Isabelle Le Ber
Reference centre on rare dementias& Brain and spine institute-ICM
CNRS UMR7225, INSERM UMR_S1127, UPMC U75, Paris
Parkinsonism-dementia genetics
C9orf72, GRN and MAPT - clinical and genetic aspects
http://icm-institute.org/
Disclosures
Scientific board of Prevail therapeutics
1995 2000 2005 2010 2015
FTLD
gen
es
MAPTVCP
CHMP2B
GRN
DCTN1 TARDBP
ANGFUSOPTN
C9orf72SQSTM1
CSF1R
PFN1
MATR3
UBQLN2
CHCHD10
TBK1
CCNF
TREM2
2020
Sanger sequencing Next generation sequencing
GRN 25%
C9orf7225%
MAPT15%
Others15%
Unknown 20%
Genetics of frontotemporal lobar degeneration an increasing complexity
Holler et al., 2017
Genetics of frontotemporal lobar degeneration Pathomechanisms of FTD mutations - GRN
Nonsense,
Frameshift
Deletions
Sellami et al., 2020
Progranulin haploinsuficiency
Cut-off value 71
Genetics of frontotemporal lobar degeneration Pathomechanisms of FTD mutations – C9orf72
Ling, Polimenidou & Cleveland, 2013
Pathogenic >30 G4C2
4100 5 6 1110 144a 87
12
139 122 317q21
Genetics of frontotemporal lobar degeneration Pathomechanisms of FTD mutations – MAPT
0N3R
1N3R
2N3R
0N4R
2N4R
1N4R
4 or 3 MTBD
E10
TAU
Microtubule
3 microtubule domains (3R, exon 10-) 4 four microtubule domains (4R, exon 10+)
Missense mutations in exons 9, 11-12 Reduce MT assembly (3&4R in N)
Exon 10 and intronic mutations Ex 10 splicing - ↗ 4R/3R ratio (4R in N&G)
• PNFA• SD • bvFTD• FTD-Parkinsonism
• Behavioural variant FTD (bvFTD) / bvFTD-Parkinsonism
• Semantic variant of Primary Progressive aphasia (svPPA)
• Non-fluent variant of PPA (nvfPPA/PNFA)
Behavior
Language
Clinical spectrum of frontotemporal lobar degeneration :
FTLD
• PNFA• SD • bvFTD• FTD-Parkinsonism
• Behavioural variant FTD (bvFTD) / bvFTD-Parkinsonism
• Semantic variant of Primary Progressive aphasia (svPPA)
• Non-fluent variant of PPA (nvfPPA/PNFA)
• FTD associated with Amyotrophic Lateral Sclerosis (FTD-ALS)
• Corticobasal syndrome (CBS)
• Progressive supranuclear palsy syndrome (PSPS)
Behavior
Language
Parkinsonism
ALS
Clinical spectrum of frontotemporal lobar degeneration : At the intersection of ALS and parkinsonism
ParkinsonismFTLDALS
• FTD/ALS• ALS • PSP (4R)• CBS (4R)• FTD/MAPT
• PNFA• SD • bvFTD• FTD-Parkinsonism • PSP (4R)
• CBS (4R)• FTD/MAPT
Clinical spectrum of frontotemporal lobar degeneration : At the intersection of ALS and parkinsonism
ParkinsonismFTLDALS
TDP-43
TAU
• FTD/ALS• ALS
• bvFTD & PNFA: variably TDP-43 or TAU • PSP : TAU, CBS TAU >> TDP-43• SD : TDP43 (type C)• FTD-ALS & ALS : TDP-43
3403 GRN, MAPT and C9orf72 mutation carriers
Clinical genetic correlations Moore et al., Lancet Neurol, 2020
Clinical genetic correlationsMoore et al., Lancet Neurol, 2020
GRN associated phenotypes: bvFTD ~ 40% >> PPA ~ 13% >> CBS 4%
• ALS, FTD/ALS & PSP : rare
MAPT associated phenotypes : bvFTD ~ 45% >> PSP/CBS ~ 6% > PPA ~ 4%
Clinical genetic correlationsMoore et al., Lancet Neurol, 2020
• Epilepsy, psych. Disord.
•FTD/ALS, ALS rare
Clinical genetic correlationsMoore et al., Lancet Neurol, 2020
C9orf72 phenotypes: bvFTD ~ 30%, ALS ~ 20%, FTD/ALS ~ 11%
• SD, PNFA, CBS, PSP: possible but rare
(1-2% each)
Clinical genetic correlationsMoore et al., Lancet Neurol, 2020
C9orf72 phenotypes: bvFTD ~ 30%, ALS ~ 20%, FTD/ALS ~ 11%
Psychiatric dis. ~ 10-20% Prodromal (jaleousy, paranoia delusions); Late-onset schizophrenia
• SD, PNFA, CBS, PSP: possible but rare
(1-2% each)
FTD gene mutations and parkinsonian disorders ?
• Parkinsonism associated to FTD ?
• Atypical parkinsonian disorders : PSP & CBS >>> LBD, MSA
• Do FTD genes directly contribute to/mimick PD phenotype ?
FTD gene mutations and parkinsonian disorders ?
.
Characteristics of FTD-parkinsonism
• All genetic forms of FTLD : GRN (40-60%), MAPT (20-40%) > c9orf72 (10-35%) > others
• During the disease course, within the 2 first years of FTD
• Patients with bvFTD or FTD/ALS (rarely associated with PPA or ALS)
• Typically moderate akinetic-rigid, without resting tremor
• C9orf72: Postural and action tremor, not at rest (Boeve et al., 2012)
• Limb > axial, symetric or not
• Unresponsive or temporary dopa-responsive (rarely sustained during disease course)
• Datscan -Reduced uptake
GRNControl c9orf72MAPT
Characteristics of FTD-parkinsonism
Atypical parkinsonian disorders and FTD gene mutations
• PSP: MAPT >>>> C9orf72, other genes
• CBS: GRN >> MAPT >>>> other genes
A dichotomization
PSP associated with MAPT mutations
39 patients with PSP carrying MAPT mutations
PSP associated with MAPT mutations
Features predicting MAPT mutations in PSP
PSP criteria* PSP
Autopsy confirmed
(n=100)
MAPT carriers
(n=39)
AA onset, ys 65.2 43.9
Inheritance Sporadic 90% AD
Falls, < 1 year 94-100% 25%
Cognitive/frontal dis., < 2 ys 50% 98%
Levodopa responsivness Limited/absent Limited/absent
DaTSCAN Reduced uptake Reduced uptake
*Litvan et al., 1996; Morris et al., 2003; Resondek et al. 2014; Fujioka et al., 2015; Siuda et al., 2015
Best predictors of MAPT mutation…
1. Early AAO
2. Family history (bvFTD, PSP, CBS)
3. Absence of early falls
4. Early frontal dysfunction/dementia
CBS associated with GRN mutations35 cases described in the litterature
Phenotype similar to sporadic CBS, rapidly progressive
• Asymetric akinetic-rigid syndrome
• Parietal symptoms, limb/orobuccal apraxia, cortical sensory deficit
(alien limb is rare)
• Myoclonus, dystonic postures
• Frontal behavioural/cognitive dysfunction
± Language and visuopatial deficits
• DatScan: abnormal
Rademakers et al., 2008; Le Ber et al., 2008; Pickering-Brown et al., 2008; Seelaar et al., 2008; Tartaglia et al., 2010; Picillo et al., 2020
CBS associated with GRN mutations
Whitwell et al., 2007
35 cases described in the litterature
Phenotype similar to sporadic CBS, rapidly progressive
• Asymetric akinetic-rigid syndrome
• Parietal symptoms, limb/orobuccal apraxia, cortical sensory deficit
(alien limb is rare)
• Myoclonus, dystonic postures
• Frontal behavioural/cognitive dysfunction
± Language and visuopatial deficits
• DatScan: abnormal
Evocative features
• Brain MRI : marked asymetry, frontal to parietal regions,
WM HS
• Family history combining bvFTD, PPA, CBS (90%)
• Progranulin plasma level decreased GRN CBS
Cut-off value 71
FTD genes and IPD phenotype ?
Possible…..
Frequency early cognitive disordersFamily history of FTD & ALS
Early AAO
FTD genes and IPD phenotype ?
C9orf72: lower limb, favorable dopa responsiveness, dyskinesias
Moore et al., Lancet Neurol, 2020
… but rare !
FTD genes and IPD phenotype ?
Puschmann et al. 2013
Recommandations for testing FTD genes in parkisnonian disorders
• Parkinsonism associated with FTD: all genes
• Parkinsonism associated with ALS and/or FTD : C9orf72
• PSP: MAPT >>> C9orf72
• CBS: GRN (plasma) >>> MAPT
• PD phenotype: according to family history (FTD/ALS) & AAO
When and what to test ?
• Symptomatic individuals (expert centres, consents)
• NGS and gene panels allow for multiple genes of different diseasespectrum (FTD, PD) to be tested at the same time (except C9orf72)
• Sometimes pathogenicity of variants is difficult to establish (VUS)
• Delicate interpretation when variants of unknwon pathogencity arefound in association with unexpected phenotype
• Some people may carry two mutations
When and what to test ?
Thanks for your attention
