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Genetics of parkinsonian and dystonic syndromes
Enza Maria Valente
CSS-Mendel Institute, RomeUniversity of Salerno
2
Genetic forms of Parkinson disease
Genetic factors in PD pathogenesis
Heterozygous mutationsin autosomal recessive
PD genes: RR 1.5-2
heterozygous mutationsin other recessive
genes: RR 4-6
polymorphisms(++ in autosomal dominant
PD genes: RR 1.1-1.4
mutations in autosomal dominant PD genes: reduced penetrance (30%): RR 10-20
mutations in autosomalrecessive PD genes:
full penetrance: 100%3
late onset early onsetpure PD
complicated PD (dementia, dystonia, psychiatric etc)
sporadic familial
multifactorial mendelian
4
Autosomal recessive early onset «pure» parkinsonisms
Distinct genes, same phenotype
• early onset (<40 years) DJ1 < Parkin < PINK1
• slow progression
• excellent and sustained response to treatment
Variable phenotypic features, same gene
• dystonia at onset
• sleep benefit, diurnal fluctuations
• hyperreflexia
• treatment-related complications (dyskinesias, behavioral problems)
Parkin >>> PINK1 > DJ-150% fam
10-15% spor1-8% in different
populations< 1%
α-synuclein mutations and autosomal dominant PD
33
2
+
+
onset27aa
onset50 aa
† 45aa † 67aa
† 58 aa
Onset 50 aa† 45aa
onset30 aa
onset26 aa
I:1 I:2
II:1 II:2 II:3 II:4
III:1
II:5
III:2 III:3 III:4† 57aa
III:5 III:6 III:7 III:8-10
3
III:11-13III:14 III:15
IV:1 IV:2 IV:3 IV:4-5 IV:6 IV:7 IV:8 IV:9 IV:10
+_ _
+ +
+
PD
PD and psychiatric
Psychiatric disease
+ SNCA mutation A53T
– SNCA mutation A53T
SNCA A53T mutation
Courtesy: M.C. Sensi, A. Fasano, L. Ricciardi
SNCA mutations p.A53T p.A30P p.E46K p.H50Q p.G51D
onset 40s 60s 60s 60s 40s
parkinsonism ++, rapid progr. + + + ++, rapid progr.
cognitive impairment ++ + ++ ++ -
psychiatric involvement + - + - ++
autonomic disturbance + - - - -/+
L-Dopa response + + + + +/-
pyramidal signs - - - - ++
Five mutations reported after screening of thousands PD cases
_
SNCA gene multiplications and PD phenotypes
Three SNCA copies Four SNCA copies
Subjects 73 27
Asymptomatic carriers 20 0
Age at onset 50 ± 12 (30-77) 37 ± 10 (24-60)
Autonomic dysfunction 41% 100%
Psychiatric disturbances 61% 87%
Cognitive impairment 52% 96%
Elia et al, Mov Disord 2013
Multiplications of the genomic region containing the SNCA gene
cause α-syn overexpression
correlation between the number of SNCA copies and phenotypic severity
PARK8 - LRRK2 - Dardarin
2482 aminoacids, several active domains including a kinase domain
Phenotype of LRRK2 mutations:
• variable presentation, onset 3rd-8th decade
• reduced penetrance: 15-30%, increasing with age
• usually indistinguishable from idiopathic PD
G2019S mutation1-2% of sporadic PD
5-8% of familial PD
Founder effect among Ashkenazi Jews and North African Arabs
other mutations are rare (about 10 different mutations reported)
8
9
FMR1 expansions and PD
CGG expansions in the promoter region of X-Fragile mental retardation 1 gene (FMR1, >200 rpts) is the most frequent genetic cause of intellectual disability
in males
• FMR1 gray zone (49-54 rpts) → parkinsonism and idiophatic PD (1-7,5%; 0-11%), gait ataxia.
• FMR1 premutation (55-200 rpts) → progressive degenerative movement disorder with kinetic tremor, cerebellar gait ataxia, parkinsonism and cognitive decline (FXTAS) in males and females. MCP signs and/or cerebral atrophy on MRI; normal ß-CIT SPECT.
heterozygous GBA mutations represent the most common genetic risk factor for PD identified to date (4-8% PD vs <1% controls)
OR = 5.43
Clinical picture of GB-related PD :
• ++ earlier onset, positive family history
• ++ non-motor features; + severe PD
Sidransky et al, NEJM, 2009; Brockmann et al, Neurology 2011
Glucocerebrosidase and PD (++ non-motor signs)
Glucocerebrosidase deficiency Gaucher’s disease
11
Heterozygous GBA mutations and PD
• 606 probands analyzed• 64 probands with single and 5 with
biallelic GBA gene mutations (11,4%) 20/113 (17,7%)
28/ 300(9,3%)
16/123(13%)
5/70(7,1%)
27/259(10,4%) 29/231
(12,6%)
6/82(7,3%)
5/24 2/10
23,2%
17,4%
13%
33,3%
7,2%5,8%
Genotyping of the two common mutationsidentifies only about 40% of cases!
24 different mutations (21 known and 3 novel)
12
Dystonic syndromes
13
Disease (OMIM) Gene Locus Phenotype Trasmission
Isolated dystonias DYT1 (128100) TOR1A 9q34 Early onset generalized limb onset dystonia AD DYT2 (224500) - - Early onset generalized dystonia with prominent cranio-cervical involvment AR DYT4 (128101) - - Whispering dysphonia AD DYT6 (602629) THAP1 8p11.21 Generalized cervical and upper-limb-onset dystonia AD DYT7 (602124) - 18p Adult-onset cervical dystonia AD DYT13 (607671) - 1p36.32-p36.13 Cervical and upper-limb dystonia AD DYT17 (612406) - 20p11.2-q13.12 Segmental or generalized dystonia with prominent dysphonia AR DYT21 (614588) - 2q14.3-q21.3 Adult-onset generalised or multifocal dystonia, often starting with blepharospasm AD DYT23 (614860) CIZ1 9q13.4 Adult onset cervical dystonia AD DYT24 (615034) ANO3 11p14.2 Cranio-cervical dystonia with laryngeal and upper limb involvment AD DYT25 (615073) GNAL 18p11 Adult-onset cervical dystonia AD Combined, persistent dystonias DYT3 (314250) TAF1 Xq13.1 Dystonia-parkinsonism X-R DYT5 (218230) GCH1 14q22.2 Dopa-responsive dystonia AD DYT11 (159900) SGCE 7q21.3 Myoclonus dystonia AD DYT12 (128235) ATP1A3 19q13.2 Rapid-onset dystonia parkinsonism AD DYT15 (607488) - 18p11 Myoclonus-dystonia AD DYT16 (612067) PRKRA 2q31.2 Early-onset dystonia parkinsonism AR Combined, paroxysmal dystonias DYT8 (118800) MR1 2q35 Paroxysmal non kinesigenic dystonic choreoathetosis AD
DYT9 (601042)/ DYT18 (612126)
SLC2A1 1p34.2 Paroxysmal dyskinesias with episodic ataxia and spasticity/Paroxysmal exercise-induced dystonia
AD
DYT10 (128200) PRRT2 16p11.2 Paroxysmal kinesigenic dyskinesia AD DYT19 (611031) - 16q13-q22.1 Paroxysmal kinesigenic dyskinesia 2 AD DYT20 (611147) - 2q31 Paroxysmal non-kinesigenic dyskinesia 2 AD
Monogenic dystonias
Isolated dystonias Combined dystonias
Persistent Paroxismal
Lohmann and Klein, Mov Disord 2013
Disease (OMIM) Gene Locus Phenotype Trasmission
Isolated dystonias DYT1 (128100) TOR1A 9q34 Early onset generalized limb onset dystonia AD DYT2 (224500) - - Early onset generalized dystonia with prominent cranio-cervical involvment AR DYT4 (128101) - - Whispering dysphonia AD DYT6 (602629) THAP1 8p11.21 Generalized cervical and upper-limb-onset dystonia AD DYT7 (602124) - 18p Adult-onset cervical dystonia AD DYT13 (607671) - 1p36.32-p36.13 Cervical and upper-limb dystonia AD DYT17 (612406) - 20p11.2-q13.12 Segmental or generalized dystonia with prominent dysphonia AR DYT21 (614588) - 2q14.3-q21.3 Adult-onset generalised or multifocal dystonia, often starting with blepharospasm AD DYT23 (614860) CIZ1 9q13.4 Adult onset cervical dystonia AD DYT24 (615034) ANO3 11p14.2 Cranio-cervical dystonia with laryngeal and upper limb involvment AD DYT25 (615073) GNAL 18p11 Adult-onset cervical dystonia AD Combined, persistent dystonias DYT3 (314250) TAF1 Xq13.1 Dystonia-parkinsonism X-R DYT5 (218230) GCH1 14q22.2 Dopa-responsive dystonia AD DYT11 (159900) SGCE 7q21.3 Myoclonus dystonia AD DYT12 (128235) ATP1A3 19q13.2 Rapid-onset dystonia parkinsonism AD DYT15 (607488) - 18p11 Myoclonus-dystonia AD DYT16 (612067) PRKRA 2q31.2 Early-onset dystonia parkinsonism AR Combined, paroxysmal dystonias DYT8 (118800) MR1 2q35 Paroxysmal non kinesigenic dystonic choreoathetosis AD
DYT9 (601042)/ DYT18 (612126)
SLC2A1 1p34.2 Paroxysmal dyskinesias with episodic ataxia and spasticity/Paroxysmal exercise-induced dystonia
AD
DYT10 (128200) PRRT2 16p11.2 Paroxysmal kinesigenic dyskinesia AD DYT19 (611031) - 16q13-q22.1 Paroxysmal kinesigenic dyskinesia 2 AD DYT20 (611147) - 2q31 Paroxysmal non-kinesigenic dyskinesia 2 AD
Disease (OMIM) Gene Locus Phenotype Trasmission
Isolated dystonias DYT1 (128100) TOR1A 9q34 Early onset generalized limb onset dystonia AD DYT2 (224500) - - Early onset generalized dystonia with prominent cranio-cervical involvment AR DYT4 (128101) - - Whispering dysphonia AD DYT6 (602629) THAP1 8p11.21 Generalized cervical and upper-limb-onset dystonia AD DYT7 (602124) - 18p Adult-onset cervical dystonia AD DYT13 (607671) - 1p36.32-p36.13 Cervical and upper-limb dystonia AD DYT17 (612406) - 20p11.2-q13.12 Segmental or generalized dystonia with prominent dysphonia AR DYT21 (614588) - 2q14.3-q21.3 Adult-onset generalised or multifocal dystonia, often starting with blepharospasm AD DYT23 (614860) CIZ1 9q13.4 Adult onset cervical dystonia AD DYT24 (615034) ANO3 11p14.2 Cranio-cervical dystonia with laryngeal and upper limb involvment AD DYT25 (615073) GNAL 18p11 Adult-onset cervical dystonia AD Combined, persistent dystonias DYT3 (314250) TAF1 Xq13.1 Dystonia-parkinsonism X-R DYT5 (218230) GCH1 14q22.2 Dopa-responsive dystonia AD DYT11 (159900) SGCE 7q21.3 Myoclonus dystonia AD DYT12 (128235) ATP1A3 19q13.2 Rapid-onset dystonia parkinsonism AD DYT15 (607488) - 18p11 Myoclonus-dystonia AD DYT16 (612067) PRKRA 2q31.2 Early-onset dystonia parkinsonism AR Combined, paroxysmal dystonias DYT8 (118800) MR1 2q35 Paroxysmal non kinesigenic dystonic choreoathetosis AD
DYT9 (601042)/ DYT18 (612126)
SLC2A1 1p34.2 Paroxysmal dyskinesias with episodic ataxia and spasticity/Paroxysmal exercise-induced dystonia
AD
DYT10 (128200) PRRT2 16p11.2 Paroxysmal kinesigenic dyskinesia AD DYT19 (611031) - 16q13-q22.1 Paroxysmal kinesigenic dyskinesia 2 AD DYT20 (611147) - 2q31 Paroxysmal non-kinesigenic dyskinesia 2 AD
PTD: age of onset, family history and distribution
de Carvalho Aguiarand Ozelius, 2002
early onset PTD generalised
mainly familial
late onset PTDfocal / segmentalmainly sporadic
AD, 20-40% penetrance
early-onset (< 28 years), usually in a limb
frequent generalisation (in about 5 years)
sparing of cranial-cervical region
good response to DBS
the DYT1 gene (TOR1A) and typical phenotype
recurrent mutation: GAG del
- founder mutation in Ashkenazi Jewish
- also arisen de novo several times
4 affecteds and 15/38 healthy carriers(penetrance 21%)
- onset 43 retrocollis generalized (mild)
- onset 22 writer’s cramp focal
- onset 10 writer’s cramp other hand only
- onset 43 shoulder generalized (severe)
DYT1 phenotypic variability
the DYT6 gene (THAP1) and typical phenotype
AD, 20-40% penetrance
++ early-onset (1-2 decade)
generalisation in about 50%
frequent cranial-cervical involvement
++ speech involvement (laryngeal and oro-mandibular dystonia)
++ in familial cases with at least one early onset patient (up to 25%)
low frequency among sporadic patients (1-2%)
Fuchs et al, 2009; Bressman et al, 2009; Djarmati et al, 2009; Bonetti et al, 2009
18
DYT6-mimicking dystonia and ATM mutations
- NO ocular telangiectasias
- NO frank ataxia (butclumsy gait in childhood)
- NO cerebellar atrophy
Saunders-Pullman, Neurology 2012
- 12 patients (3 families) with primary early onset dystonia(mean 12 yrs), often generalized
- ++ cervical, cranial and brachial involvement (++ tongue, jaw, speech)
- associated myoclonus in two cases
- elevated AFP, (malignancy in about 50% of cases )
Charlesworth, Neurology 2013, Cummins, Parkins Relat Disord 2013
PTD: age of onset, family history and distribution
de Carvalho Aguiarand Ozelius, 2002
late onset PTDfocal / segmentalmainly sporadic
Adult onset dystonia: the ANO3 gene – DYT24
Charlesworth et al, AJHG 2012
- AD, incomplete penetrance
- Variable age at onset (first to fifth decade)
- cranio-cervical, laryngeal, upper limb dystonia and dystonic tremor
- 4 additional mutations in about 200 subjects tested
Ca2+-gated chloride channel highly expressed in the striatum.
Fuchs Nat Genet 2013; Vemula, HMG 2013, Kumar JAMA Neurol 2014; Dufke 2014
Adult onset dystonia: the GNAL gene – DYT25
- Adult onset (mean age 31,3 yrs range 7-54 y)
- cervical dystonia spreading to other muscles (cranial, laringeal or upper limb involvement)
Mutations identified in further 6/29 families (15%)
GTP-binding protein, ++ expressed in the brain
De novo mutations identified in several sporadic patients with
cervical dystonia importance of mutation screening
- Autosomal dominant, highly penetrant
- Adult-late onset of laryngeal dysphoniaprogressing to generalized dystonia
- characteristic facies and body habitus, peculiar “hobby horse” ataxic gait
- good response to alcohol and propranolol
- mutations not found in >500 dystonia pts
- allelic to hypomielinating encephalopathy with atrophy of basal ganglia and cerebellum
isoform a of beta-tubulin, necessary for the autoregulation of the mRNA
Hershesonet al, Ann Neurol 2013; Hamilton Brain 2014; Vemula Neurology 2014
Whispering dyphonia: the DYT4 (TUBB4a) gene
23
Overlapping phenotypes
Complicated parkinson-dystonia phenotypes
abnormal ocularmovements
psychiatric & behavioral
disturbances
opticatrophy
iron deposition in the BG and SN
cerebral and/or cerebellar atrophy
dystonia
spasticitycognitive
impairment,dementia
parkinsonism
NBIA:- PANK2- PLA2G6- WDR45- C19orf12- ATP13A2- COASY…
Other conditions:- DRD- rapid onset D-P- PRKRA- Lubag…
Indication of genetic testing – 1: ensure dystonia is primary
Charlesworth, Brain 2013
Indication of genetic testing – 2: algorithm for primary dystonia
Charlesworth, Brain 2013
27
The movement disorder panels @ Mendel
AD PD ± CI
• PARK1-4/SNCA• PARK8/LRRK2• PARK17/VPS35• PARK18/EIF4G1• GBA*• MAPT*
Mitochondrial PD
• POLG1• Twinkle
NBIA
• PANK2• PARK14/PLA2G6• WDR45• FA2H• C19orf12• COASY
The PD Panel @ Mendel
Atypical AR EOP
• PARK9/ATP13A2• PARK15/FBXO7• PARK19/DNAJC6• PARK20/SINJ1
Pure AR EOP
• PARK2/PRKN• PARK6/PINK1• PARK7/DJ-1
The Dystonia Panel @ Mendel
Isolated dystonia
• DYT1/ TOR1A• DYT6/ THAP1• DYT23/ CIZ1• DYT24/ ANO3• DYT25/ GNAL
Paroxysmal dystonia
• DYT8/ MR1• DYT9/ SLC2A1• DYT10/ PRRT2
Persistent combined dystonia
• DYT3/ TAF1• DYT4/TUBB4a• DYT5/ GCH1• TH
• SPR• DYT11/ SGCE• DYT12/ ATP1A3• DYT16/ PRKRA
• TIMM8A• ATM• SLC6A3 (DAT1)
IsolatedDystonia(58)
ParoxysmalDystonia(4)
PersistentcombinedDystonia(11)
34
12 122 1 1 4124
28
Dystonia panel – preliminary results
60
5
74
5
Damaging mutations: genotype-phenotype correlations
Unpredictable
‐ PRRT2 p.P215R in a dystonia-myoclonic pt‐ SLC2A1 p.R93W in a CD pt‐ SGCE p.T138I + TOR1A p.R288*in a CD pt
Expected
‐ PRRT2 p.R217P fs*8 in a PKD pt‐ THAP1 p.A39V in a generalized ID pt
The emerging riddle of not classified variants
• rare• predicted to be damaging
Gene Mutation Phenotype
CIZ1 p.R903Q BPS
CIZ1 p.R903Q BPS+OMD+CD
SGCE p.D433N CD
SGCE p.S432N CD+ head tremor
SGCE p.S432N BPS+OMD+CDHow to approach?