TWO UNEXPECTED CASES OF VARIABLY PROTEASE SENSITIVE PRIONOPATHY PRESENTING WITH A MOTOR NEURON/FRONTOTEMPORAL DEMENTIA SYNDROME IN A SMALL REGION IN NORTHERN SPAIN IDENTIFIED WITHIN ONE YEAR

Introduction

Variably protease-sensitive prionopathy (VPSPr) is a very rare sporadic prion disease.

Objective

To describe clinical, biochemical, and neuropathological findings of two new patients with VPSPr presenting with a motor-neuron/frontotemporal dementia syndrome.

Methods

Clinical evaluation, genetic analysis, postmortem neuropathological examination and biochemical analyses of the cellular prion protein (PrP^sc).

Results

The patients were two men from unrelated families with an age at onset of 57 and 74 years. Mean disease duration was 46 and 67 months, respectively. Both presented with a motor-neuron syndrome compatible with primary lateral sclerosis with frontotemporal dementia. Neuropathology revealed a similar phenotype in both with mild spongiform change, neuronal loss and gliosis in fronto-temporal lobar distribution involving the motor system, and more severe affection of the thalamus. Peculiar PrP^sc deposition pattern with extracellular fine-synaptic, fleecy and freckle-like accumulations, irregular patches, and micro-plaques as well as intracellular fine-granular and dotted aggregates in thalamic and motor-neurons, as described in VPSPr. Western blotting revealed PrP^sc resistant proteolytic fragment after very mild digestion with PK, with clear non-glycosylated and mono-glycosylated bands of approximately 19 and 22-25 kDa respectively, and complete lack of di-glycosylated fragment. PRPN sequencing showed methionine-homozygosity (Met/Met) at codon 129 in both, and no mutations.

Conclusion

VPSPr is a very rare sporadic prion disorder which can manifest with motor neuron symptoms over several years in methionine-homozygous patients mimicking ALS/PLS and be associated with an FTD phenotype. These two cases contribute to broaden the knowledge about its clinical, biochemical, and neuropathological features, providing hints for its early recognition.