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From: TSS ()
Subject: GSS with the Q217R mutation mimicking frontotemporal dementia
Date: October 6, 2005 at 2:20 pm PST


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


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


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


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


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.


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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

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patterns seen in sporadic Creutzfeldt-Jakob disease


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