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Fondazione IRCCS – Istituto Neurologico “Carlo Besta” Milano

Gerstmann-Str ä ussler-Scheinker disease. Fabrizio Tagliavini. Fondazione IRCCS – Istituto Neurologico “Carlo Besta” Milano. Human Prion Diseases Kuru - acquired ( ritualistic cannibalism) Creutzfeldt-Jakob disease - sporadic - genetic - acquired (iatrogenic, new variant)

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Fondazione IRCCS – Istituto Neurologico “Carlo Besta” Milano

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

  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 changesin layers II-III of cerebral cortex Diagnosis: peculiar form of degenerative spino-cerebellar atrophy

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

  6. Phenotypic heterogeneity in GSS P102L Typical form CJD-like form T1 DWI

  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 mutations associated with GSS

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

  10. Diagnostic Problems 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 : no pseudoperiodic bi-triphasic complexes MRI: regional atrophy without signal abnormalities CSF: • 14-3-3 absent or weakly positive • Tau normal or slightly increased 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. Nosology • Only GSS P102L has been successfully transmitted 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

  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 AD and vice versa • Treatments strategies for AD targeting neurofibrillary pathology may be effective 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. PrP Ph-Tau Thioflavine PrP/Tau GSS F198S

  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

  17. Thank you for your attention and support !

  18. GSS F198S-V129 Silver Thioflavine S PrP

  19. PrP Ph-Tau Thioflavine PK - + PrP/Tau PrPres profile GSS F198S-V129

  20. GSS, Indiana kindred (F198S)

  21. Microglia PrP (3F4) C1q SAP

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

  23. PrPSc profile of GSS differs from that of CJD GSS F198S CJD E200K • + - + • - - + + • + - + • - - + + PK PNG

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

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