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PRNP E146G mutation inherited prion disease: distinctive clinical, pathological and fluid biomarker features

Thomas Coysh1,2, Zane Jaunmuktane3, Laszlo L P Hosszu1

  • 1MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.

Journal of Neurology
|March 29, 2025
PubMed

Insights

A novel PRNP E146G mutation causes inherited prion disease (IPD) with distinct clinical and biomarker features. This finding aids in identifying this rare neurodegenerative condition.

Area of Science:

  • Neurogenetics
  • Neuropathology
  • Molecular Biology

Background:

  • Inherited prion diseases (IPDs) are rare, fatal neurodegenerative disorders.
  • Mutations in the prion protein gene (PRNP) cause IPDs, leading to diverse clinical presentations.
  • Accurate diagnosis and characterization of IPDs are crucial for understanding disease mechanisms.

Purpose of the Study:

  • To describe a novel PRNP E146G mutation associated with a unique form of inherited prion disease.
  • To detail the clinical, neuroimaging, and fluid biomarker characteristics of patients with this mutation.
  • To compare the phenotype with existing IPD classifications, such as Gerstmann-Sträussler-Scheinker disease.

Main Methods:

  • Clinical phenotyping of a three-generation family with a novel PRNP mutation.
  • Neuroimaging (MRI) analysis to identify structural brain changes.
  • Cerebrospinal fluid (CSF) and plasma biomarker analysis, including S100B, tau, GFAP, NFL, 14-3-3, and RT-QuIC.
  • Post-mortem neuropathological examination, including PrP amyloid plaque assessment and immunoblotting.

Main Results:

  • A novel PRNP E146G mutation was identified in a family with IPD.
  • Patients presented with slowly progressive dysarthria, prominent myoclonus, and gait ataxia, with minimal early cognitive decline.
  • Distinctive fluid biomarker profile: elevated CSF S100B, moderately elevated CSF tau, negative NFL/14-3-3/RT-QuIC, and markedly elevated plasma GFAP with normal plasma NFL.
  • Post-mortem findings included cerebellar atrophy, widespread PrP amyloid plaques, and low molecular weight protease-resistant PrP fragments.

Conclusions:

  • The PRNP E146G mutation defines a distinct subtype of inherited prion disease.
  • The unique clinical and biomarker profile can aid in early identification.
  • This IPD variant expands the spectrum of Gerstmann-Sträussler-Scheinker disease, highlighting the phenotypic diversity of PRNP mutations.
Keywords:
BiomarkersInherited prion diseaseMutationNeurodegenerationPathologyPrion

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