Objective: Delineation of clinical and genetic features of PRNP-related movement disorders in two families.

Background: Genetic prion disease can have a variable and overlapping phenotypic presentation based on the type of mutation affecting the PRNP gene, commonly manifesting as progressive gait ataxia, myoclonus, cognitive decline, chorea and parkinsonism [1-3].

Method: We assessed the clinical, radiological and genetic data of 2 patients of PRNP– related movement disorders, who attended the movement disorder clinics at Institute of Neurosciences Kolkata (I-NK), India and London Health Sciences Centre (LHSC), Canada.

Results: Case 1 (I-NK): 36/M, started having progressive gait imbalance for 3 yr, slurring of speech for 1.5 yr and slowness in ADLs for 6 months with episodic memory problem. There was an early death of his father, with an undiagnosed gait imbalance. On examination, MoCA was 24/30. Bilateral horizontal gaze-evoked nystagmus, ataxic dysarthria, dysmetria, distal myoclonus in upper limbs and gait ataxia were noted with impaired tandem. Mild appendicular rigidity appreciated in all 4 limbs. MRI brain showed mild cerebellar atrophy. SCA panel was negative. Whole exome sequencing revealed pathogenic c.305C>T (P102L) mutation at exon 2 of the PRNP gene, confirming the diagnosis of Gerstmann–Sträussler–Scheinker disease (GSS).

Case 2 (LHSC): 67/M, presented with fidgetiness for the last 3 years, progressive cognitive decline for 2yr and behavioral change (irritability, depression) for 1yr. His father had history of fidgetiness and dementia. On examination, MoCA was 14/30. Generalized chorea with myoclonus in the upper limbs were noted with mild-moderate rigidity and bradykinesia in all 4 limbs. MRI brain showed generalized cortical and cerebellar atrophy along with caudate atrophy. Genetic tests for Huntington disease (HD), SCA17 and C9ORF72 were negative. Finally, heterozygous repeat expansion in the PRNP gene identified at 20p13, four octapeptide in one allele and eight octapeptide in the other. Thus, four extra octapeptide repeat insertion (OPRI) led to Huntington disease like 1 (HDL1) phenotype in this patient.

Conclusion: PRNP-related movement disorder should be kept in the differentials for patients with undiagnosed cerebellar ataxia (GSS) and HD phenocopy (HDL1). While P102L mutation is common for GSS, OPRI can lead to HDL1.

References: [1] Rodriguez-Porcel F, Ciarlariello VB, Dwivedi AK, Lovera L, Da Prat G, Lopez-Castellanos R, Suri R, Laub H, Walker RH, Barsottini O, Pedroso JL, Espay AJ. Movement Disorders in Prionopathies: A Systematic Review. Tremor Other Hyperkinet Mov (N Y). 2019 Dec 12;9. doi: 10.7916/tohm.v0.712.
[2] Stephen CD, de Gusmao CM, Srinivasan SR, Olsen A, Freua F, Kok F, Montes Garcia Barbosa R, Chen JYH, Appleby BS, Prior T, Frosch MP, Schmahmann JD. Gerstmann-Sträussler-Scheinker Disease Presenting as Late-Onset Slowly Progressive Spinocerebellar Ataxia, and Comparative Case Series with Neuropathology. Mov Disord Clin Pract. 2024 Jan 23. doi: 10.1002/mdc3.13976.
[3] Paucar M, Xiang F, Moore R, Walker R, Winnberg E, Svenningsson P. Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation. Prion. 2013 Nov-Dec;7(6):501-10. doi: 10.4161/pri.27260.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-variability-of-prnp-and-related-movement-disorders/