Genetics of parkinsonian and dystonic syndromes

Transcription

1 Genetics of parkinsonian and dystonic syndromes Enza Maria Valente CSS-Mendel Institute, Rome University of Salerno

2 Genetic forms of Parkinson disease 2

3 polymorphisms (++ in autosomal dominant PD genes: RR Genetic factors in PD pathogenesis mutations in autosomal dominant PD genes: reduced penetrance (30%): RR sporadic familial late pure onset PD complicated PD (dementia, early onset dystonia, psychiatric etc) multifactorial mendelian Heterozygous mutations in autosomal recessive PD genes: RR heterozygous mutations in other recessive genes: RR 4-6 mutations in autosomal recessive PD genes: full penetrance: 100% 3

4 4

5 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 Parkin >>> PINK1 > DJ-1 50% fam 10-15% spor 1-8% in different populations < 1% treatment-related complications (dyskinesias, behavioral problems)

6 α-synuclein mutations and autosomal dominant PD Five mutations reported after screening of thousands PD cases 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 I:1 I:2 onset 27aa SNCA A53T mutation II:1 Onset 50 aa II:2 II:3 II:4 45aa 45aa 67aa + _ onset III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:14 III:15 50 aa 58 aa 57aa onset onset III:8-10 III: aa 26 aa IV:1 IV:2 IV:3 IV:4-5 IV:6 IV:7 IV:8 IV:9 IV:10 II:5 Psychiatric disease PD PD and psychiatric + SNCA mutation A53T SNCA mutation A53T Courtesy: M.C. Sensi, A. Fasano, L. Ricciardi

7 SNCA gene multiplications and PD phenotypes Multiplications of the genomic region containing the SNCA gene cause α-syn overexpression correlation between the number of SNCA copies and phenotypic severity Three SNCA copies Four SNCA copies Subjects 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

8 PARK8 - LRRK2 - Dardarin 2482 aminoacids, several active domains including a kinase domain 1-2% of sporadic PD G2019S mutation 5-8% of familial PD Founder effect among Ashkenazi Jews and North African Arabs other mutations are rare (about 10 different mutations reported) Phenotype of LRRK2 mutations: variable presentation, onset 3rd-8th decade reduced penetrance: 15-30%, increasing with age usually indistinguishable from idiopathic PD 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 premutation ( 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. FMR1 gray zone (49-54 rpts) parkinsonism and idiophatic PD (1-7,5%; 0-11%), gait ataxia. 9

10 Glucocerebrosidase and PD (++ non-motor signs) Glucocerebrosidase deficiency Gaucher s disease heterozygous GBA mutations represent the most common genetic risk factor for PD identified to date (4-8% PD vs <1% controls) Clinical picture of GB-related PD : ++ earlier onset, positive family history ++ non-motor features; + severe PD OR = 5.43 Sidransky et al, NEJM, 2009; Brockmann et al, Neurology 2011

11 Heterozygous GBA mutations and PD 20/113 (17,7%) 28/ 300 (9,3%) 16/123 (13%) 5/70 (7,1%) 606 probands analyzed 64 probands with single and 5 with biallelic GBA gene mutations (11,4%) 24 different mutations (21 known and 3 novel) 27/259 (10,4%) 29/231 (12,6%) 6/82 (7,3%) 33,3% 5,8% 7,2% 13% 23,2% 17,4% 5/24 2/10 Genotyping of the two common mutations identifies only about 40% of cases! 11

12 Dystonic syndromes 12

13 Monogenic dystonias Isolated dystonias Combined dystonias Persistent Paroxismal 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 exerciseinduced dystonia AD DYT10 (128200) PRRT2 16p11.2 Paroxysmal kinesigenic dyskinesia AD DYT19 (611031) - 16q13-q22.1 Paroxysmal kinesigenic dyskinesia 2 AD 13 DYT20 (611147) - 2q31 Paroxysmal non-kinesigenic dyskinesia 2 AD Lohmann and Klein, Mov Disord 2013

14 PTD: age of onset, family history and distribution de Carvalho Aguiar and Ozelius, 2002 early onset PTD generalised mainly familial late onset PTD focal / segmental mainly sporadic

15 the DYT1 gene (TOR1A) and typical phenotype 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 recurrent mutation: GAG del - founder mutation in Ashkenazi Jewish - also arisen de novo several times

16 DYT1 phenotypic variability 4 affecteds and 15/38 healthy carriers (penetrance 21%) - onset 22 writer s cramp focal - onset 10 writer s cramp other hand only - onset 43 retrocollis generalized (mild) - onset 43 shoulder generalized (severe)

17 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 oromandibular 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 - 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 ) - NO ocular telangiectasias - NO frank ataxia (but clumsy gait in childhood) - NO cerebellar atrophy 18 Saunders-Pullman, Neurology 2012 Charlesworth, Neurology 2013, Cummins, Parkins Relat Disord 2013

19 PTD: age of onset, family history and distribution de Carvalho Aguiar and Ozelius, 2002 late onset PTD focal / segmental mainly sporadic

20 Adult onset dystonia: the ANO3 gene DYT24 Ca 2+ -gated chloride channel highly expressed in the striatum. - 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 Charlesworth et al, AJHG 2012

21 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 Fuchs Nat Genet 2013; Vemula, HMG 2013, Kumar JAMA Neurol 2014; Dufke 2014

22 Whispering dyphonia: the DYT4 (TUBB4a) gene isoform a of beta-tubulin, necessary for the autoregulation of the mrna - Autosomal dominant, highly penetrant - Adult-late onset of laryngeal dysphonia progressing 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 Hershesonet al, Ann Neurol 2013; Hamilton Brain 2014; Vemula Neurology 2014

23 Overlapping phenotypes 23

24 Complicated parkinson-dystonia phenotypes abnormal ocular movements psychiatric & behavioral disturbances optic atrophy spasticity dystonia cognitive impairment, dementia NBIA: - PANK2 - PLA2G6 - WDR45 - C19orf12 - ATP13A2 - COASY iron deposition in the BG and SN cerebral and/or cerebellar atrophy parkinsonism Other conditions: - DRD - rapid onset D-P - PRKRA - Lubag

25 Indication of genetic testing 1: ensure dystonia is primary Charlesworth, Brain 2013

26 Indication of genetic testing 2: algorithm for primary dystonia Charlesworth, Brain 2013

27 The movement disorder Mendel The PD Mendel AD PD ± CI Pure AR EOP Atypical AR EOP Mitochondrial PD NBIA PARK1-4/SNCA PARK8/LRRK2 PARK17/VPS35 PARK18/EIF4G1 GBA* MAPT* PARK2/PRKN PARK6/PINK1 PARK7/DJ-1 PARK9/ATP13A2 PARK15/FBXO7 PARK19/DNAJC6 PARK20/SINJ1 POLG1 Twinkle PANK2 PARK14/PLA2G6 WDR45 FA2H C19orf12 COASY The Dystonia Mendel Isolated dystonia Paroxysmal dystonia Persistent combined dystonia DYT1/ TOR1A DYT6/ THAP1 DYT23/ CIZ1 DYT24/ ANO3 DYT25/ GNAL DYT8/ MR1 DYT9/ SLC2A1 DYT10/ PRRT2 DYT3/ TAF1 DYT4/TUBB4a DYT5/ GCH1 TH SPR DYT11/ SGCE DYT12/ ATP1A3 DYT16/ PRKRA TIMM8A ATM SLC6A3 (DAT1) 34 Isolated Dystonia (58) Paroxysmal Dystonia (4) Persistent combined Dystonia (11) 27

28 Dystonia panel preliminary results Damaging mutations: genotype-phenotype correlations Expected PRRT2 p.r217p fs*8 in a PKD pt THAP1 p.a39v in a generalized ID pt 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 The emerging riddle of not classified variants rare predicted to be damaging How to approach? 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+CD 28