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