Amalia C. Bruni Centro Regionale di Neurogenetica Lamezia ...6+A2 + A53 307155 306155 308155 309155...

Amalia C BruniCentro Regionale di Neurogenetica

Lamezia Terme

Lamezia Terme 3 giugno 2015

raquo Consuetudine a diagnosticare solo forme che si conosconohellip

raquoNecessitagrave di conoscere e approfondire hellipaltre diagnosi

raquo bull Esordio (Etagrave - Sintomatologia)

raquo bull Evoluzione (tipologia di sintomi ndash durata)

bullAtrofia Corticale Posteriore

bullAfasia progressiva (variante logopenica)

bullVariante laquofrontaleraquo

Atrofia corticale posteriore (Benson 1988)

bull Gruppo di demenze degenerative caratterizzato da un iniziale e preminente disturbo visivoseguito da un progressivo declinodelle funzioni cognitive

bull CRITERI (MENDEZ 2001)

raquo bullInizio insidioso e progressione graduale

raquo bullPresentazione con disturbi visivi ma acuitagrave conservata

raquo bullEvidenza di disturbi visivi complessi

raquo bullDisturbo relativamente minore della memoria e del linguaggio

raquo bullConsapevolezza conservata con o senza depressione

Crutch et al Lancet Neurology 2012

raquo 71 anni laurea ex dirigente tecnico dellrsquoUniversitagrave

raquo Vita attiva con svariati interessi intellettuali

raquo Una sorella di 73 anni affetta da m di Alzheimer

raquo Padre affetto da riferito complesso Parkinson-demenza

raquo A 69 anni infarto acuto del miocardio con intervento chirurgico in urgenza di 3 by-pass aorto-coronarici anestesia totale per 6 ore

raquo Sintomi riferiti dal paziente Non riesce piugrave a leggere senza tenere il rigo con il dito della mano

Non trova le lettere sulla tastiera del computer

raquo Sintomi riferiti dalla moglie Difficoltagrave nel reperire le parole piugrave appropriate durante un discorso

Rallentamento motorio globale

Apatia riduzione degli interessi sonnolenza diurna

Labilitagrave emotiva

CASO CLINICO

Marcata atrofia del lobo parietale

Relativa integritagrave delle strutture ippocampali

Alterazioni di intensitagrave putaminali e pallidali

Rievocazione immediataRievocazione immediata

rievocazione differita

raquo Le afasie primarie progressive fenotipi clinici

raquo bullVariante logopenicofonologica

raquo bullVariante non fluenteagrammatica

raquo bullVariante semantica

˃ Allrsquoetagrave di 69 anni il paziente (medico) comincia a presentare un disturbo del linguaggio caratterizzato da difficoltagrave nella denominazione degli oggetti e perdita di memoria per i nomi delle persone Progressivamente sviluppa anedonia riduzione degli interessi isolamento sociale

˃ Lrsquo Insight egrave integro

La valutazione neuropsicologica effettuata a tre anni dallrsquoesordio delinea un profilo neurocognitivo caratterizzato da

+ plurisettoriale deficit della funzione mnesica

+ deficit della produzione verbale su stimolo fonologico e semantico

+ deficit delle funzioni esecutive (capacitagrave di concettualizzazione e di programmazione)

raquo LINGUAGGIO SPONTANEOComportamento comunicativo adeguato ma la conversazione egrave rallentata da numerosi fenomeni

afasici Assenza di stereotipe verbali e di ecolalia non deficit articolatori neacute della prosodiapresenti numerose parafasie semantiche ed anomie qualche parafasia fonemica qualche

flessione errataraquo RIPETIZIONE

Indenne la ripetizione di suoni parole e parole straniere moderatamente compromessa la ripetizione di parole composte sintagmi e frasi sia semplici che complesse

raquo DENOMINAZIONEraquo Indenne la capacitagrave di denominare i colori moderatamente compromessa la denominazione di oggetti ad

alta frequenza drsquouso di nomi composti e la capacitagrave di descrivere figure sia semplici che complesse

ESAME DEL LINGUAGGIO Aachener Aphasie Test

raquoLETTURA E SCRITTURAraquoIndenni

raquoCOMPRENSIONEraquoIndenne la comprensione orale e scritta di parole lievemente compromessa la comprensione orale e scritta di frasi

raquoConclusioni

Moderato deficit della capacitagrave di ripetizione e di denominazione associato a lieve deficit della

comprensione orale e scritta di frasi complesse

Afasia Primaria Progressiva

Forma Logopenica




Amnestic

Disoriented

Apathetic

Dysexecutive

Neurology 2010

AD possible Atypical course

Onset 82Death 85

AD

3 2Stroke

I

II

Onset 72Death 77

AD

3 2Stroke

Death 65

Onset 75Death 80

I

II

III

Rossi et al 2004

Onset 82Death 85

AD

3 2Stroke

I

II

Memory disorder disorientationApathy behavioral disorientationNo difference between heterozygous and homozygous patients

bull Overlapping sintomatologico AD FTD PDDDLB ADLBDhelliphellip

bull Overlapping geneticohelliphellip

bull Overlapping di proteine patologichehellip

Figure 1

raquo Rates of Psychiatric Diagnosis within each Neurodegenerative Disease

raquo Percentage of patients given a psychiatric diagnosis for symptoms that eventually led to a ND diagnosis separated by gender denotes male while denotes female patients (=plt001 dagger=plt005)

raquo FTD phenotype and corticobasal degeneration in the same family (Bugiani et al 1999)

raquo Parkinsonism and epileptic seizures (Sparked 1999)

raquo Parkinsonism followed by cognitive impairment (Kawamata 2005)

Bugiani O Murrell JR Giaccone G et al (1999) Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau

J Neuropathol Exp Neurol 58(6)667-77

Sperfeld AD Collatz MB Baier H et al (1999) FTDP-17 an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation Ann Neurol 46(5)708-15

Kawamata T et al (2005) Phenotypic heterogeneity within a new family with the MAPT P301S mutation Ann Neurol 58(6)920-8

onset 500+34

death 530+75

Memory impairment troubles of language disorientation

troubles of behaviour and personalityapathy lack of personal and

social awareness delusions hallucinations

psychomotor agitation aggressivity and violence

Extrapyramidal signs rigidity amimia supraspinal signs No tremor

Epilepsia myoclonus

RB Family ascertained 1989

133546 Lives in Milan

Onset 46 Uninterested in home

management disinhibited

Insight absent Frequent collapse

agitatated disoriented

After 6 yrs mutacic but able to sing

old songs echolalia wandering

After 8 yrs completely mute

aggressive bulimic fatuous

expression Diagnosis FTD

133548 Lives in Turin onset 48

Language poor and stereotypic

childish cognitive troubles

(concentration abstraction and

planning deficits) but spatially

oriented insight absent No delusions

Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)

(RB Family) (Pul Family)778 2729

D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1

(D17S951) is different it is possible that a single recombination event has occurred in this region




Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy

Early onsetAltered mood disturbed personalityand behaviour planning difficulties Altered critic and judgement attention disturbances and distractibilitysevere speech disorder severe impairment of executive In contrast memory functions relatively spared

Bernardi et al 2011 JAD




Scintigrafia miocardicaDenervazione

normale Alpha syn e tau colocalizzano

inclusionineuronali

TDP43+ (FTLD)

Degenerazionemotoneuronale

(SLA)

placcheamiloidi (AD)

tangles neurofibrillari

(AD)

overlapping

Demenze atipiche early onset

Sherrington R et al Cloning of a gene bearing missense mutation in

early-onset familial Alzheimers disease Nature 1995 375754-760

Rogaev EI et al Familial Alzheimerrsquos disease in kindreds with missense mutation

in a gene on chromosome 1 related to the Alzheimerrsquos disease type 3 gene Nature

1995 376775-778

Early-onset Alzheimers disease caused by mutations at codon 717

of the beta-amyloid precursor protein gene

Chartier-Harlin MC Crawford F Houlden H Warren A Hughes D Fidani L

Goate A Rossor M Roques P Hardy J et al

Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014

Lrsquoetagrave di esordio egrave una media con amplissime dispersioni

65 yrs

Harvey RJ Skelton-Robinson M Rossor MN The prevalence and causes of dementia in people underthe age of 65 years J Neurol NeurosurgPsychiatr 2003741206ndash09 [PubMed 12933919]

EARLY ONSET DEMENTIA

47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439

Family history for EOD

426 pz EOD mean age 57 yrs

Early onset dementia

Quando porre il sospetto diagnostico

Etagrave di Esordio Giovanile-adulta

Sintomi Cognitivo-comportamentali francamente psicotici

Evoluzione Rapida (mesipochi anni)

Sintomi associati neurologici (cerebellareextrapiramidalepiramidale

Sintomi extraneurologici Sistemici con coinvolgimento viscerale talora sfumato

Trasmissione Dominante (HD SCA Cadasil CJD)

Recessiva malattie metaboliche

Malattia rara neurodegenerativa

Sintomi psichiatricicomportamentali

Sintomi cognitivi

Sintomi motori

raquo Behavioural disorder psychiatric symptoms absentinsight memory troubles disorientation absence of agnosia

raquo Dementia

raquo Dysarthria Rigidity Tremor Dystonia

raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13

Dementia plusSchizophrenia

Behavioural symptoms Psychiatric symptoms

Exclusion of 23 diseases

bullFilla A De Michele G Cocozza S Parignani A Volpe G Castaldo I Ruggiero G Bonavita V Masters C Casari G Bruni AC

bullEarly Onset Autosomal dominant Dementia with Ataxia Extrapyramidal Features and Epilepsy Neurology 2002 26(58) 922-928

Cervello piccolo peso 600 g

Atrofia marcata delle aree prefrontaliAtrofia del cervelletto

Degenerazione ipertrofica delleolive bulbari

MV 49 anni

A) Microspongiosi nella corteccia frontale (HE)

B) Perdita neuronale e gliosi nel nucleo caudato (HE)

C) Perdita neuronale nello strato delle cellule di Purkinje (HE)

D) Anticorpo anti ubiquitina

E) Anticorpo anti TBP

F ndash G) Ab 1C2

16 affetti in 4 generazioni Esordio 333 + 10 (17-53)Morte 546 + 73 (48-69)

Durata 23 + 67 (13-30)Trasmissione autosomica dominante

134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14

Generazioni di affetti 5

Generazioni ricostruite 9

Onset (media+devst) 510+117

Death (media+devst) 573+101

Durata (media+devst) 40+23

Frontal dementia Ataxia

Case 2

17 yrs Behaviouralproblems aggressivity 20yrs Tremor frankataxia disartria

28yrs Epileptic seizures

30 Progressive cognitive impairment and dementia

Death at 42- brain autopsy

Case 1

32 yrs Depression and cognitive decline

41 yrs Rare seizures

ataxia dysarthria pyramidal -extrapyramidal signs

progressive dementiaand motor disability

bedridden at 51

Anamnesi Familiare

bullNonna materna deceduta in etagrave avanzata

con tremori e disturbi motori ingravescenti

bullFratello della nonna materna con crisi

convulsive deceduto dopo prolungato ricovero

in ospedale psichiatrico

bullMadre deceduta a 60 anni con demenza a

rapida evoluzione ed ictus recidivanti

GENETICA MOLECOLARE Escluse

Malattia di Huntington DPRLA SCA17

Malattia di Alzheimer (mutazioni PS1 PS2 APP)

FTDP-17

Malattie da prioni

La diagnosi di certezza puograve essere ottenuta soltanto con lo studio del tessuto cerebrale in quanto la negativitagrave delle biopsie periferiche non egrave sufficiente ad escludere la diagnosi

Altre patologiehelliphellip

La malattia di Niemann Pick

Malattia lisosomiale a trasmissione autosomica recessiva panetnica

Forme cliniche perinatale infantile precoce (2m-2 aa) infantile tardiva (2-6 aa)

adolescenziale-adulta (gt15 aa)

INCIDENZA 1120 000 ndash 150 000

PREVALENZA 066-083 per 100000 nati

(Vanier MT 2010 Carluccio MA amp Federico A 2011)

Npc1 e NPC 2 lavorano in tandem e in direzione opposta

bull I pazienti non possonometabolizzarecorrettamente ilcolesterolo ed altri lipidiallinterno della cellula

bull Le quantitagrave eccessive di colesterolo siaccumulano allinternodel fegato e della milza e quelle di altri lipidi siaccumulano nel cervello

bull

bull Il difetto primitivo risiede nel gene NPC1 (95 dei casi) ed NPC2 (5) codificanti proteine che interagiscono nel trasporto del colesterolo e altre molecole

13 DEI PAZIENTI CON NPC HA UNA FORMA LATE ONSET

Niemann-Pick type C is frequent in adult ataxia with cognitive decline and vertical gaze palsy

Niemann-Pick type C (NPC) disease is a rare usually fatal neurodegenerative lysosomalstorage disorder It is inherited in an autosomal-recessive fashion and caused by mutationof either NPC1 (95) or NPC2 gene Age atonset is broadly variable ranging from neonatal fatal neurovisceral manifestations to a primarily neurodegenerative disease in

adulthood that may be recognized as late as 70 years of age(1) Due to

its diverse clinical manifestation correct diagnosis is challenging frequencies might be underestimated and diagnosis may be delayed in particular in patients with adult-onset disease

Neurology 2013 Mar 1980(12)1169-70 doi 101212WNL0b013e31828869f9 Epub 2013 Feb 20

Schicks J et al

Adult onset gt50 yrs

Cerebellar ataxia (76) vertical supranuclear ophthalmoplegia(75) dysarthria (63) cognitive troubles (61) movementdisorders (58) splenomegaly (54) psychiatric disorders (45) and dysphagia (37) Movement disorders (dystonia Parkinsonism chorea) are more frequent than in the juvenile form Some patients show severe ataxia dystonia and dysarthria with variable cognitive dysfunction whereas psychiatric symptoms and dementia dominate in others Epilepsy is rare in adult onset NP-C (15) Later course is similar to that in the juvenile form

552

Clinica delle forme dellrsquoadulto-anziano

Segni viscerali epatomegalia e splenomegalia non semprepresenti

Segni corticali sintomi di tipo psichiatrico deficit cognitivi di tipo frontale crisi epilettiche

Segni sottocorticali

disfunzione nuclei della base distonia corea parkinsonismo disfunzione cerebellare atassia disfunzione tronco encefalica paralisi verticale dello sguardo disartria disfagia

Sedel Arch Pediatr 2010 suppl 2S50-53

Le diagnosi comunemente ipotizzate prima di giungere

alla diagnosi di Niemann-Pick C

bull Schizofrenia

bull Malattia di Alzheimer

bull Demenza fronto-temporale

bull Malattia di Parkinson

bull Malattia di Wilson

bull Sclerosi multipla

bull Malattia di Creutzfeldt-Jakob

bull Encefalopatia di Wernicke

bull Paralisi sopranucleare progressiva

bull Impairment cognitivo di tipo frontale

bullAtassia

bullParalisi dello sguardo verso il basso lrsquoalto

bull Disartria

bull Distonie

raquo Studio pilota di screening in Germania raquo Sono stati inclusi 485 pazienti psichiatrici o neurologici giovani e adulti raquo Ersquo stato effettuato lo screening per la mutazione del gene NP-C 1

- Trovati 28 pazienti con mutazioni

raquo Nei pazienti negativi egrave stato screenato il gene NP-C 2- Trovati 3 pazienti con mutazione del gene NP-C 2

Sono in totale stati diagnosticati 31 pazienti con mutazioni NP-C (64)

Pilot study

Patients 25 F 25 M Mean age at onset 51 plusmn 1876 years

Clinical phenotype dementia with laquoplusraquo symptoms (motor behaviour)

Genetic analyses and biochemical study

Screening for mutations in causative genes for FTLD (MAPT GRNC9ORF72) AD (PSEN1 PSEN2 APP) and PRNP

Sequence analysis for NPC1 and NPC2 genes

Filipin fluorescent staining for lipids on skin fibroblasts

MLPA to exclude deletion and duplication

Oxisterols

Analysis of total cellular RNA to exclude discrepancy between cDNA andgenomic DNA

Retrospective study on 50 unrelated subjects affectedby atypical dementia

PSPprogressive supranuclearpalsy CBScorticobasalsyndrome VSGP verticalsupranucleargaze palsy Nnormal A altered

N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61

Clinical Picture PSP CBS CBS CBS

First Symptoms Dysarthria PsychosisCognitive decline

Limb dystonia ideomotorapraxia cognitive decline

Anomic aphasiaIdeomotor apraxiaBehavioural changes

Dementia + + + +

Parkinsonism + - + +

Dysphagia amp dysarthria

+ + + -

VSGP + - + +

Other signs Gait apraxia Hemidystonia Gait apraxia Non fluentaphasia Myoclonus

Non fluent aphasiaVisual agnosia Visual hallucinantionsMyoclonus

Filipin staining Biochemicalvariant

Negative Negative Biochemical variant

Oxysterols N N N N

mRNA N N N A

MLPA N N N N

Mutation NPC1 F284LFsX26

NPC1 N222S amprs66620415

NPC2V30M NPC2 c441+1GgtA (rs140130028)

N 1 2 3 4Age 67 57 52 69Onset 64 32 39 61Clinical Picture PSP CBS CBS CBSSymptoms Dysarthria Dementia

Parkinsonism Dysphagia amp dysarthria VSGP

Psychosis Cognitive decline Dementia Dysphagia amp dysarthria

Limb dystonia Ideomotor apraxia Cognitive decline Dementia Parkinsonism Dysphagia amp dysarthria VSGP

Anomic aphasiaIdeomotor apraxiaBehavioural changes Dementia Parkinsonism VSGP

Other signs Gait apraxia Hemidystonia Gait apraxiaNon fluent aphasia Myoclonus

Non fluent aphasiaVisual agnosia Visual hallucinations Myoclonus

Filipin staining

MRI

Oxysterols N N N NmRNA N N N A

Mutation NPC1 F284LFsX26NPC1 N222S amprs66620415

NPC2V30MNPC2 c441+1GgtA (rs140130028)

Population frequency Not reported 1250 1500 1200Miglustat Improved - - -

Patient 1 Patient 2 Patient 3 Patient 4

Vertical supranuclear gaze palsy Y N Y Y

Gelastic cataplexy N Y N N

Prolonged unexplained neonatal jaundice or cholestasis N N N N

Isolated unexplained splenomegaly with or without hepatomegaly N N N N

Presenile cognitive decline or dementia Y Y Y Y

Ataxia clumsiness or frequent falls Y N N Y

Dysarthria andor dysphagia Y N Y Y

Dystonia Y Y Y Y

Psychotic symptoms N N Y Y

Acquired amp progressive spasticity N N N N

Treatment-resistant psychiatric symptoms N Y N Y

Other psychiatric disorders Y N N Y

Hydrops fetalis N N N N

Siblings with fetal ascites N N N N

Hypotonia N N N N

Delayed developmental milestones Y Y N N

Seizure (partial or generalised) N Y N Y

Myoclonus N N Y Y

Disruptive or aggressive behaviour in adolescence and childhood N N N N

Parent or sibling with NP-C N N N N

Cousin with NP-C N N N N

Total score 116 97 111 132

raquo Collegamento per video

Generalexamination

blood analyses hellipvisceral

investigations

Neurologicalexamination

careful searching for motor neuron

signs cerebellar etclooking for dysphagia dysarthria

Cognitive and Neuropsychiatric

examinationassessing also

executive function-language behavior

Morphological and functional neuroimaging(MRI - look hyperintensities corticospinal bundles focal atrophy) Spect ndashSpect datscan- FdgPETOther investigation (EMGEEG)

Familial history asking for ldquoall diseasesrdquo in the family Reconstruction of the pedigreeasking for consanguinityPersonal history (emphasis on onset psychotic episodes premorbid personality mental deficiency course of the disease)

Molecular genetics

Neuropathology

1

2

3

4

raquo Le demenze ad esordio precoce sono frequentemente di tipo degenerativo ( AD-FTD ndash LBD ndashprioniche) hanno spesso una causa genetica e sono spesso atipiche hellip

raquo Le demenze possono essere atipiche (rispetto ad un quadro clinico e ad una etagrave di esordio laquomediaraquo) per molti aspetti clinici genetici e neuropatologici helliphellip

raquo Le demenze atipiche early onset rimangono tali fino a quando non si riescono ad individuare e diagnosticare

raquo Necessitano sempre di un metodo di studio rigoroso

raquo La neuropatologia e la biologia molecolare sono spesso fondamentali per il loro inquadramento eziologico

raquo Vanno accuratamente ricercate percheacute alcune potenzialmente curabili helliphellip

raquo Lrsquoobiettivo principale della ricerca genetica nel campo delledemenze egrave quello di sottolineare gli specifici profile di rischio cheda soli o in combinazione con fattori ambientali possono modularelo sviluppo la severitagrave e la progressione delle malattie

raquo Oggi crsquoegrave la tendenza ad una medicina personalizzata poicheacute egrave importante focalizzare sullrsquounicitagrave della persona con il suo specifico proficlo e le sue specifiche caratteristiche cliniche

raquo Quando saremo in grado di avere maggiori certezze circa le cause genetiche il loro modularsi e avremo compreso quali quanti e come I fattori genetici e ambientali modulano I quadri clinici saragraveallora possibile studiare trattamenti UNICI e soprattutto preventivi

raquo helliphellipThe road is long and difficult but also feasible given the emerging scientific findings

Miglustat inhibits glucosylceramide synthase an essential enzymefor the synthesis of most glycosphingolipids

raquo Consuetudine a diagnosticare solo forme che si conosconohellip

raquoNecessitagrave di conoscere e approfondire hellipaltre diagnosi


























CASO CLINICO

























raquoConclusioni




Forma Logopenica




Amnestic

Disoriented

Apathetic

Dysexecutive

Neurology 2010


Onset 82Death 85

AD

3 2Stroke

I

II

Onset 72Death 77

AD

3 2Stroke

Death 65

Onset 75Death 80

I

II

III

Rossi et al 2004

Onset 82Death 85

AD

3 2Stroke

I

II





Figure 1










onset 500+34

death 530+75






Epilepsia myoclonus


















Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4





































CASO CLINICO

























raquoConclusioni




Forma Logopenica




Amnestic

Disoriented

Apathetic

Dysexecutive

Neurology 2010


Onset 82Death 85

AD

3 2Stroke

I

II

Onset 72Death 77

AD

3 2Stroke

Death 65

Onset 75Death 80

I

II

III

Rossi et al 2004

Onset 82Death 85

AD

3 2Stroke

I

II





Figure 1










onset 500+34

death 530+75






Epilepsia myoclonus


















Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4




































raquoConclusioni




Forma Logopenica




Amnestic

Disoriented

Apathetic

Dysexecutive

Neurology 2010


Onset 82Death 85

AD

3 2Stroke

I

II

Onset 72Death 77

AD

3 2Stroke

Death 65

Onset 75Death 80

I

II

III

Rossi et al 2004

Onset 82Death 85

AD

3 2Stroke

I

II





Figure 1










onset 500+34

death 530+75






Epilepsia myoclonus


















Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4













Forma Logopenica




Amnestic

Disoriented

Apathetic

Dysexecutive

Neurology 2010


Onset 82Death 85

AD

3 2Stroke

I

II

Onset 72Death 77

AD

3 2Stroke

Death 65

Onset 75Death 80

I

II

III

Rossi et al 2004

Onset 82Death 85

AD

3 2Stroke

I

II





Figure 1










onset 500+34

death 530+75






Epilepsia myoclonus


















Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4















Amnestic

Disoriented

Apathetic

Dysexecutive

Neurology 2010


Onset 82Death 85

AD

3 2Stroke

I

II

Onset 72Death 77

AD

3 2Stroke

Death 65

Onset 75Death 80

I

II

III

Rossi et al 2004

Onset 82Death 85

AD

3 2Stroke

I

II





Figure 1










onset 500+34

death 530+75






Epilepsia myoclonus


















Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4













Onset 82Death 85

AD

3 2Stroke

I

II

Onset 72Death 77

AD

3 2Stroke

Death 65

Onset 75Death 80

I

II

III

Rossi et al 2004

Onset 82Death 85

AD

3 2Stroke

I

II





Figure 1










onset 500+34

death 530+75






Epilepsia myoclonus


















Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4
















Figure 1










onset 500+34

death 530+75






Epilepsia myoclonus


















Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4



















onset 500+34

death 530+75






Epilepsia myoclonus


















Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4




























Diagnosis AD

onset 475+07

death 555+64

Pul family

P301L

Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4












Marker (~ position)


D17S951 (39 Mb) 1 3 4 5

D17S579 (40 Mb) 1 3 1 2

MAPT (41 MB)

D17S920 (42 Mb) 1 3 1 3

D17S806 (43 Mb) 1 3 1 1





Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4















Clinical

characteristics

of the CBS

patients with

expansions in

the C9orf72

gene and the

clinically

diagnosed PSP

patient with an

allele of 27

repeats

Key CBD

corticobasal

degeneration

CBS

corticobasal

syndrome F

female M

male MRI

magnetic

resonance

imaging PD

Parkinsonrsquos

disease PSP

progressive

supranuclear

palsy








inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4



















inclusionineuronali

TDP43+ (FTLD)


(SLA)



(AD)

overlapping






1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4

















1995 376775-778





Nature 1991 Oct 31353(6347)844-6

Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4












Ryman D et al 2014


65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4












65 yrs



47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4














47

AD49

FTLD33

dementia of NDD

6

rare diagnosis

4

VaD3

PD3

LBD2

OTHER 18

0

10

20

30

40

50

ALL AD FTLD OTHER

F

M

472 459

309

439














Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4























Sintomi cognitivi

Sintomi motori


raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4













raquo Dementia


raquo Ataxia

raquo Incontinence

raquo Epilepsy

raquo Myoclonus

raquo Agitation

58 59

60 74 77___

1 2 89 99 80 84

25 26

27 30 31___

29 28

111___

120___

121___

20 21

220___

24 22 23

4 105___

104___

3 15 16

18 231 17

5 6

7 8 9 10 11 1238646

47484950 51

87

243 24614

13









MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4



















MV 49 anni






F ndash G) Ab 1C2



134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4














134729134738 134777 134720

134794 134775 134725134759 134735 134774134815 134736 134724134818

134733134734134750134758 134755 134749134752

134748 134747

+ A 66+ A62

O nset 58+A61

onset 53+ A59

O nset 43

+A46+ A79 onset 57

+ A60

E

+ A55

134625 134657 13 46 58

1 34631134630

134656134654 134655

13465 3 13 46 52 13 46511346331 34 63 2

13464613464 5

134647 134648

1 34704134703

onset 36

o nset 52+ A57

onset 59+ A61

+A45 onset 55+A62

+A69onset 50

+A54

onset 31+A34

onset 43+A47

+A62

+ A53

135057 135056

135059135058

135083135082

135120135121

135074 135075

135066

135041135042

+ A54

135067

1700 Affetti

Maschi 12

Femmine 14







Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4












Case 2





Case 1





bedridden at 51

Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4












Anamnesi Familiare











FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4















FTDP-17

Malattie da prioni













bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4























bull








Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4


















Schicks J et al



552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4














552









bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4




















bull Schizofrenia










bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4













bullAtassia


bull Disartria

bull Distonie





Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4
















Pilot study








Oxisterols




N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4













N 1 2 3 4

Age 67 57 52 69

Onset 64 32 39 61





Dementia + + + +



+ + + -

VSGP + - + +





Oxysterols N N N N

mRNA N N N A

MLPA N N N N











Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4



















Filipin staining

MRI













Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4




















Dystonia Y Y Y Y







Hypotonia N N N N



Myoclonus N N Y Y




Total score 116 97 111 132


Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4













Generalexamination


investigations









Molecular genetics

Neuropathology

1

2

3

4












Amalia C. Bruni Centro Regionale di Neurogenetica Lamezia ...6+A2 + A53 307155 306155 308155 309155...

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Transcript of Amalia C. Bruni Centro Regionale di Neurogenetica Lamezia ...6+A2 + A53 307155 306155 308155 309155...