Inherited Prion Disease with a 5-octapeptide Repeat Insertion in the PRNP Gene Presenting with Familial Juvenile Dementia

Abstract

A 47-year-old man with a family history of juvenile dementia in his mother presented with memory loss and cognitive decline. Neuropsychological tests revealed impaired orientation, working memory, and apraxia. Magnetic resonance imaging revealed diffuse brain atrophy, and fluorodeoxyglucose positron emission tomography (PET) showed hypometabolism in the bilateral parietal lobes, posterior cingulate gyri, and precuneus, suggestive of Alzheimer's disease. However, amyloid-beta and tau PET scans were negative. Genetic testing revealed an abnormal repeat insertion in the prion protein gene, confirming inherited prion disease. This case highlights the need to consider inherited prion disease in the differential diagnosis of early-onset familial dementia.

Introduction

Inherited prion diseases are caused by mutations in the genes encoding prion proteins (PRNP). These conditions include three major clinicopathological subtypes: genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Other subtypes, including one- to nine-octapeptide repeat insertions (OPRIs) (1-5) and octapeptide repeat deletions (6,7), have been recently reported.

We herein report a patient with a family history of early-onset dementia who gradually developed memory disturbances with neuroimaging results suggestive of Alzheimer's disease (AD). He was finally diagnosed with inherited prion disease using 5-OPRI via genetic testing because of the lack of amyloid-beta and tau accumulation on positron emission tomography (PET).

Case Report

A 47-year-old man presented with memory loss and a progressive cognitive decline. He had lost his job as a construction worker at 39 years old. After working several temporary jobs, he started receiving welfare benefits at 45 years old but frequently forgot to collect payments at the city office. The office staff visited him and found his home in disarray. Owing to his inability to communicate properly or follow simple commands in support of an independent life, he was referred to our hospital. His mother had died of juvenile dementia at 43 years old. No further information about the family history was available because he had become estranged from his family long before being admitted to our hospital.

On admission, the patient was right handed and alert. A neurological examination revealed a poor concentration and an apathetic effect. The patient showed poor orientation, although his delayed recall ability was relatively stable. His word fluency was severely impaired, but he named objects relatively accurately. The patient presented with acalculia and agraphia as well as construction apraxia but no visuospatial agnosia or hemiasomatognosia. Neuropsychological testing revealed a Mini-Mental State Examination score of 17 of 30 and a Japanese version of the Montreal Cognitive Assessment score of 11 of 30. The Frontal Assessment Battery score was 9 of 18; points were lost on conceptualization, verbal fluency, conflicting instructions, and the Go/No-Go test. No abnormalities other than cognitive impairment were found on neurological examinations, including the cranial nerve function, manual muscle function, deep tendon reflex, and sensory and cerebellar function tests. No myoclonus or other involuntary movement was observed.

Blood tests revealed no abnormalities in the blood count or general biochemical parameters, including vitamin levels or thyroid function. The serum syphilis test results were negative. A cerebrospinal fluid (CSF) examination revealed the following: initial pressure, 13 cmH₂O; cell count, 3/mm³ (mono 100%); protein, 68 mg/dL; and sugar, 80 mg/dL (blood sugar, 158 mg/dL). The phosphorylated and total tau protein levels were 21 pg/mL and 194 pg/mL, respectively, both within the normal range. The amyloid-beta 42/40 ratio was 0.095, showing no decrease, and the 14-3-3 protein test results were negative.

T1-weighted brain magnetic resonance imaging (MRI) revealed diffuse brain atrophy, whereas diffusion-weighted imaging revealed no abnormal signals. The cerebral blood flow was evaluated using single-photon emission computed tomography and rated using z-scores projected onto the cerebral cortex with three-dimensional mapping. A markedly decreased cerebral blood flow was observed in the posterior cingulate gyrus, precuneus, and frontal lobes, including in the medial aspect of the frontal and bilateral temporal lobes. PET images obtained with [¹⁸F]fluorodeoxyglucose (FDG) and analyzed using three-dimensional stereotactic surface projections (8) showed extensive hypometabolism in the bilateral frontal and parietal lobes, the posterior cingulate gyrus, and the precuneus (Fig. 1). Tau PET scans obtained using [¹⁸F]PM-PBB3 and amyloid PET scans obtained using [¹⁸F]flutemetamol showed no accumulation (Fig. 2).

Figure 1.

Brain magnetic resonance imaging (MRI) (A, B) and positron emission tomography (C-F). A: Diffusion-weighted MRI shows no apparent signal abnormality. B: A coronal section of the fluid-attenuated inversion recovery image shows no atrophy in the bilateral medial temporal lobes. C-F: Fluorodeoxyglucose-positron emission tomography images analyzed using three-dimensional stereotactic surface projection showing a decreased uptake in the posterior cingulate gyrus and precuneus (E, F) as well as in the temporal and occipital lobes (C, D).

Figure 2.

A, B: Axial sections of [¹⁸F]-flutemetamol positron emission tomography (PET) images showing no increase in the flutemetamol uptake. C, D: Axial sections of [¹⁸F]-PM-PBB3 PET showing no increase in the PM-PBB3 uptake. [¹⁸F]-PM-PBB3: 2-[(1E, 3E)-4-[6-[¹⁸F]methylamino] pyridin-3-yl] buta-1,3-dien-1-yl-1,3- benzothiazol-6-ol.

Electroencephalography revealed no epileptic or periodic synchronous discharges. Whole-exome sequencing identified a heterozygous c.269_270ins mutation (insertion of five eight-amino-acid repeats) in exon 2 of the PRNP prion-related gene. This insertion was confirmed by polymerase chain reaction testing, followed by Sanger sequencing, which confirmed the diagnosis of hereditary prion disease (Fig. 3). Codon 129 was the Met/Met type. No abnormalities in the APP, PSEN1, or PSEN2 genes associated with dominantly inherited AD were observed.

Figure 3.

Structure of the five octapeptide repeats identified in the present case. Five repeats consisting of R2, R2a, R3, and R3 g were inserted between the first R3 and R4 as indicated by the closed red box.

Discussion

We herein report a case in which the patient's family history of juvenile dementia, progressive cognitive decline, and reduced metabolism and blood flow in the posterior cingulate gyrus and precuneus on functional brain imaging led us to suspect hereditary AD. However, amyloid-beta and tau PET findings were negative, which ultimately led to the diagnosis of inherited prion disease based on the genetic testing results.

Inherited prion diseases are associated with heterozygous pathogenic variants of the PRNP gene, whose most common phenotypes are genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Most variants are missense mutations, whereas others rarely involve deletions or insertions in octapeptide repeat regions. Only four families with OPRIs have been reported in Japan: two cases reported by the 1999-2017 CJD Surveillance Committee, one case reported by Douzono et al. (4), and one family (three cases) reported by Hamada et al. (5). Owen et al. first reported OPRIs in the PRNP gene in familial atypical dementia (9). The OPRI region is located in codons 51-91 of the PRNP gene and consists of a 9-amino acid sequence (R1) followed by 4 repeats of 8-amino-acid sequences (R2, R2, R3, and R4) (5). OPRIs with 2-12 additional octapeptide repeats have significant clinical and neuropathological variability. Insertions of one to four octapeptide repeats typically manifest as a phenotype of sporadic Creutzfeldt-Jakob disease (6). Insertions of five to seven octapeptide repeats reportedly result in a younger age at the onset and longer disease duration than those with fewer than four insertions and often present as sporadic Creutzfeldt-Jakob disease in early to middle adulthood (2). In a study of 164 cases of hereditary prion disease with OPRIs, 75.6% of patients with 5-7 repeats had cognitive impairment, 11.1% had cerebellar ataxia, 15.6% had psychiatric symptoms, 20% had gait disturbance, 4.4% had visual impairment, and 2.2% had sensory impairment (7). In contrast, only cognitive dysfunction was observed in the present case with a 5-OPRI. The exact percentage of patients with hereditary prion diseases who present with cognitive impairment alone is unknown. However, there are few cases where there are no overt neurological findings, and the patient is diagnosed with AD based on FDG-PET findings (8,9).

In the present case, brain MRI revealed no significant changes, including cortical hyperintensities on diffusion-weighted MRI (characteristic of prion disease), and a CSF examination showed no elevated total tau or 14-3-3 protein levels. Therefore, it is difficult to diagnose prion disease clinically. In a previous report, the positivity rates of abnormalities typical of Creutzfeldt-Jakob disease in patients with OPRIs were low at 23.9% for MRI signal abnormalities, 22.5% for periodic synchronous discharge on electroencephalography, and 63.0% for CSF 14-3-3 protein (11).

The classical phenotype of AD, or frontotemporal dementia, is a characteristic feature of hereditary prion diseases associated with OPRIs (5,7,12). In the present case, in addition to the clinical symptoms of AD, such as memory loss and visuospatial dysfunction, the patient had symptoms of frontotemporal dementia, including environmental dependency and executive dysfunction, suggesting a dysexecutive variant of Alzheimer's (13). In addition, FDG-PET revealed hypometabolism in the posterior cingulate gyrus, precuneus, and frontal and parietal lobes, which is a typical pattern in AD. In contrast, head MRI revealed diffuse brain atrophy without characteristic focal hippocampal atrophy. In a report on a PRNP gene analysis in patients with solitary AD and frontotemporal dementia, OPRI/D was detected in 1.5% (3/206) of the patients (7). Furthermore, hereditary prion diseases may also occur in patients with no apparent genetic history.

In the present case, amyloid and tau PET results were negative. In a PET study of hereditary prion disease using OPRIs, FDG-PET showed a typical pattern of AD, whereas amyloid PET was negative (12). We previously reported that a patient with hereditary AD with the Osaka mutation had no accumulation of amyloid-beta, but predominant accumulation of tau was noted in the brain on PET (14). In the present case, we performed [¹⁸F]PM-PBB3 PET, as the patient showed a phenotype of AD without amyloid-beta accumulation on PET, but the results were negative. To our knowledge, this is the first case of tau PET in hereditary prion disease with an OPRI. In early-onset dementia with negative amyloid and tau PET findings, as in the present case, hereditary prion disease should be considered as a differential diagnosis.

Written informed consent was obtained from the patient for the publication of potentially identifiable images or data included in this article.

The authors state that they have no Conflict of Interest (COI).

Financial Support

This study is supported by AMED 23dk0207055s0103(KI), JP24dk0207060 (TI).