Serial changes in regional cerebral blood flow in Gerstmann–Sträussler–Scheinker disease caused by a Pro-to-Leu mutation at codon 105 in the prion protein gene

ABSTRACT

Gerstmann–Sträussler–Scheinker disease with a Pro-to-Leu substitution at codon 105 in the prion protein gene (GSS-P105L) is a rare variant of human genetic prion disease. Herein, we report the case of a patient with GSS-P105L, who showed serial changes in regional cerebral blood flow (rCBF) on single-photon emission computed tomography (SPECT). A 42-year-old woman, with an affected father presenting with similar symptoms, had a 1-year history of progressive gait disturbance, lower-limb spasticity, and psychiatric symptoms. Genetic analysis confirmed the diagnosis of GSS-P105L. Eleven months after disease onset, brain magnetic resonance imaging (MRI) showed bilateral frontal lobe-dominant cerebral atrophy without hyperintensity on diffusion-weighted imaging (DWI) sequences; meanwhile, SPECT revealed non-specific mild hypoperfusion. Follow-up MRI at 52 months after onset demonstrated progressive frontal lobe-dominant cerebral atrophy without hyperintensity on DWI, while SPECT revealed a marked decrease in rCBF in the bilateral right-dominant frontal lobe. Patients with GSS with a Pro-to-Leu substitution at codon 102 (GSS-P102L) have been reported to exhibit hyperintensity on DWI-MRI and a diffuse decrease in CBF with a mosaic-like pattern on SPECT, which is absent in patients with GSS-P105L, thereby possibly reflecting the differences in pathophysiology between GSS-P102L and GSS-P105L.

KEYWORDS:

• Gerstmann–Sträussler–Scheinker disease
• GSS-P102L
• GSS-P105L
• MRI
• PrPSc
• SPECT
• spongiform changes

Introduction

Gerstmann–Sträussler–Scheinker disease (GSS) is one of a few phenotypes of human genetic prion disease (PrD), and is dominantly inherited through mutation in the prion protein gene (PRNP) [1]. While GSS with a Pro-to-Leu substitution at codon 102 in the PRNP (GSS-P102L) is the most common form in Europe, the U.S., and Japan [2], GSS with a Pro-to-Leu substitution at codon 105 (GSS-P105L) is a rare variant mostly reported in Japan [3]. Representative clinical features of GSS-P105L include early age of onset, prolonged disease duration, and characteristic clinical symptoms, including spastic paraplegia, ataxia, extrapyramidal signs, dementia, and emotional instability [4]. However, patients with GSS-P105L have been occasionally misdiagnosed with other neurodegenerative diseases in the early stage due to the absence of abnormal imaging findings such as periodic sharp-wave complexes (PSWCs) on electroencephalography (EEG) and signal hyperintensity on brain magnetic resonance imaging (MRI) [3]. Meanwhile, the diagnostic value of single-photon emission computed tomography (SPECT) and the radiologic-pathologic correlation remains unclear in GSS-P105L due to the extremely limited number of patients who have undergone SPECT [5,6]. Herein, we present the case of a patient with GSS-P105L in whom SPECT revealed serial changes in regional cerebral blood flow (rCBF), providing insights into the diagnostic and prognostic value of SPECT in GSS-P105L detection as well as the potential of SPECT to reflect a distinct pathophysiology compared to GSS-P102L.

Case report

A 42-year-old woman presented with a 1-year history of progressive spastic gait and psychiatric symptoms, including depression and emotional lability. Her father had developed similar symptoms at the age of 45 years and passed away at the age of 62 years. On admission, she was distracted and uncooperative. Neurological examination revealed cognitive impairment (Mini-Mental Status Examination Score of 15/30), cerebellar ataxia with lateral gaze directional nystagmus, spastic paraparesis with hyperreflexia in the lower limbs, and extrapyramidal signs with cogwheel rigidity and resting tremor; in contrast, myoclonus was absent. Cerebrospinal fluid examination revealed that 14-3-3 protein and total tau protein were not elevated, and misfolded pathological prion protein (PrP^Sc) measured by real-time quaking-induced conversion was negative. No PSWCs were detected on EEG. Brain MRI at 11 months after the onset showed bilateral frontal lobe-dominant cerebral atrophy without hyperintensity on diffusion-weighted imaging sequences (DWI; Figure 1a,b); meanwhile, SPECT imaging using N-isopropyl-p-[123I] iodoamphetamine (123I-IMP SPECT) revealed non-specific mild hypoperfusion (Figures 1c,d). Genetic test revealed a Pro-to-Leu substitution at codon 105 (P105L) in the PRNP and she was diagnosed with GSS-P105L. Genotypes at codons 129 and 219 which can modify inherited prion diseases. Her genotypes were methionine with valine heterozygosity at codon 129 of the same allele. Another polymorphism at codon 219 exhibited glutamic acid homozygosity. Three years later, she became bedridden and was unable to utter any meaningful word, but capable of oral intake of food. Follow-up MRI at 52 months after the onset showed progressive frontal lobe-dominant cerebral atrophy without hyperintensity on DWI (Figures 1e,f). A marked decrease in rCBF was detected in the bilateral right dominant frontal lobes on follow-up 123I-IMP SPECT (Figures 1g,h), which was evidently stronger and wider than that from cerebral atrophy imaging.

Figure 1. Brain MRI and SPECT.

(a–d) MRI and ¹²³I-IMP SPECT at 11 months post-onset.

(a) FLAIR MRI sequence shows bilateral frontal lobe-dominant cerebral atrophy (arrow heads). (b) No signal hyperintensity change detected on DWI MRI sequence. ¹²³I-IMP SPECT (c) and 3D-SSP hypoperfusion maps (d) reveal non-specific mild hypoperfusion, probably associated with cerebral atrophy.

(e–h) MRI and ¹²³I-IMP SPECT at 52 months post-onset.

(e) FLAIR shows apparent cerebral atrophy, especially in the bilateral frontal lobe (arrow heads). (f) No signal hyperintensity change detected on DWI. ¹²³I-IMP SPECT (g) and 3D-SSP hypoperfusion maps (h) reveal marked decreased regional CBF, predominantly in the bilateral right-dominant frontal lobe (yellow arrows).

Colors indicate degree of CBF perfusion: red, severely decreased; yellow, moderately decreased; green and blue, mildly decreased. Areas with low blood flow are indicated. Areas with Z-scores >2 had a statistically significant reduction in blood flow. MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography; FLAIR, fluid-attenuated inversion recovery; SSP, stereotactic surface projections; IMP, iodoamphetamine; CBF, cerebral blood flow.

Discussion

The signal hyperintensity change on DWI in PrD, which is commonly observed in sporadic Creutzfeldt–Jakob disease and sometimes observed in GSS-P102L, whereas it is always absent in GSS-P105L, is speculated to be associated with spongiform changes and independent of PrP^Sc deposition. Pathological analysis revealed that spongiform changes are evident in GSS-P102L [7], unlike in GSS-P105L [6]. Decreased rCBF on SPECT imaging is observed in both GSS-P102L and -P105L variants and is associated with abundant neurotoxic PrP^Sc plaque deposition in the cerebral cortex, causing neural dysfunction, especially in the frontal cortex in GSS-P105L. On the other hand, a diffuse decrease in CBF with a mosaic-like pattern has been reported in GSS-P102L [8,9]. Differences in the radiological findings as well as clinical features between GSS-P102L and -P105L are probably due to their pathological differences.

Our study is the first to show serial rCBF changes on SPECT in GSS-P105L. Furthermore, it reveals clinical and pathological features of GSS-P105L which differ radiologically from those of GSS-P102L, which is quite useful for diagnosis and prognosis.

Ethical statement

The protocol followed all ethical requirements and was approved by the Institutional Ethics Committee of the Tokyo Medical and Dental University (ID: G2000–141). Written informed consent was obtained from the patient.

Author contributions

HK drafted and revised the article for content, including medical writing for content, and acquired the data. TM revised the article for content and acquired the data. TY supervised the study. NS revised the article, conceived of and designed the study, supervised the study, and managed the patient.

Acknowledgments

The authors are grateful to the members of the Japanese Prion Disease Surveillance Committee. We also would like to thank the members of the Department of Neurology and Neurological Science, Tokyo Medical and Dental University Hospital. We thank the patient for granting permission to publish this information.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was partly supported by a Grant-in-Aid from the Research Committee of Prion Disease and Slow Virus Infection of the Ministry of Health, Labour, and Welfare of Japan (NS), and a Grant-in-Aid from the Research Committee of Surveillance and Infection Control of Prion Disease of the Ministry of Health, Labour, and Welfare of Japan (NS).