1. Dystonia 101 (& 102) John Fang, M.D. September 19, 2011

2. Key Topics Types of Dystonia: – Primary vs. Secondary – Dopa-Responsive – Kinesigenic Genetic Dystonias Basic Management Strategies

3. Dystonia Vocabulary Blepharospasm Craniocervical (Meige) Oromandibular Focal Segmental Hemi- Generalized Geste Antagonist (Sensory Trick) Tardive ε-Sarcoglycan TorsinA Westphal variant Wilson’s disease

4. Generalized Dystonia

5. Secondary Dystonia Drug-induced (D 2 blockers, flecainide) Structural Psychogenic Toxic (Mn, CO, CS 2, Hymenoptera) Metabolic DRD - TH deficiency, sepiapterin, GCH-deficiency Lesch-Nyhan PKAN NBIA

6. Wilson’s Disease Excessive copper accumulation due to mutation of the ATP7B gene Low ceruloplasmin High urine copper, sometimes requiring penicillamine challenge Kayser-Fleischer Rings May affect liver, bone, behavior

8. Wilson’s Disease Treatment Acute treatments: – Penicillamine – Trientene – TTMB Long-term treatments: – Zn – low Cu diet – Liver transplant

9. Pseudo-Dystonia Atlanto-axial subluxation CN IV palsy Camptocormia (Bent spine) Pleurotonus (Pisa syndrome)

10. Degenerative Dystonias CBD – Alien-limb Lubag – aka DYT3 – x-linked – Philippines

11. Tyrosine Hydroxylase Deficiency TH converts Tyr to DOPA Tetrahydrobiopterin is cofactor – GTP cyclohydrolase (GCH) – 6-pyruvoyltetrahydropterin synthase (PTPS) – Sepiapterin reductase (SR) Tetrahydrobiopterin also affects metabolism of nitric oxide, serotonin, and phenylalanine Sapropterin is FDA approved for PKU

12. Treatment Options Anticholinergics Dopamine agonists or levodopa GABA agonists (A and B, also intrathecal) Other anticonvulsants VMAT inhibitor Botulinum toxins Surgical (Myectomy, SDR, DBS, thalamotomy)

13. Tetrabenazine Inhibits Vesicular Monoamine Transporter 2 Typical starting dose = 6.25mg bid Typical effective dose = 25mg bid Metabolism affected by CYP2D6 FDA approved for Huntington’s Chorea Also effective for tardive dyskinesia and some dystonias Sleepiness and depression are major SE’s

14. Botulinum Toxin Inhibits presynaptic Ach release by destroying SNARE proteins Dosing can be tricky FDA approved for cervical dystonia, blepharospasm, and a few other disorders Typical duration of action = 90-120 days Weakness is the major SE Four current formulations: 3 A and 1 B

15. Botulinum Toxin Formulations abobotulinumtoxinA (Dysport) incobotulinumtoxinA (Xeomin) onabotulinumtoxinA (Botox) rimabotulinumtoxinB (Myobloc)

16. Quiz: What is the diagnosis?

17. Final Points There are many types and causes for dystonia Do not miss: – DRD – Wilson’s disease – Pseudo-

18. The End