1997) Neuro.brillary tangles in Gerstmann- Stra¨ ussler-Scheinker syndrome with the A117V prion gene mutation. J Neurol Neurosurg Psychiatry 63:240–246 14. Yamada M, Itoh Y, Fujigasaki H, Naruse S, Kaneko K, Kitamoto T, Tateishi J, Otomo E, Hayakawa M, Tanaka J (1993) A missense mutation at codon 105 with codon 129 polymorphism of the prion protein gene in a new variant of Gerstmann- Stra¨ ussler-Scheinker disease. Neurology 43:2723–2724 Fig. 2 Proteinase K-treated PrP immunoblot shows prominent bands (arrows) of 18–19 and 27–29 kDa, a truncated fragment at 8 kDa and higher molecular mass fragments (lane 1). This pattern is distinct from the type 2a (lane 2) and type 1 (lane 3) banding patterns seen in sporadic Creutzfeldt-Jakob disease 319TSS
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