PRNP Octapeptide repeat insertions: research

What phenotype do they produce?

Geng and colleagues reviewed genetically confirmed 5-OPRI cases with available clinical data, assembling 25 patients from 14 families. Age at onset ranged from 26 to 63 years, mean 44.8 with standard deviation 9.9, and disease duration from 4 to 192 months. Dementia was present in all patients, and 84 percent showed frontotemporal dementia-like features. Cerebellar signs occurred in 68 percent, extrapyramidal symptoms in 60 percent and myoclonus in 44 percent. Periodic sharp wave complexes were detected in 29.4 percent of EEGs.

Two features of that distribution deserve emphasis. A duration range from 4 months to 16 years inside a single mutation class makes any individual prognosis unquotable. And a picture of young-onset dementia with frontotemporal features, cerebellar and extrapyramidal signs, in which the classic EEG finding is usually absent, is a picture that will usually be investigated as something other than prion disease first.

Nishikawa and colleagues illustrate exactly that. A 47-year-old man with a family history of juvenile dementia had impaired orientation, working memory and apraxia, with MRI showing diffuse atrophy and FDG PET showing hypometabolism in bilateral parietal lobes, posterior cingulate and precuneus, a pattern suggestive of Alzheimer disease. Amyloid-beta and tau PET were negative, and genetic testing identified a 5-OPRI insertion.

Why are these variants diagnosed as Huntington disease phenocopies?

Because the movement disorder can dominate. Ni and colleagues report the first Chinese family with Huntington disease-like 1, caused by a novel 8-OPRI insertion. The proband, a 36-year-old woman, had six years of progressive involuntary movements, bradykinesia, cognitive decline and personality change, with similar manifestations in her grandmother, father and aunt. Imaging showed increased T2-FLAIR signal in the hippocampi with frontal and parietal atrophy, and EEG showed a slowed background rhythm. Their literature review identified five families with this phenotype. Four-repeat insertions have also been reported as Huntington disease phenocopies.

The practical consequence is for test selection. A dominant, young-onset chorea and dementia syndrome with a negative HTT test is a situation in which PRNP repeat analysis is relevant, and repeat insertions are not reliably reported by every sequencing panel, since detecting them depends on the assay used rather than on single-nucleotide variant calling.

What distinguishes the pathology?

In the genetic CJD classification series, codon 129 heterozygous patients carrying 5-OPRI or 6-OPRI insertions all showed kuru-type PrP amyloid plaques in the cerebellum, while heterozygous E200K patients showed none. Plaque-like PrP deposits in the cerebellar granular layer, thalamus and deep cortical layers were generally more pronounced in insertion carriers than in E200K carriers, and cerebellar stripe-like linear granular deposits were listed as a mutation-specific feature of insertions. Three MV heterozygotes with 5 or 6 repeats in cis with 129V showed an unglycosylated PrPSc doublet at 19 and 20 kDa, the same pattern seen in sporadic MV2K.

Those features are what allows a neuropathologist to suspect an insertion before the genetic result returns, and they place these cases closer to the plaque-forming subtypes than to classic CJD. See MV2 and GSS.

What about detection in life?

In the substrate comparison reported for inherited prion disease, all 4 OPRI cases were detected by every assay format tested, which places insertions with E200K among the inherited variants that current CSF assays find, rather than with D178N and GSS; see D178N.

Family history interpretation and any decision about testing belong with a genetics service. See counselling comes first and inherited prion disease explained.

Related: the PRNP gene, penetrance, variants and codon 129.