Abstract
BackgroundMore than 40 pathogenic heterozygous PRNP mutations causing inherited prion diseases have been identified to date. Recessive inherited prion disease has not been described to date.MethodsWe describe the clinical and neuropathological data of inherited early-onset prion disease caused by the rare PRNP homozygous mutation R136S. In vitro PrPSc propagation studies were performed using recombinant-adapted protein misfolding cyclic amplification technique. Brain material from two R136S homozygous patients was intracranially inoculated in TgMet129 and TgVal129 transgenic mice to assess the transmissibility of this rare inherited form of prion disease.ResultsThe index case presented symptoms of early-onset dementia beginning at the age of 49 and died at the age of 53. Neuropathological evaluation of the proband revealed abundant multicentric PrP plaques and Western blotting revealed a ~ 8 kDa protease-resistant, unglycosylated PrPSc fragment, consistent with a Gerstmann-Sträussler-Scheinker phenotype. Her youngest sibling suffered from progressive cognitive decline, motor impairment, and myoclonus with onset in her late 30s and died at the age of 48. Genetic analysis revealed the presence of the R136S mutation in homozygosis in the two affected subjects linked to homozygous methionine at codon 129. One sibling carrying the heterozygous R136S mutation, linked to homozygous methionine at codon 129, is still asymptomatic at the age of 74. The inoculation of human brain homogenates from our index case and an independent case from a Portuguese family with the same mutation in transgenic mice expressing human PrP and in vitro propagation of PrPSc studies failed to show disease transmissibility.ConclusionIn conclusion, biallelic R136S substitution is a rare variant that produces inherited early-onset human prion disease with a Gerstmann-Sträussler-Scheinker neuropathological and molecular signature. Even if the R136S variant is predicted to be “probably damaging”, heterozygous carriers are protected, at least from an early onset providing evidence for a potentially recessive pattern of inheritance in human prion diseases.
Highlights
More than 40 pathogenic heterozygous PRNP mutations causing inherited prion diseases have been identified to date
According to the clinic-neuropathological features, inherited prion diseases can be classified as genetic Creutzfeldt-Jakob disease, Gerstmann-SträusslerScheinker (GSS) syndrome, Fatal Familial Insomnia, and Prion diseases associated to octapeptide insertions there are some variants presenting an intermediate clinical phenotype or not fitting into these categories [7]
We describe the clinical, neuropathological, and biochemical phenotype of genetic prion disease associated with a biallelic R136S substitution in the PRNP gene in a Spanish family
Summary
More than 40 pathogenic heterozygous PRNP mutations causing inherited prion diseases have been identified to date. Recessive inherited prion disease has not been described to date. Genetic prion diseases represent ~ 15% of human prion diseases [1] and are caused by genetic variants in the PRNP gene, located on the chromosome 20. More than 40 rare variants have been described to cause genetic prion disease. According to the clinic-neuropathological features, inherited prion diseases can be classified as genetic Creutzfeldt-Jakob disease, Gerstmann-SträusslerScheinker (GSS) syndrome, Fatal Familial Insomnia, and Prion diseases associated to octapeptide insertions there are some variants presenting an intermediate clinical phenotype or not fitting into these categories [7]. Analysis of the human PRNP gene is recommended whenever such as disease form is suspected [8, 9]
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