Objective: To broaden the clinical manifestation of PRNP gene mutation-related ataxia.

Background: Genetic forms of prion diseases caused by PRNP mutation account for about 10-15%, and the clinical phenotypes vary with incomplete penetrance. The genotype and frequency of genetic mutation also show geographical variation in which PRNP Val180Ile (V180I) is reported very rarely in the West¹, while as the most common pathogenic mutation of genetic prion disease in East Asia². By far, most of the reported cases of V180I mutation showed late-onset slowly progression with higher cortical dysfunctions³. We present a young man with a slowly progressive spastic ataxia without obvious cognitive impairment, associated with V180I mutation in the PRNP.

Method: case report

Results: A 37-year-old man visited our hospital complaining of slowly progressive dysarthria and gait disturbance that had started 2 years ago. The patient had a history of admission due to alcohol addiction 15 years ago, and his symptoms temporarily worsened after drinking. Past medical history was unremarkable except for sudden sensorineural hearing loss 3 years ago. Current medications included flurazepam, alprazolam, and lorazepam, but there were no other medications that could cause neurological symptoms. He was a 10 pack years current smoker. In the family history, his father also seemed to have dysarthria, but the exact diagnosis was unknown. He denied memory impairment, dysuria, or defecation difficulty. On neurological examination, cerebellar speech and symmetric bilateral limb dysmetria were found. Deep tendon reflexes were hyperactive on both knees, and spastic ataxia was found during walking.

A diagnostic test was performed, including genetic causes, in consideration of the course of a chronic disease that gradually progressed from a young age. In brain MRI, there was no abnormal diffusion restriction lesions on diffusion-weighted images, but cerebellar atrophy and diffuse cerebral cortical atrophy were found on T2-weighted images. SCA 1, 2, 3, 6, 7, 8, and DRPLA, a common cause of genetic cerebellar ataxia, were negative for mutation, and PRNP showed a known pathogenic mutation of c.538G>A (p.180V>I) by whole exome sequencing.

Conclusion: Our case implies that PRNP mutation might be manifested as early onset insidious ataxia without obvious cognitive impairment, thus broadens the phenomenology of PRNP mutation related diseases.

References: 1. Kovács GG, Puopolo M, Ladogana A, Pocchiari M, Budka H, van Duijn C, Collins SJ, Boyd A, Giulivi A, Coulthart M, Delasnerie-Laupretre N, Brandel JP, Zerr I, Kretzschmar HA, de Pedro-Cuesta J, Calero-Lara M, Glatzel M, Aguzzi A, Bishop M, Knight R, Belay G, Will R, Mitrova E; EUROCJD. Genetic prion disease: the EUROCJD experience. Hum Genet. 2005 Nov;118(2):166-74. doi: 10.1007/s00439-005-0020-1. Epub 2005 Nov 15. PMID: 16187142.

2. Lee, S. M., Chung, M., Hyeon, J. W., Jeong, S. W., Ju, Y. R., Kim, H., … & Kim, S. Y. (2016). Genomic characteristics of genetic creutzfeldt-jakob disease patients with V180I mutation and associations with other neurodegenerative disorders. Plos One, 11(6), e0157540.

3. 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 Aug 14;14:2067-2085. doi: 10.2147/NDT.S165445. PMID: 30147320

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-onset-spastic-ataxia-in-a-patient-with-prion-prnp-p-val180ile-mutation/