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 tyrosine 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