1. Fondazione IRCCS – Istituto Neurologico “Carlo Besta” Milano Gerstmann-Sträussler-Scheinker disease Fabrizio Tagliavini

2. Human Prion Diseases Kuru - acquired (ritualistic cannibalism) Creutzfeldt-Jakob disease - sporadic - genetic - acquired (iatrogenic, new variant) Gerstmann-Sträussler-Scheinker Disease - genetic Fatal Insomnia - genetic - sporadic

3. Z. Neurol. 154:736-762, 1936 Berta H Onset 26 yrs, gait disturbances Clinical picture: severe ataxia, dysmetria, dysartria, Babinski sign, personality and behavioural changes Death 31 yrs Family history: several family members showed a similar disease, with onset in the 3rd-4th decade and duration of 6-8 yrs, consistent with autosomal dominant transmission Clinical diagnosis: Hereditary Spino-Cerbellar Ataxia

4. Cerebellum: loss of granule cells and severe degeneration of dentate nuclei Spinal Cord: pallor of spino- cerebellar tracts and posterior columns Argentophilic plaques in the cerebellar cortex, cerebral cortex and basal ganglia Vacuolar changes in layers II- III of cerebral cortex Diagnosis: peculiar form of degenerative spino-cerebellar atrophy

5. Gerstmmann-Sträussler-Scheinker disease Successfull transmission to primates: spongiform Successfull transmission to primates: spongiform encephalopathy (Masters et al., Brain 1981) Prion Disease encephalopathy (Masters et al., Brain 1981) Prion Disease Amyloid plaques are composed of Prion Protein Amyloid plaques are composed of Prion Protein P102L mutation in the PRNP gene in affected members P102L mutation in the PRNP gene in affected members of the original family (Hainfellner et al., Brain Pathol. 1995) of the original family (Hainfellner et al., Brain Pathol. 1995) Phenotypic variability even within the same familiy Phenotypic variability even within the same familiy (ataxia vs dementia); cases with rapid course and more (ataxia vs dementia); cases with rapid course and more pronounced spongiform changes (CJD-like picture) pronounced spongiform changes (CJD-like picture)

6. Phenotypic heterogeneity in GSS P102L T1DWI Typical form CJD-like form

7. Genetics Systematic analysis of the PRNP gene in neurodegenerative disorders has enabled to recognize several new GSS variants with different clinical phenotype

8. PRNP mutation Main Clinical Feature Age and DurationNo. Fam. P102L Cerebellar Syndrome Dementia in late stage III-VI decade, 0.5-8 yrs > 30 P105L Spastic Paraparesis and DementiaIV-V decade, 6-12 yrs 5 A117V Atypical Parkinsonism and Dementia Cerebellar syndrome (1 family) II-VII decade, 1-11 yrs 8 G131V Dementia and Extrapyramidal Signs Ataxia in late stage V decade, 9 yrs 1 H187R Dementia and Cerebellar SyndromeIV-VI decade, 7-18 yrs 1 F198S Cerebellar Syndrome, Parkinsonism and Dementia IV-VIII decade, 2-12 yrs 3 D202N Dementia and Cerebellar SyndromeVIII decade, 6 yrs 2 Q212P Cerebellar SyndromeVI decade, 8 yrs 1 Q217R Dementia and ParkinsonismV-VII decade, 2-6 yrs 2 M232T Cerebellar Syndrome, Spastic Paraparesis and Dementia V decade, 6 yrs 1 PRNP mutations associated with GSS

9. Possible basis of phenotypic heterogeneity Distinct PrP res isoforms are associated with different GSS phenotypes 33 28 21 18 14 8 33 28 21 18 14 8 sCJD Type1 sCJD Type2 GSS P102L GSS A117V GSS F198S D202N Q217R GSS Q212P GSS G131V

10. Diagnostic Problems Diagnostic Problems Clinical features: Clinical features: broad spectrum of clinical phenotypes that mimic other neurodegenerative diseases such as spinocerebellar ataxia, parkinsonian syndromes, spastiac paraparesis, or atypical dementia (AD- or FTD-like) In most patients EEG EEG : no pseudoperiodic bi-triphasic complexes MRI MRI: regional atrophy without signal abnormalities CSF CSF: 14-3-3 absent or weakly positive Tau normal or slightly increased Diagnosis is dependent on genetics: PRNP Diagnosis is dependent on genetics: PRNP mutation Recent diagnostic tool: PET imaging with amyloid-binding probes (e.g. FDDNP, PIB)

11. Kepe et al. Brain Pathology 2009

12. Only GSS P102L has been successfully transmitted  Only GSS P102L has been successfully transmitted to experimental animals (primates and rodents) to experimental animals (primates and rodents)  Several attempts to transmit the other GSS genotypes have been unsuccessful to date Most GSS variants seem to be PrP-related neurodegenerative disorders rather than prion diseases Nosology

13. Some GSS variants have a neuropathological profile closely similar to Alzheimer’s disease (neurofibrillary tangles)  Research on GSS can help understanding the molecular basis of nerve cell degeneration in molecular basis of nerve cell degeneration in AD and vice versa AD and vice versa  Treatments strategies for AD targeting neurofibrillary pathology may be effective neurofibrillary pathology may be effective in these GSS variants in these GSS variants

14. GSS F198S-V129 Onset: IV-VIII decade Onset is 10 years earlier in patients with VV at codon 129 than in patients with MV Clinical Picture: Cerebellar syndrome, parkinsonism, dementia Duration: 2-12 years Pathology: PrP amyloid and neurofibrillary tangles similar to those of Alzheimer’s disease

15. GSS F198S PrP/Tau PrPPh-Tau Thioflavine

16. Gerstmmann-Sträussler-Scheinker disease  Chronic neurodegenerative disorder primarily involving the motor system  Needs and management of patients are partly different from those of CJD patients Educational and intervention programs designed to help long-term caregivers

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19. GSS F198S-V129 Silver Thioflavine S PrP

20. GSS F198S-V129 PrP/Tau PrPPh-Tau Thioflavine PK - + PrP res profile

21. GSS, Indiana kindred (F198S)

22. Microglia SAP C1q PrP (3F4)

25. GSS: cerebral amyloidosis Amyloid repeats 231 23   ~ 82 ~146 EM PrP Thioflavine S

26. GSS F198SCJD E200K - + - - + + PK PNG - + - - + + PrP Sc profile of GSS differs from that of CJD

27. GSS P102 L molecular basis of phenotypic variability 1.Codon 129 polymorphism P102L-M129: Cerebellar syndrome, late Dementia P102L-V129: Cerebellar syndrome, Seizures, no Dementia, slower course (up to 12 yrs) 2. PrP Sc type Amyloid Amyloid + Spongiosis - 30 kDa - 8 kDa - + - + PK Case 1 Case 2