genetics of parkinsonian and dystonic syndromescss-mendel institute, rome university of salerno 2...

Genetics of parkinsonian and dystonic syndromes

Enza Maria Valente

CSS-Mendel Institute, RomeUniversity of Salerno

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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

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

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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)

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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

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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)

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Dystonic syndromes

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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



DYT9 (601042)/ DYT18 (612126)


AD




DYT9 (601042)/ DYT18 (612126)


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

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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

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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

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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)

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12 122 1 1 4124

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Dystonia panel – preliminary results

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5

74

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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?

genetics of parkinsonian and dystonic syndromescss-mendel institute, rome university of salerno 2...

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