Phenomenology and classification of dystonia: A consensus update. Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, Hallett M, Jankovic J, Jinnah HA, Klein C, Lang AE, Mink JW, Teller JK. Update on Dystonia, Mov Disord 2013;28:863-73

• Dystonia is defined as a movement disorder characterized Chorea, and Tics by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Joseph Jankovic, MD • Dystonic movements are typically patterned and twisting. Professor of Neurology, Distinguished Chair in Movement Disorders, • Dystonia is often initiated or worsened by voluntary action Director, Parkinson's Disease Center and Movement Disorders Clinic, and associated with overflow muscle activation. Department of Neurology, Baylor College of Medicine, Houston, Texas • Some forms of dystonia, such as blepharospasm and laryngeal dystonia, are not associated with postures, but are characterized by focal involuntary contractions that interfere with physiological opening or closing of the eyelids or the larynx. • Dystonia is classified along two axes: 1. Clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features) 2. Etiology, which includes nervous system pathology and inheritance.

The prevalence of primary dystonia: A systematic review and meta‐analysis Steeves et al. Mov Disord 2012;27:1789-96

Genetic Classification of Dystonias Genetic Classification of Dystonias Primary Dystonias Dystonia Plus Syndromes Classifica Chromosome tion Pattern of Distribution, Origin Classifica Chromosome Gene mutation inheritance Onset additional features tion Gene mutation Pattern of Distribution, Origin Gene product Comment inheritance Onset additional features Gene product Comment 9q34, GAG deletion, Penetrance: Xq Filipinos (Lubag) DYT1 TOR1A/TorsinA AD C Distal limbs, generalized DYT3 XR A Parkinsonism mosaic striatal 30% AJ, 70% NJ TAF1 gliosis 19p13.3-p13.2 Whispering dysphonia, DYT2 NM AR Spanish gypsies, DYT4 AD C,A cranial, cervical, limb, facial Australian Iranian Jews TUBB4 (β-tubulin 4a) atrophy, ptosis, edentulous 8q21-22 German-American 14q22.1 AD DYT6 AD A, C Cervical, cranial, brachial DYT5a Gait disorder, parkinsonism, Dopa-responsive THAP1 Mennonite-Amish GCH1/GTP C myoclonus, spasticity dystonia, diurnal fluctuation Cervical, cranial, spasmodic cyclohydrolase I DYT7 18p AD A dysphonia, hand tremor German 11p15.5 Dopa-responsive DYT5b C Gait disorder, parkinsonism, dystonia, diurnal Cranial-cervical and hydroxylase AR myoclonus, spasticity fluctuation DYT13 1p36.13-32 AD A, C upper limb Italian 7q21-31 DYT11 SGCE AD C Myoclonus, behavioral and Alcohol-responsive Cervical dystonia, dysphonia, psychiatric problems DYT17 20p11.22-q13.12 AR C segmental, generalized Lebanese ε-sarcoglycan 19q12-13.2 Cranial, upper limbs, DYT12 ATP1A3 AD A, C parkinsonism, depression, Rapid-onset, DYT21 2q14.3-q21.3 AD A Late-onset Sweden Na/K-ATPase α3 seizures triggered by stress subunit DYT23 9q34.11,CIZ1 AD A Cervical Caucasians DYT15 18p11 AD C Myoclonus Canadian Cranial-cervical-laryngeal, DYT24 3, ANO3 AD A tremor, myoclonus European 2q31.2 PRKRA DYT25 18p, GNAL AD A Cervical>cranial>arm European protein kinase, Dystonia, axial, DYT16 interferon-inducible AR C oromandibular, laryngeal, Brazilian, German double-stranded parkinsonism A = adult onset; AJ = Ashkenazi Jewish; AD = autosomal dominant; AR = autosomal RNA-dependent recessive; C = childhood onset; NJ = Non-Jewish; NM = not mapped yet activator

1 Paroxysmal Dyskinesias The genetics of dystonia: new twists in an old tale. PKD PNKD PED Charlesworth et al. Brain 2013;136:2017-37 DYT10/19 DYT8/20 DYT9/18 • In the past few years, with the advent of new sequencing 16p11.2-q12.1 (IC) 2q33-35 (PNKD) 16p12-q12 (ICCA) technologies, there has been a step change in the pace of proline-rich 10q22 1p35-p31 discovery in the field of dystonia genetics. transmembrane protein (α-subunit of a Ca- glucose transporter 2 gene (PRRT2) sensitive K channel, type 1 (GLUT1) • In just over a year, four new genes have been shown to Infantile convulsions, KCNMA1) (SLC2A1) cause primary dystonia (CIZ1, ANO3, TUBB4A and GNAL) migraine, episodic • PRRT2 has been identified as the cause of paroxysmal ataxia Clonazepam Anticonvulsants, levodopa, BoNT kinesigenic dystonia Anticonvulsants • Other genes, such as SLC30A10 and ATP1A3, have been linked to more complicated forms of dystonia or new phenotypes.

A workable strategy for identifying the likely genetic basis Genetics and Pathophysiology of Neurodegeneration with for some of the major forms of dystonia Brain Iron Accumulation (NBIA) Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP. Curr Neuropharmacol 2013;11:59-79

Condition (Acronym) Synonym Gene Chromosomal position PKAN NBIA1 PANK2 20p13

PLAN NBIA2, PARK14 PLA2G6 22q12 FAHN SPG35 FA2H 16q23 MPAN -- C19orf12 19q12 Kufor-Rakeb disease PARK9 ATP13A2 1p36 Aceruloplasminemia -- CP 3q23

Neuroferritinopathy -- FTL 19q13 BPAN (SENDA) -- n.k. n.k.

Idiopathic late-onset -- Probably Probably Charlesworth et al. Brain 2013;136:2017-37 cases heterogene heterogeneous ous

Distinguishing features in different types of NBIA. T2* and FSE MRI distinguishes four subtypes of aCP = aceruloplasminemia; BPAN = beta-propeller protein-associated neurodegeneration; neurodegeneration with brain iron accumulation. FAHN = fatty acid hydroxylase-associated neurodegeneration; INAD = infantile neuroaxonal McNeill et al. Neurology 2008;70:1614-9 dystrophy; KRD = Kufor-Rakeb disease; MPAN = mitochondrial membrane protein-associated neurodegeneration; PKAN = pantothenate kinase associated neurodegeneration; WSS = T2* MRI Scan Woodhouse-Sakati syndrome.

PKAN Infantile 17 y/o Neuroaxonal Dystrophy 9 y/o

Neuro- Acerulo- ferritinopathy plasminemia 69 y/o 55 y/o

Horvath. Brain 2013;136:1687-91

2 T2* and FSE MRI distinguishes four subtypes of Dystonia Physical and Occupational Therapy neurodegeneration with brain iron accumulation. McNeill et al. Neurology 2008;70:1614-9 Constraint Fast Spin Echo (FSE) Induced Therapy, rTMS

Oral Medications Other Modalities PKAN Infantile 17 y/o Neuroaxonal Dystrophy Levodopa Chemodenervation Surgical Therapies 9 y/o

Anticholinergics Botulinum Botulinum Peripheral Central Toxin A Toxin B Surgeries Surgeries

Tetrabenazine Selective Myectomy Pallidotomy Neuro- Peripheral Acerulo- Benzodiazepines Denervation ferritinopathy plasminemia 69 y/o Deep Brain Stimulation 55 y/o (Globus Pallidus) Baclofen Oral, IT Jankovic J. Lancet Neurol 2009;8:844-56

Huntington Disease

Movement Disorders

Mov Disord 2013;28:1001-12

Behavioral Cognitive Symptoms Decline

First Symptoms of Huntington Disease Progression of Huntington Disease % of observed Symptom # of Pts. * symptoms ** Chorea 877 28 Trouble walking 262 9 *Number of Unsteadiness/imbalance 260 8 patients from a Difficult to get along with 167 5 total of 1,901 with Depression 165 5 initial symptom Clumsiness 154 5 information. Speech difficulty 149 5 Memory loss 93 3 Trouble holding an object 62 2 **Percent of all Lack of motivation 53 2 observed Suspicions/paranoia 48 2 symptoms from a Intellectual decline 44 1 total of 3,086. Changes in sleep 30 1 Patients could Hallucinations 23 1 report up to three Weight loss 20 0.6 initial symptoms. Sexual problems 7 0.2 Other mental 363 12 Other physical 297 10 Foroud et al. JNNP 1999;66:52-56 Ross and Tabrizi. Lancet Neurol 2011;10:83-98

3 Age-dependent Progression of HD Huntington Disease

Adult onset Juvenile onset

Juvenile/adolescent onset Age at onset 35 – 55 < 15 Early onset Inheritance AD AD (from the father) Mid-life onset Initial features Chorea, personality Personality changes, Disease changes rigidity, bradykinesia, progression Late onset dystonia Clinical onset Late features Dementia, dysarthria, Dementia, dysarthria, abnormal eye abnormal eye movements, tremor, movements, dystonia, seizures, ataxia, rigidity myoclonus

Duration 15 – 30 years 5 – 15 years 0 CAG Repeats 37 – 50 >50 Birth 10 20 30 40 50 60 70 Age

Atrophy: Putamen > Caudate

Normal HD HD Normal Harris et al. Ann Neurol 1992;31:69-75

Pathology of Huntington Disease Huntingtin Gene Htt (IT15) – 4p16.3 GPi Medium-Sized (CAG)n GABA GPe Spiny Neuron Enkephalin GABA n 2 Substance P STRIATUM 70 > ~70 - juvenile onset HD 1 Ach, Somatostatin Projecting neurons 3 Interneurons (spared) 40  40 CAG repeats – “inevitable” HD GABA 1 36 Tachykinin 36-39 CAG repeats - “reduced penetrance” GABA 27 27-35 CAG repeats - “intermediate” Tachykinin  26 CAG repeats – “normal allele” ~210 Kb SNc SNr tel cen

1 2 exon 67 • <40% loss of neurons in SN Encodes a 348 kD, 3,144 AA protein, “huntingtin“, Htt • Neuronal intranuclear inclusions formed by In HD the polyglutamine segment near the NH2 is elongated aggregation of the N-terminal huntingtin fragments

4 Genetic Diagnostic Testing Autopsy-Proven Huntington Disease with 29 Trinucleotide Repeats Kenney C, Powell S, Jankovic J. Mov Disord 2007;22:127-30

• 65 y/o man with a 5-year history of cognitive decline, chorea, inability to sustain tongue protrusion, gait and balance problems, MMSE 27/30 • 29/20 CAG repeats • Additional studies were normal including CK, anti-cardiolipin Ab, ESR, thyroid function, blood smear for acanthocytes, and DNA analysis for dentatorubral-pallido-luysian atrophy • Patient died after a fall during which he suffered SAH • Autopsy: acute SAH in the right Sylvian fissure; thinning of the cortical ribbon, moderate gliosis and neuronal loss in the caudate and putamen, ubiquitin-positive neuronal intranuclear inclusions in the cortical and other areas

• Patient’s father, who died at age 79, had cognitive decline and involuntary movements. No other FHx of neurologic disorders • The patient’s “asymptomatic”, 38 y/o, son has 32/19 CAG repeats

Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS. Killoran A, Biglan KM, Jankovic J, Eberly S, Kayson E, Oakes D, Young AB, Shoulson I. Neurology 2013;80:2022-7

• The Prospective Huntington At Risk Observational Study (PHAROS) enrolled adults at risk for HD, assessed every 9 months with the Mov Disord 2012;27:1714-7 UHDRS by investigators unaware of participants' gene status. • 50 (5.1%) of the 983 participants had an intermediate allele (IA) (27-35 CAG repeats). • The IA subjects were significantly worse on apathy and suicidal ideation and on 5 of the 9 other behavioral items and on total behavior scores than controls and expanded participants. • CONCLUSIONS: In a cohort at risk for HD, the IA was associated with significant behavioral abnormalities but normal motor and cognition. This behavioral phenotype may represent a prodromal stage of HD, with the potential for subsequent clinical manifestations, or be part of a distinct phenotype conferred by pathology independent of the CAG expansion length.

A Randomized, Double-Blind, Placebo-Controlled Mean Change in UHDRS Total Maximal Chorea Score Trial of Tetrabenazine as Antichorea Therapy in (Primary Study Endpoint: From Baseline to Week 12) Huntington’s Disease (TETRA-HD) TETRA-HD

• N = 84 HD subjects randomized, 16 centers Mean score decline (UHDRS units): 5.0 (TBZ) vs 1.5 (placebo) (p < 0.0001) 1 • Tetrabenazine (n = 54) or placebo (n = 30) 0 • Dosage increased over 7 weeks up to 8 tablets (100 mg) N = 84 -1 (TBZ = 54, placebo = 30)

daily, until the desired antichoreic effect or intolerable side effects occurred -2 Tetrabenazine

• During the last 5 weeks of the study, the dosage remained Chorea -3 Placebo constant (unless reduced because of intolerable adverse effects) -4 • Primary outcome: change from baseline in UHDRS -5 chorea score -6 -2 0 2 4 6 8 10 12 14 16 • Secondary outcomes: CGI, the UHDRS total motor score, Week functional scales, gait score, tolerability, and safety ANCOVA=analysis of covariance; ITT-LOC=intent-to-treat analysis. There was blinded washout of study drug at week 12. Change favors tetrabenazine (P=0.0001; ANCOVA, ITT-LOC). Chorea Scale range: 0 to 28 Huntington Study Group. Mov Disord 2006;11:136-142 Huntington Study Group. Mov Disord 2006;11:136-142

5 Expert Opinion on Orphan Drugs 2013

• Tetrabenazine (TBZ) is a centrally-acting, depleting drug that has been used for treatment of hyperkinetic movement disorders but was not commercially available in the United States until 2008, when the Food and Drug Administration (FDA) approved TBZ for the management of chorea associated with Huntington’s disease (HD) under an orphan drug designation. • While sedation, insomnia, mood changes, parkinsonism, and restlessness may occur, these adverse effects can be managed effectively with appropriate titration and monitoring. A black box warning against depression and suicidality warrants careful patient selection, close monitoring and judicious use of antidepressants. • TBZ possesses a unique mechanism of action as a presynaptic dopamine depletor that offers possible advantages over blocking drugs. • TBZ has a strong potential for application in other hyperkinetic movement disorders, particularly tardive dyskinesia and Tourette syndrome, but randomized, controlled clinical trials are lacking.

Experimental Therapeutics • Pridopidine (ACR16; Huntexil, “ stabilizer”) (MermaiHD and HART trials) • Ethyl-EPA (Miraxion) • Latrepirdine (Dimebon) (DIMOND and HORIZON trials) • Creatine, CoQ10, Lithium • Selististat (sirtuin deacetylase), • Histone deacetylase inhibitors (HDACi 4b) • Phosphodiesterase PDE10A inhibitors (TP-10) • PBT2 • Ganglioside GM1 • Rhes inhibitors • Neurturin • Anti-htt Ab (intrabody) • Small interfering (si) RNA • Antisense oligonucleotides • Cell replacement (fetal cells, embryonic stem cells or Jankovic J. Treatment of hyperkinetic Jankovic J. Treatment of hyperkinetic induced pluripotent cells) movement disorders. movement disorders. Lancet Neurol 2009;8:844-56 Lancet Neurol 2009;8:844-56

N Engl J Med 2012;367:1753-4 Phenocopies of HD

• HDL1 – AD, seizures (prion protein, PRNP; 20p12) • HDL2 – AD, no seizures (junctophilin, JPH3; 16q24.3) • HDL3 – AR (4p16.3) • DRPLA – AD (c-Jun NH-terminal kinase, JNK, 12p) • Neuroacanthocytosis – AR (VPS13A, 9q21) • McLeod syndrome – X-linked (HK, Xp21) • Mitochondrial encephalomyopathies • Benign hereditary chorea (NKX2-1/TITF-1, 14q13.1-q21.1) • Ataxia-Chorea: • SCA1(ataxin-1, CAG expansion, 6p23) • SCA2 (ataxin-2, CAG expansion, 12q24.1) • SCA17 (TATA-Box binding protein, CAG expansion, 6q27) • Friedreich’s ataxia (frataxin, GAA expansion, 9p13) • Ataxia telangiectasia (protein kinase PI-3, ATM gene, 11q22) • Neurodegeneration with brain iron accumulation (NBIA) • Psychogenic chorea

6 Tics Tic Characteristics • Simple or complex movements (motor) or sounds (phonic) • Jerk-like (clonic), dystonic, tonic, or blocking • Premonitory feelings or sensations TS • Intermittent ADHD PLUS OCD • Repetitive (stereotypic) • Temporary suppressibility • Suggestibility • Increase with stress Behavioral problems • Increase during relaxation after stress poor impulse control, self-injurious behavior, • Decrease with distraction and with concentration and other behavioral problems • Waxing and waning, transient remissions Jankovic. Tourette's Syndrome. N Engl J Med 2001;345:1184-92 • Persist during sleep

Malignant Tourette Syndrome Malignant Tourette Syndrome Cheung MC, Shahed J, Jankovic J. Mov Disord 2007;22:1743-50 Cheung MC, Shahed J, Jankovic J. Mov Disord 2007;22:1743-50

• Malignant TS defined as ≥ 2 emergency room visits or ≥ 1 hospitalizations for TS symptoms or its associated In one patient with a “whiplash” tic behavioral co-morbidities causing compressive cervical myelopathy, we were able to reverse • Of 332 TS patients evaluated during the three-year period, the neurological deficit with botulinum 17 (5.1%) met criteria for malignant TS toxin injections into the cervical • Compared to patients with non-malignant TS, those with muscles. This treatment modality can malignant TS were significantly more likely to have a be particularly effective and even life- personal history of obsessive compulsive saving in patients with tics manifested behavior/disorder, complex phonic tics, coprolalia, by severe, repetitive, neck extension. Such tics, if left untreated could results copropraxia, self-injurious behavior, mood disorder, in secondary compressive myelopathy suicidal ideation, and poor response to medications and quadraparesis.

Krauss JK, Jankovic J. Severe motor tics causing cervical myelopathy in Tourette’s syndrome. Mov Disord 1996;11:563-6

Age When Tic and OCD Symptoms Are at Their Worst Tic and OCD Severity at Initial Assessment in Childhood (time 1) and Follow-up in Early Adulthood (time 2)

1/3 → remission  IQ →  OCD

46 children with TS (N = 19)

Structured interview at a mean age of 11.4 years and again at 19.0 years (N = 46)

Tic Severity (N = 46) measured by the Yale Global Tic Severity Scale (YGTSS), OCD (N = 19) by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Bloch et al. Arch Pediatr Adolesc Med 2006;160:65-9 Bloch et al. Arch Pediatr Adolesc Med 2006;160:65-9

7 Widespread abnormality of the GABA-ergic system Tourette Syndrome in Adults in Tourette syndrome. Jankovic J, Gelineau-Kattner R, Davidson A. Mov Disord 2010;25:2171-5 Lerner et al. Brain 2012;135:1926-36

• We reviewed medical records of all new TS patients, ≥ 19 y/o on initial evaluation, referred to our Movement Disorders Clinic over the past 5 years, and compared them with 100 TS patients ≤18 y/o • The mean age of 43 adult TS patients was 58.8 ± 6.7 years; the mean age at initial visit of children with TS was 12.9 ±2.0 years • Of the adult TS patients, 35 (81.4%) had a history of tics with onset Decreased binding of [11C]flumazenil: bilateral ventral striatum (VS), bilateral thalamus (Th), right insula (Ins) and bilateral amygdala (Amg) before age 18 (mean age at onset 8.5 ± 3.4 years); 8 (18.6%) reported first occurrence of tics after age 18 (mean age at onset 37.8 ± 13.2 years); only 2 (4.7%) patients reported tic onset after age 50 • Conclusion: Adult TS largely represents re-emergence or exacerbation of childhood-onset TS. During the course of TS, phonic and complex motor tics, self-injurious behaviors, and ADHD tend to improve, but facial, neck and trunk tics dominate the adult 11 TS phenotype. Increased binding of [ C]flumazenil: bilateral SN, left periaqueductal grey (PAG), right posterior cingulate cortex (PCC) (Cing) and bilateral cerebellum, dentate nuclei (CB).

The bereitschaftspotential TOURETTE SYNDROME in jerky movement disorders. Therapeutic Strategies van der Salm et al. J Neurol Neurosurg Psychiatry 2012;83:1162-7

TICS OCD ADHD

6/14 TS patients had a BP prior to tics, two of which were late BPs First Line First Line First Line Cognitive Behavioral Guanfacine Behavioral Therapy Therapy Tetrabenazine Guanfacine SSRI’s

Second Line Second Line , Second Line Clonidine Atypical Clonazepam Atypical Antipsychotics Topiramate Other CNS stimulants BotulinumToxin Atomoxetine Habit Reversal

Third Line Third Line Deep Brain Stimulation Deep Brain Stimulation Jankovic, Kurlan. Mov Disord 2011;26:1149-56

Deep Brain Stimulation for TS – Target Selection Viswanathan A, Jimenez-Shahed J, Baizabal-Carvallo F. Jankovic J. Bilateral GPi DBS in TS Stereotact Funct Neurosurg 2012;90:213-24 Baylor College of Medicine

8 Parkinson’s Disease Center and Movement Disorders Clinic

www.jankovic.org

THANKS

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