The Pathogenesis of Dystonia: Past, Present and Future

The Pathogenesis of Dystonia: Past, Present and Future NIH Grant Disclosures U54 TR001456, R21 NS096445, R56 NS102980 Private Foundation Disclosures Benign Essential Blepharospasm Research Foundation Cure Dystonia Now Industry Disclosures Allergan, Ipsen, Medtronics, Merz, Retrophin, Saol H. A. (Buz) Jinnah, MD PhD Professor, Dept Neurology, Human Genetics & Pediatrics Emory University School of Medicine hjinnah@emory.edu

The Pathogenesis of Dystonia: Goals for this presentation Genetics Old and new genes Changes in gene nomenclature and classification Anatomy Traditional view centering on the basal ganglia The expanded motor network model Physiology Three traditional themes from human physiology Novel insights from animal models

Dystonia Genetics: The DYTz list Locus Disease Gene Inheritance Phenotype DYT1 Oppenheim s dystonia TOR1A AD isolated DYT2 Early-onset recessive dystonia HPCA AR isolated DYT3 X-linked dystonia-parkinsonism (Lubag) TAF1 X-R combined DYT4 Whispering dysphonia TUBB4 AD (isolated) DYT5 (14) DOPA-responsive dystonia GCH1, TH, SPR AD (AR) combined DYT6 Craniocervical dystonia of Amish/Mennonite THAP1 AD isolated DYT7 Familial torticollis unknown AD isolated DYT8 Paroxysmal nonkinesigenic dyskinesia MR1 AD combined DYT9 (18) GLUT1 deficiency syndromes SLC2A1 AD combined DYT10 Paroxysmal kinesigenic dyskinesia PRRT2 AD combined DYT11 Myoclonus-dystonia SCGE AD combined DYT12 Rapid-onset dystonia-parkinsonism ATP1A3 AD combined DYT13 Adolescent-onset multi-focal/segmental dystonia unknown AD isolated DYT15 Myoclonus-dystonia unknown AD combined DYT16 Early onset dystonia-parkinsonism PRKRA AD combined DYT17 Adolescent-onset unknown AR isolated DYT19 Paroxysmal kinesigenic dyskinesia 2 unknown AD combined DYT20 Paroxysmal non-kinesigenic dyskinesia 2 unknown AD combined DYT21 Adult onset generalized/multifocal unknown AD combined (DYT22) Reserved, not published unknown AD combined DYT23 Myoclonus dystonia CACNA1B AD isolated DYT24 Adult-onset tremulous cervical dystonia ANO3 AD isolated DYT25 Adult-onset cervical dystonia GNAL AD isolated DYT26 Myoclonic dystonia KCTD17 AD combined DYT27 Early-onset isolated dystonia COL6A3 AR isolated DYT28 Complex early-onset dystonia KMT2B AD combined

Some Problems With DYTz It is not really a classification system Many DYTz never confirmed DYT22 reserved but never published Several DYTz come from single families Some turned out to be wrong One DYTz does not signify one gene DYT9 and 18 are same gene (SLC2A1 or GLUT1) DYT5 is three genes (GCH1, TH, SPR) Some entries for DYTz are not dystonia DYT11 predominant phenotype is myoclonus, not dystonia DYT8, 10, 19, 20 are paroxysmal with mixed phenotypes List is not complete; many dystonias missing e.g. Wilson s disease several recently discovered genes (e.g. Mn transporters)

A Proposal to Fix DYTz Replace DYT number with gene name DYT1 becomes DYT-TOR1A DYT6 becomes DYT-THAP1 If dystonia is not the only phenotype, add relevant prefix DYT5 (dopa-responsive dystonia) becomes DYT/PARK-GCH1 HPRT1 (Lesch-Nyhan disease) becomes DYT/CHOR-HPRT

Clinical Genetics: Do We Need DYTz? Pattern of inheritance Autosomal recessive Autosomal dominant X-linked Mitochondrial AADC ATP7B CYP27A1 GCDH GCH1 MUT NPC1 or 2 PCCA or B SLC19A3 SLC39A14 SPR TH TTPA ANO3 ATP1A3 CIZ1 GLUT1 GNAL HTT PRRT2 SCA3 SLC2A1 TOR1A TUBB4 ARX HPRT MECP2 PLP1 TAF1 TIMM8a WDR45 MT-ATP6 MT-CO3 MT-ND1 MT-ND4 MT-TL1 MT-TK Jinnah and Hess, Park Rel Disord, 2017

Neuroscience: Do We Need DYTz? Biological Pathways Dopamine signaling Cation transporters Heavy metal accumulation Mitochondrial dysfunction AADC GCH1 GNAL HPRT Parkin Pink1 SPR TH VMAT ATP1A3 ANO3 CACNA1A CACNA1B HPCA KCTD17 ATP7B ATP13A2 COASY CP FA2H FTL PANK2 PLA2G6 SLC30A10 SLC39A14 WDR45 ADAR MT-ND1 MT-ND4 MT-ATP6 NDUFAF6 PLA2G6 POLG SUCLA2 TIMM8A Jinnah and Hess, Park Rel Disord, 2017

Genetics Nomenclature & DYTz : Summary and future directions The DYTz has become obsolete It has too many flaws New proposal is confusing and complex It is not particularly useful for clinicians or neuroscientists We should stop teaching it to students, residents and fellows (We should start calling it the ditzy list ) Use simpler strategies for classification of genes Classification based on inheritance is more useful in the clinic Classification by biological pathways is more useful for science

Anatomical Basis for Dystonia: Traditional view centered on the basal ganglia Downloaded from http://brain.oxfordjou

Anatomical Basis for Dystonia: A brief history of lesion studies Study Dystonia BG CTX THAL BS CRB Other Marsden, 1985 Hemi 45 1 7 0 0 IC=13 Pettigrew, 1985 Hemi 11 0 1 0 0 IC=1 Obeso, 1988 Mixed 68 8 16 1 6 NR LeDoux, 2003 Cervical 6 0 0 11 SC=6 Strader, 2011 Mixed 4 12 1 0 0 NR Khooshnoodi, 2013 Blepharo 9 1 12 11 9 MB=7 Liuzzi, 2016 Upper limb 17 4 39 4 1 SC=7 Jinnah et al, TOHM 2017

Anatomical Basis for Dystonia: The Motor Network Model 2011 2017

Anatomical Basis for Dystonia: The Motor Network Model Cerebellum DCN Thalamus Basal Ganglia Neostriatum Cerebellar cortex PN STN Hoshi et al, The Cerebellum Communicates with the Basal Ganglia, Nature Neurosci 2005 Cerebral cortex Bostan et al, The Basal Ganglia Communicate with the Cerebellum, PNAS 2010 Motoneurons

The Motor Network Model: Multiple anatomical pathways for dystonia A. Normal B. Nodes independently cause dystonia C. Communication D. Two-hit hypothesis normal movements dystonia dystonia dystonia dystonia

One brain region does not cause all types of dystonia Basal ganglia, cerebellum, thalamus Communication or network disturbances We need to be cautious about over-interpretation Results from one human dystonia may not generalize to all Results from one animal model may not generalize to all Consider exploiting this knowledge or novel therapies Anatomical Basis for Dystonia: Summary and future directions DBS of GPi works well for some dystonias, but not all Think about targeting other nodes in the network

Physiology of Dystonia: Three common themes from human studies Loss of inhibition Occurs at levels of the nervous system Documented for many types of dystonia Abnormal sensori-motor integration Abnormal sensory thresholds or processing Documented for many types of dystonia Abnormal neural plasticity Abnormal adaptive changes to various stimuli Documented for many types of dystonia

Human Physiology in Dystonia: Some unanswered questions Which one is most relevant? Are all themes equally relevant to all dystonias? Are these themes somehow related? Lack of specificity? Similar abnormalities in other disorders Similar abnormalities in psychogenic dystonia Cause or consequence? Do these abnormalities cause dystonia? Does dystonia cause these abnormalities?

Physiology of Dystonia: Animal studies focusing on basal ganglia

Physiology of Dystonia: Animal studies focusing on cerebellum Abnormal burst-firing of cerebellar Purkinje neurons in the DT rat model of dystonia; LeDoux & Lorden, Exp Brain Res, 2002

Physiology of Dystonia: Animal studies focusing on cerebellum

Many physiological abnormalities have been documented Human studies: inhibition, sensorimotor integration, plasticity Animal studies: abnormal neuronal activity in BG and CRB There is a need to dissect cause from consequence Human studies: cause or consequence? Animal studies: cause or consequence? Consider exploiting this knowledge for novel therapies Physiology of Dystonia: Summary and future directions Target abnormal striatal cholinergic neurons? Target abnormal cerebellar Purkinje neurons?

The Pathogenesis of Dystonia: Conclusions Dystonia is not one disorder, it is a group of disorders Genetic heterogeneity: multiple molecular pathways Anatomic heterogeneity: different brain regions in a motor network Physiologic heterogeneity: basal ganglia and/or cerebellum Implications of clinical and etiologic heterogeneity Avoid over-interpretation of data from one type of dystonia Understanding pathogenesis points to targets for novel therapies These targets will vary across different types of dystonia