PRNP A117V

What syndrome does it cause?

A Gerstmann-Straussler-Scheinker phenotype. A117V and P102L are named in the literature as the two commonest causes of GSS, and A117V is also one of the four variants, with E200K, D178N and P102L, that together account for more than half of all genetic prion disease.

GSS presents with early cerebellar dysfunction, parkinsonism or a frontotemporal dementia-like picture, with cognitive decline typically following the motor syndrome rather than leading it. Gerstmann-Straussler-Scheinker disease: more detail sets out the syndrome, and this page covers what is specific to the variant.

What ages at onset and durations are reported?

Reported onset in the literature ranges from 20 to 64 years, with durations of 1 to 11 years. In the UCSF rapidly progressive dementia centre’s own A117V patients, mean onset was 34 years with a standard deviation of 14 and a range of 14 to 49, and mean duration 46 months with a standard deviation of 21 and a range of 27 to 78.

Two features of those numbers matter in clinic. Onset can be strikingly early, in the second or third decade in some reported patients, which is younger than most clinicians associate with prion disease. And the duration, measured in years rather than months, means the illness is managed as a progressive neurological disability over a long period, which brings in physiotherapy, speech and language therapy and equipment provision alongside symptom control.

A referral centre series overrepresents the cases that get referred, and the UCSF figures come from a small number of patients, so they are better read as confirmation of the wide spread than as central estimates.

What is known about penetrance?

A117V is in the high-penetrance group. The 2016 population-control analysis compared 16,025 prion disease cases against 60,706 ExAC exomes and 531,575 genotyped individuals, estimating lifetime risk from case and control allele frequencies against a baseline of roughly 1 in 5,000. For E200K, D178N, P102L and A117V, the allele frequencies were consistent with up to 100 percent penetrance.

That is an upper bound compatible with the data rather than a measured figure, and the authors noted that their confidence intervals span more than an order of magnitude. A 2022 review places D178N and P102L as nearly completely penetrant without giving a separate A117V figure, so the honest statement for a family is that A117V sits with the high-penetrance variants and that no precise number exists for it.

A low penetrance estimate would not be a reassurance for an individual, and a high one is not a timetable. Interpretation for a particular person belongs with the reporting laboratory and a genetic counsellor; genetic counselling comes first sets out the published sequence.

Does it change how the disease is detected?

Yes, and the direction is important: the usual CJD investigations are least reliable in exactly this variant.

Reviews report that periodic sharp wave complexes on EEG and CSF 14-3-3 are usually absent in GSS, with CSF RT-QuIC positivity and MRI hyperintensity seen only sometimes, depending on the variant.

The 2026 Canadian assay comparison included one A117V case among 116 diagnostic CSF samples. It was detected by the modified end-point assay using a deer mouse recombinant substrate, and missed by both the standard hamster end-point assay and second-generation IQ-CSF RT-QuIC. Across the twelve GSS cases in that panel, 9 of 12 by the hamster assay became 12 of 12 with the modified substrate, while overall sensitivity rose from 87.1 percent and 72.4 percent to 96.6 percent.

One case is one case. What it supports is a procedural point rather than a performance estimate: a negative CSF seeding result in a suspected A117V case should be recorded with the substrate named, and it does not exclude the diagnosis. Where the family variant is known, the laboratory should be told, because it determines how the result should be read.

What should counselling cover for this variant specifically?

Three things beyond the general framework.

Age at onset. Because reported onset extends into the 20s and 30s, the conversation about predictive testing, and about reproductive options, often arises earlier in life than in E200K families. Family planning options sets out the published routes, including testing that does not require the prospective parent to learn their own status.

Duration. A course measured in years changes planning: income protection, work, care at home and the timing of advance care planning all look different from a four-month illness.

Phenotype expectation. Relatives who have read about CJD may expect a rapid dementia and find the ataxic, slowly progressive presentation unrecognisable, which has led to long diagnostic delays in GSS families. Telling them what the family variant typically looks like is part of preparing them.

What research applies?

Work specific to A117V exists mainly in laboratory models. Grant reports from prion research groups describe A117V model systems alongside FFI and sporadic CJD models, and material from patients with rarer GSS variants has been used to study mechanism. That is preclinical work, and A117V for researchers is where it belongs.

For trials, eligibility is usually written around a pathogenic PRNP variant and clinical stage rather than a named variant, so the question for an A117V family is whether a given study accepts their variant and their stage. Current trials records sponsor-stated eligibility with dates.

Where next?

PRNP variants is the overview of how variants differ, D178N and V210I the two ends of the penetrance range, and genetic prion disease: more detail the clinical picture across the inherited forms.

This page summarises published literature and is not clinical or genetic advice. No figure here describes the position of any particular person, and nothing on this page is a reason to have, or not to have, a genetic test.