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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) - PowerPoint PPT Presentation
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Fondazione IRCCS – Istituto Neurologico “Carlo Besta”Milano
Gerstmann-Sträussler-Scheinker disease
Fabrizio Tagliavini
Human Prion DiseasesHuman Prion Diseases
• Kuru - acquired (ritualistic cannibalism)
• Creutzfeldt-Jakob disease- sporadic- genetic- acquired (iatrogenic, new variant)
• Gerstmann-Sträussler-Scheinker Disease
- genetic
• Fatal Insomnia- genetic- sporadic
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
• 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:Diagnosis: peculiar form of degenerative spino-cerebellar peculiar form of degenerative spino-cerebellar atrophyatrophy
Gerstmmann-StrGerstmmann-Strääussler-Scheinker ussler-Scheinker diseasedisease
• Successfull transmissionSuccessfull transmission to primatesto primates: spongiform : spongiform
encephalopathy encephalopathy (Masters et al., Brain 1981) (Masters et al., Brain 1981) Prion Prion Disease Disease
• Amyloid plaques are composed of Prion ProteinAmyloid plaques are composed of Prion Protein
• P102L mutation in the P102L mutation in the PRNPPRNP gene gene in affected in affected members members of the original familyof the original family (Hainfellner et al., Brain Pathol. 1995)(Hainfellner et al., Brain Pathol. 1995)
• Phenotypic variabilityPhenotypic variability even within the same familiy even within the same familiy (ataxia vs dementia)(ataxia vs dementia); cases with rapid course and ; cases with rapid course and more more pronounced spongiform changes pronounced spongiform changes (CJD-like picture)(CJD-like picture)
Phenotypic heterogeneity in Phenotypic heterogeneity in GSS P102LGSS P102L
T1 DWI
Typical form
CJD-like form
Genetics
Systematic analysis of the PRNP gene in neurodegenerative disorders has enabled to recognize several new GSS variants with different clinical phenotype
PRNPPRNP mutatiomutatio
nn
Main Clinical FeatureMain Clinical Feature Age and Duration
No. Fam
.
P102L Cerebellar Syndrome Dementia in late stage
III-VI decade, 0.5-8 yrs > 30
P105L Spastic Paraparesis and Dementia
IV-V decade, 6-12 yrs 5
A117V Atypical Parkinsonism and DementiaCerebellar syndrome (1 family)
II-VII decade, 1-11 yrs 8
G131V Dementia and Extrapyramidal SignsAtaxia in late stage
V decade, 9 yrs 1
H187R Dementia and Cerebellar Syndrome
IV-VI decade, 7-18 yrs 1
F198S Cerebellar Syndrome, Parkinsonism and Dementia
IV-VIII decade, 2-12 yrs 3
D202N Dementia and Cerebellar Syndrome
VIII decade, 6 yrs 2
Q212P Cerebellar Syndrome VI decade, 8 yrs 1
Q217R Dementia and Parkinsonism V-VII decade, 2-6 yrs 2
M232T Cerebellar Syndrome, Spastic Paraparesis and Dementia
V decade, 6 yrs 1
PRNPPRNP mutations associated with GSS mutations associated with GSS
Possible basis of phenotypic Possible basis of phenotypic heterogeneityheterogeneity
Distinct PrPDistinct PrPresres isoforms are associated with isoforms are associated with different GSS phenotypesdifferent GSS phenotypes
33
28
21
18
14
8
33
28
21
18
14
8
sCJDType1
sCJDType2
GSSP102L
GSSA117V
GSSF198SD202NQ217R
GSSQ212P
GSSG131V
Diagnostic ProblemsDiagnostic 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
EEGEEG : no pseudoperiodic bi-triphasic complexes
MRIMRI: regional atrophy without signal abnormalities
CSFCSF: • 14-3-3 absent or weakly positive• Tau normal or slightly increased
Diagnosis is dependent on genetics: Diagnosis is dependent on genetics: PRNPPRNP mutation
Recent diagnostic tool: PET imagingRecent diagnostic tool: PET imaging with amyloid-binding probes (e.g. FDDNP, PIB)
Kepe et al. Brain Pathology 2009
Only GSS P102L has been successfully Only GSS P102L has been successfully transmitted transmitted to experimental animals to experimental animals (primates and rodents) (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
Some GSS variants have a Some GSS variants have a
neuropathological profile closely similar neuropathological profile closely similar
to Alzheimer’s diseaseto Alzheimer’s disease (neurofibrillary (neurofibrillary
tangles)tangles)
Research on GSS can help understanding Research on GSS can help understanding thethe molecular basis of nerve cell degeneration molecular basis of nerve cell degeneration in in AD and AD and vice versavice versa
Treatments strategies for AD targeting Treatments strategies for AD targeting neurofibrillary pathology may be effective neurofibrillary pathology may be effective in these GSS variantsin these GSS variants
GSS F198S-V129GSS F198S-V129
Onset:Onset: IV-VIII decade IV-VIII decadeOnset is 10 years earlier in patients with VV at codon 129 Onset is 10 years earlier in patients with VV at codon 129 than in patients with MVthan in patients with MV
Clinical Picture:Clinical Picture: Cerebellar syndrome, parkinsonism, Cerebellar syndrome, parkinsonism, dementiadementia
Duration:Duration: 2-12 years 2-12 years
Pathology:Pathology: PrP amyloid and neurofibrillary tangles PrP amyloid and neurofibrillary tangles similar to similar to those of Alzheimer’s disease those of Alzheimer’s disease
GSS F198SGSS F198S
PrP/Tau
PrP Ph-Tau
Thioflavine
Gerstmmann-StrGerstmmann-Strääussler-Scheinker ussler-Scheinker diseasedisease
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
Thank you Thank you for your attention and supportfor your attention and support ! !
GSS F198S-V129GSS F198S-V129
Silver Thioflavine S
PrP
GSS F198S-V129GSS F198S-V129
PrP/Tau
PrP Ph-Tau
Thioflavine
PK - +
PrPres profile
GSS, Indiana kindred (F198S)GSS, Indiana kindred (F198S)
Microglia
SAPC1q
PrP (3F4)
GSS: cerebral amyloidosisGSS: cerebral amyloidosis
Amyloid
repeats
23123
~ 82 ~146
EM
PrP
Thioflavine S
GSS F198S CJD E200K
- + - +- - + +
PKPNG
- + - +- - + +
PrPPrPScSc profile of GSS differs profile of GSS differs from that of CJDfrom that of CJD
GSS P102 LGSS P102 L molecular basis of phenotypic
variability
1.1.Codon 129 polymorphismCodon 129 polymorphism
• P102L-M129: Cerebellar syndrome, late Dementia
• P102L-V129: Cerebellar syndrome, Seizures, no Dementia, slower course (up to 12 yrs)
2. PrP2. PrPScSc type type
AmyloidAmyloid Amyloid + Amyloid + SpongiosisSpongiosis
- 30 kDa
- 8 kDa
- + - +PK
Case 1
Case 2
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