A Unique Case of Genetic Creutzfeldt-Jakob Disease (E200K Mutation) with CSF-restricted Anti Myelin Oligodendrocyte Glycoprotein Antibody

Abstract

Creutzfeldt-Jakob disease (CJD) is a rare, fatal neurodegenerative disorder that can share clinicoradiologic features with autoimmune cortical encephalitis (CE); however, the pathological significance of myelin oligodendrocyte glycoprotein (MOG)-IgG, which is one of the causes of CE, has not yet been explored in the context of CJD.

We herein present the case of a man in his mid-70s with a family history of CJD and rapidly progressive cognitive decline. Genetic testing confirmed the E200K mutation in PRNP. CSF analysis revealed CSF-restricted MOG-IgG that became undetectable after corticosteroid therapy without clinical improvement. This case highlights the need for cautious interpretation of the CSF-restricted MOG-IgG in CJD.

Introduction

Human prion disease is a rare and fatal neurodegenerative disease attributed to the accumulation of misfolded prion protein. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form, typically presenting with rapidly progressive cognitive impairment and various motor symptoms including myoclonus, pyramidal and extrapyramidal signs, and ataxia. Although much less common, cases of genetic CJD (gCJD) with mutations in the prion gene (PRNP) (MIM #176640) have been reported. Of the more than 60 different disease-causing mutations in PRNP, E200K is the most common (1).

Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)-associated disease (MOGAD) is an inflammatory demyelinating disease of the central nervous system with diverse clinical presentations, including acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, optic neuritis, and cerebral cortical encephalitis (CCE). MOG-IgG is primarily detected in the serum, but cases with cerebrospinal fluid (CSF)-restricted MOG-IgG have been reported, particularly in CCE (2). The clinicoradiographic features of CCE, such as rapidly progressive cognitive impairment and cortical hyperintensities in diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) imaging (3-5), can potentially mimic those of CJD. We herein report the first case of gCJD with an E200K mutation in PRNP, and CSF-restricted MOG-IgG, thereby highlighting the diagnostic challenges and potential pathophysiological implications.

Case Report

A 75-year-old male presented with a two-month history of confusion and memory impairment. His medical history was unremarkable, but his family history included a sibling diagnosed with CJD who died two months after diagnosis at 64 years of age. Additionally, the patient's father exhibited rapidly progressive dementia and died within a year in his 90s.

On admission, a neurological examination revealed right-dominant limb-kinetic apraxia, non-fluent aphasia, acalculia, right-dominant limb ataxia, hyperreflexia in all four limbs with right predominance, and a positive Babinski sign on the right side. Myoclonus was observed in the lower limbs. Despite the relatively preserved language comprehension and writing abilities, heterophasia and grammatical errors were frequent. Memory and attention were also impaired. The patient's Mini-Mental State Examination score was 20, with missing points in orientation (-1), attention/calculation (-5), recall (-3), and language (-1). Laboratory data showed normal blood counts and a normal biochemical profile. A CSF analysis showed a slightly elevated protein level (57 mg/dL, reference range: 8-43 mg/dL). Polymerase chain reaction tests for herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, cytomegalovirus, and human herpesvirus 6 yielded negative results in the CSF. 14-3-3 protein was positive, and total tau protein was elevated in the CSF (＞1,200 pg/mL, reference range: 146-410 pg/mL). Paraneoplastic antibodies were negative in the serum and anti-N-methyl-D-aspartate receptor antibody was negative in the CSF. Anti-voltage-gated potassium channel-complex antibodies and anti-aquaporin4 antibody were negative in both serum and CSF. MOG-IgG was negative in the serum, but positive in the CSF (titer: 1:1, live cell-based assay). Electroencephalography revealed a generalized slow activity, without periodic sharp complexes. Brain magnetic resonance imaging (MRI) revealed diffusion restriction unilaterally in the head of the left caudate nucleus and cortex in the left frontal lobe, which showed slight hyperintensities on FLAIR imaging (Figure A-C). Cortical edema and contrast enhancement were not observed. Single-photon emission computed tomography (SPECT) using N-isopropyl-p-[¹²³I]-iodoamphetamine revealed decreased perfusion of the left frontal and parietal lobes. A real-time quaking-induced conversion (RT-QuIC) test detected abnormal prion protein in CSF (6) and Sanger sequencing identified a heterozygous c.598G＞A (p.Glu200Lys) mutation in PRNP (NM_000311.5), commonly known as an E200K mutation, confirming the diagnosis of gCJD. He was homozygous for methionine (M/M) at PRNP codon 129 and for glutamic acid (E/E) at PRNP codon 219. These two confirmatory diagnostic findings became available later during hospitalization.

Figure.

Brain MRI findings on admission (A-C) and after IVMP therapy (D-F). (A-C) Diffusion weighted imaging (DWI) (A) and apparent diffusion coefficient (ADC) map (B) showed diffusion restriction unilaterally in the head of left caudate nucleus and the cortex in left frontal lobe, which showed slight hyperintensities in fluid-attenuated inversion recovery (FLAIR) imaging (C) on admission. (D-F) DWI (D) and ADC map (E) after IVMP therapy showed an expanded diffusion restriction, which was still mainly confined to the left hemisphere in FLAIR imaging (F).

Although the possibility of CJD was considered at the time of admission based on diffusion-restricted lesions in the left caudate nucleus and frontal cortex, confirmatory results from RT-QuIC and genetic testing were not yet available. Given the presence of CSF-restricted MOG-IgG and unilateral cortical involvement, the co-occurrence of unilateral CCE could not be definitively excluded. Therefore, intravenous methylprednisolone (IVMP) therapy was initiated. After two courses of IVMP, analysis of the CSF showed further elevated protein levels (70 mg/dL, reference range: 8-43 mg/dL). Anti-MOG antibody became negative in the CSF. However, clinical deterioration was observed, and brain MRI showed expanded diffusion restriction, which remained predominantly confined to the left hemisphere, although possible diffusion restriction was noted in the right caudate head (Figure D-F). The patient died of aspiration pneumonia three months after admission to our hospital. No autopsy was performed.

Discussion

The differential diagnosis of rapidly progressive cognitive impairment entails a wide spectrum of treatable diseases, such as autoimmune encephalitis and infectious encephalitis, along with untreatable neurodegenerative diseases, including CJD. Although autoimmune encephalitis can mimic the clinicoradiological features of CJD, autoimmune encephalitis-associated antibodies, such as anti-voltage-gated potassium channel antibodies and anti-N-methyl-D-aspartate receptor antibody, have been reported to be detected non-specifically in patients with CJD (7,8). In this report, we describe a unique case of gCJD with an E200K mutation in PRNP and CSF-restricted MOG-IgG. Although MOG-IgG is a highly specific and well-established biomarker for diagnosing MOGAD (9), the clinical and radiological findings in this case, combined with the lack of response to steroid therapy and the exclusive detection of MOG-IgG in the CSF, suggest that MOG-IgG was a secondary by-product rather than a marker indicative of MOGAD.

CCE with MOG-IgG is a rare but well-documented presentation of MOGAD (3-5,7). Reported cases of MOG-IgG-positive CCE typically exhibit unilateral cortical hyperintensities on DWI or FLAIR and are often accompanied by clinical symptoms such as seizures, fever, and headache (3-5). In the present case, the unilateral cortical lesion and rapidly progressive cognitive impairment were consistent with some aspects of MOG-IgG-positive CCE. However, the absence of seizures and cortical edema, as well as the coexistence of a confirmed diagnosis of gCJD, suggests that this case deviates from the typical characteristics of MOG-IgG-positive CCE. In addition, brain MRI revealed cortical involvement and basal ganglia lesions in the present case. Although lesion distribution alone may not allow for a definitive differentiation between CJD and MOGAD, considering that cases of MOGAD presenting with both cortical and basal ganglia involvement have been reported (10), a more prominent signal on DWI than on FLAIR was more compatible with CJD rather than MOG-IgG-positive CCE (3,11). SPECT imaging revealed reduced perfusion in the affected region, which further distinguished this case from MOG-IgG-positive CCE, where increased perfusion is typically observed (3). Additionally, while CCE cases usually respond well to steroid therapy (3-5), IVMP was ineffective in this patient despite the negative conversion of MOG-IgG after treatment. These findings led us to conclude that MOG-IgG in this case was an unspecific finding, possibly secondary to extensive and rapid neuronal destruction caused by gCJD (7). However, it may also indicate the potential white matter involvement of CJD (12), thus warranting further investigation into the pathological relationship between MOG-IgG and CJD.

While MOG-IgG is highly specific for MOGAD (9), similar findings could occur in sporadic or acquired forms of CJD, particularly in those with rapid progression. This case underscores the need for careful interpretation of the CSF-restricted MOG-IgG, particularly in patients with atypical clinical or radiological features.

Conclusion

To our knowledge, this is the first reported case of gCJD with the E200K mutation presenting with CSF-restricted MOG-IgG. MOG-IgG can emerge as a secondary phenomenon in neurodegenerative diseases, thus emphasizing the importance of cautious interpretation of its presence in such cases despite its recognized specificity for MOG antibody-associated disease.

Written informed consent for publication of this case and accompanying images was obtained from the patient.

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

Funding Statement

This research was supported by JSPS KAKENHI Grant Number 22K07533 to T.M.