Objective: To report the clinical and genetic features in a patient with an insertion of 8 extra octapeptide repeats in the prion protein gene (PRNP).

Background: Only 15% of all prion diseases are caused by mutations in PRNP. The majority of which are point mutations or premature stop codon mutations. Very few are insertions of extra octapeptide repeats (OPRI). Core phenotypes include; Familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. A fourth phenotype identified in a Swedish family was labeled as Huntington disease-like 1 (HDL1). This consisted of rapidly progressive dementia, psychiatric symptoms, and a variety of movement abnormalities.

Method: A 33 y/o Hispanic female presented with gradual cognitive decline over the previous 8 years, with balance and coordination issues starting just 4 years prior. This caused frequent falls, car accidents, and lead to her early retirement from driving. Examination revealed mild ataxia, dystonia, astereognosis, visuospatial abnormalities, and executive dysfunction. MRI brain showed generalized cerebral atrophy and EEG was normal. Neuropsychiatric testing showed impairments in processing visual perceptual and visuospatial information.  Further workup including blood, urine, and CSF analysis were unrevealing. The patient was referred to the NIH Undiagnosed Diseases Network for evaluation and underwent duo whole genome sequencing with her unaffected mother which revealed the 8-OPRI (c.225_226ins192, p.Q75_P76ins64) in PRNP.

Results: Polymerase chain reaction amplification follower by bi-directional sequence analysis of DNA sample was used to analyze the gene encoding PRNP for changes associated with inherited prion disease. The patient was found to have the 129M/M polymorphism and an 8 octapeptide insert in the PRNP gene.

Conclusion: After receiving the diagnosis the patient was transitioned into our Huntington’s disease clinic where access to a social worker and genetic counselor was readily available. Genetic counseling was provided to her at risk family members. Though her condition continues to progress there have been some improvements in mood and behaviors with venlafaxine and clonazepam.

References: Paucar M, Xiang F, Moore R, Walker RH, Winnberg E, Svenningsson P. Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation. Prion. 2013;7(6):501-510. doi:10.4161/pri.27260.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/prion-disease-with-8-octapeptide-repeat-insertional-mutation-presenting-with-hdl1-phenotype/