KMDS
E-submission
Articles
- Page Path
- HOME > J Mov Disord > Volume 18(4); 2025 > Article
-
Letter to the editor
Early-Onset Spastic Ataxia in a Patient With the Prion (PRNP) p.Val180Ile Variant -
Seungmin Lee1
, Dallah Yoo2, Kyung-Sun Park3, Tae-Beom Ahn2
-
Journal of Movement Disorders 2025;18(4):379-381.
DOI: https://doi.org/10.14802/jmd.25108
Published online: July 21, 2025
1Department of Medicine, Graduate School, Kyung Hee University, Seoul, Korea
2Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
3Department of Laboratory Medicine, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
- Corresponding author: Tae-Beom Ahn, MD, PhD Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea / Tel: +82-2-958-8448 / Fax: +82-2-958-8490 / E-mail: taebeom.ahn@khu.ac.kr
• Received: April 21, 2025 • Revised: July 8, 2025 • Accepted: July 21, 2025
Copyright © 2025 The Korean Movement Disorder Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- 1,690 Views
- 55 Download
Dear Editor,
Prion diseases are rare but fatal neurodegenerative disorders in humans that are characterized by the accumulation of misfolded prion proteins. Genetic forms of prion diseases, which are caused by pathogenic variants in the PRNP gene, account for approximately 10%–15% of cases, with clinical phenotypes exhibiting considerable heterogeneity and incomplete penetrance [1]. Among these, the V180I variant is one of the most frequently reported mutations, particularly in East Asian populations, and is associated with genetic Creutzfeldt–Jakob disease (CJD) [2]. Most individuals with this variant experience late-onset symptoms—typically in their 60s or 70s—with a clinical course marked by rapid progression and cognitive decline [1,2]. However, emerging evidence suggests that PRNP variants may have broader phenotypic expression beyond classical genetic CJD, including overlap with other neurodegenerative disorders such as Parkinson’s disease [1].
Herein, we report a case of young-onset, slowly progressive spastic ataxia with preserved cognition in a patient carrying the V180I variant of PRNP, thereby contributing to a broader understanding of the diverse phenotypic manifestations of PRNP mutations.
A 37-year-old man presented to our movement disorder center with complaints of slowly progressive dysarthria and gait disturbance that had begun 2 years prior. Approximately 15 years prior, he had been hospitalized for episodes of binge drinking that led to blackouts and behavioral disturbances. However, the patient denied habitual alcohol use and reported complete abstinence over the past 3 years. Mild anxiety and depressive mood were suspected on the basis of psychiatric inventories conducted at another center 1 year earlier (Beck Depression Inventory: 18/63; Beck Anxiety Inventory: 15/63; Insomnia Severity Index: 12/28). A family history revealed that the patient’s father reportedly had speech disturbances, although no formal diagnosis was made.
The patient denied memory impairment, urinary dysfunction, or constipation. His Mini-Mental State Examination (MMSE) score was normal (30/30). Physical and neurological examinations revealed cerebellar speech. Ocular movements showed no marked abnormalities. A finger-to-nose test demonstrated bilateral upper-limb ataxia, with dysdiadochokinesia resulting from rapid alternating movements. A dystonic posture was observed in the left hand, accompanied by bilateral postural tremors, evident in the wing-beating position. Myoclonus and rigidity were absent. Deep tendon reflexes were hyperactive in both knees. The patient had no difficulty rising from a chair, but a spastic-ataxic gait was observed (Supplementary Video 1 in the online-only Data Supplement). His Scale for the Assessment and Rating of Ataxia (SARA) score was nine.
Brain magnetic resonance imaging (MRI) revealed mild cerebellar atrophy (Figure 1A). Genetic testing for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, and 17, as well as dentatorubral-pallidoluysian atrophy, yielded negative results. Whole-exome sequencing revealed a heterozygous variant, c.538G>A (p.Val180Ile), in PRNP (NM_000311.5), which is pathogenic.3,4 Additional investigations, including chest radiography and abdominal sonography, revealed no evidence of malignancy. Orthostatic blood pressure was within normal limits.Brain magnetic resonance imaging (MRI) revealed mild cerebellar atrophy (Figure 1A). Genetic testing for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, and 17, as well as dentatorubral-pallidoluysian atrophy, yielded negative results. Whole-exome sequencing revealed a heterozygous variant, c.538G>A (p.Val180Ile), in PRNP (NM_000311.5), which is pathogenic [3,4]. Additional investigations, including chest radiography and abdominal sonography, revealed no evidence of malignancy. Orthostatic blood pressure was within normal limits.
At the 5-year follow-up, the patient remained cognitively intact, with an MMSE score of 30 and a Montreal Cognitive Assessment score of 28. A follow-up neurological examination revealed mild aggravation of ataxia (Supplementary Video 1 in the onlineonly Data Supplement), with a mean SARA score of 10.5. Follow-up brain MRI revealed slightly increased cerebellar atrophy, without any features suggestive of PRNP-related disorders such as CJD (Figure 1B).
The patient had no history of chronic alcohol abuse. Although diagnostic evaluations for alternative causes, such as paraneoplastic syndromes and CJD, were not performed, the clinical course and serial neuroimaging findings did not support these diagnoses. Taken together, the observed clinical findings strongly support a pathogenic PRNP-related ataxic syndrome.
Several cases of the V180I PRNP variant have been reported across East Asian countries. In a Japanese case series, nine patients with the V180I mutation developed symptoms in their 60s to 80s, and these patients most commonly presented with greater cortical dysfunctions such as aphasia or apraxia. No cerebellar signs were observed in these patients. Most patients progress to akinetic mutism within 1–1.5 years of symptom onset [5]. One patient had symptom onset at the age of 57 years and showed slow progression over more than 10 years; however, early cognitive impairment and cortical signal changes on MRI were observed [6]. Reports from Korea described patients with symptom onset between the ages of 57 and 75 years, typically with early cognitive decline and rapid disease progression. Even the youngest-onset patient became bedridden within 8 years, although the extent of cognitive decline and clinical trajectory have not been fully described [2,6]. Two Chinese patients experienced disease onset after 70 years of age, with one showing rapid disease progression and early cognitive decline and the other lacking detailed clinical information [6,7]. In contrast, our patient presented symptoms at a substantially younger age and remained cognitively intact and ambulatory at 5 years after symptom onset. This case represents a potential novel phenotypic manifestation of the V180I PRNP variant—young-onset spastic ataxia without apparent cognitive impairment—and contributes to the expanding clinical spectrum of PRNP-related disorders.
Supplementary Materials
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.25108.
Video 1.
The first segment (0:00–0:32), recorded 2 years after symptom onset, demonstrates a dystonic posture, spastic‒ataxic gait, and appendicular ataxia. The second segment (0:33–2:58), filmed 5 years after symptom onset, reveals mild aggravation, characterized by cerebellar dysarthria, impaired tandem gait, and increased deep tendon reflexes.
-
Ethics Statement
All procedures conducted in studies involving human participants adhered to the ethical standards of the Institutional Review Board (IRB) of Kyung Hee University Hospital (IRB No. KHUH 2025-04-015), as well as the 2013 Declaration of Helsinki and its subsequent amendments. Informed consent was obtained from the patient participating in the study.
-
Conflicts of Interest
The authors have no financial conflicts of interest.
-
Funding Statement
None
-
Acknowledgments
None
-
Author Contributions
Conceptualization: Tae-Beom Ahn. Data curation: Seungmin Lee, Dallah Yoo, Tae-Beom Ahn. Formal analysis: all authors. Investigation: all authors. Methodology: all authors. Supervision: Dallah Yoo, Kyung-Sun Park, Tae-Beom Ahn. Validation: all authors. Visualization: Seungmin Lee, Tae-Beom Ahn. Writing—original draft: Seungmin Lee. Writing—review & editing: all authors.
Notes
Figure 1.
Serial brain imaging demonstrating progressive cerebellar atrophy. A: Initial brain MRI revealed mild atrophy of the cerebellar cortices on fluid-attenuated inversion recovery imaging. B: Follow-up MRI performed 5 years after symptom onset revealed slightly increased atrophy of the cerebellar cortices and middle cerebellar peduncles. MRI, magnetic resonance imaging.
- 1. Bagyinszky E, Giau VV, Youn YC, An SSA, Kim S. Characterization of mutations in PRNP (prion) gene and their possible roles in neurodegenerative diseases. Neuropsychiatr Dis Treat 2018;14:2067–2085.ArticlePubMedPMC
- 2. Lee SM, Chung M, Hyeon JW, Jeong SW, Ju YR, Kim H, et al. Genomic characteristics of genetic Creutzfeldt-Jakob disease patients with V180I mutation and associations with other neurodegenerative disorders. PLoS One 2016;11:e0157540.ArticlePubMedPMC
- 3. Xiao X, Yuan J, Haïk S, Cali I, Zhan Y, Moudjou M, et al. Glycoform-selective prion formation in sporadic and familial forms of prion disease. PLoS One 2013;8:e58786.ArticlePubMedPMC
- 4. Minikel EV, Vallabh SM, Lek M, Estrada K, Samocha KE, Sathirapongsasuti JF, et al. Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med 2016;8:322ra9.ArticlePubMedPMC
- 5. Jin K, Shiga Y, Shibuya S, Chida K, Sato Y, Konno H, et al. Clinical features of Creutzfeldt-Jakob disease with V180I mutation. Neurology 2004;62:502–505.ArticlePubMed
- 6. Kim DY, Shim KH, Bagyinszky E, An SSA. Prion mutations in republic of republic of Korea, China, and Japan. Int J Mol Sci 2023;24:625.ArticlePubMedPMC
- 7. Shi Q, Shen XJ, Zhou W, Xiao K, Zhang XM, Zhang BY, et al. Rare V180I mutation in PRNP gene of a Chinese patient with Creutzfeldt-Jakob disease. Prion 2014;8:411–414.ArticlePubMedPMC
REFERENCES
Figure & Data
References
Citations
Citations to this article as recorded by 
Comments on this article
PubReader
ePub Link
Cite
XML DownloadEarly-Onset Spastic Ataxia in a Patient With the Prion (PRNP) p.Val180Ile Variant
Figure 1. Serial brain imaging demonstrating progressive cerebellar atrophy. A: Initial brain MRI revealed mild atrophy of the cerebellar cortices on fluid-attenuated inversion recovery imaging. B: Follow-up MRI performed 5 years after symptom onset revealed slightly increased atrophy of the cerebellar cortices and middle cerebellar peduncles. MRI, magnetic resonance imaging.
Figure 1.
Early-Onset Spastic Ataxia in a Patient With the Prion (PRNP) p.Val180Ile Variant
