1. Huntington’s Disease Disease Management: current and emerging treatment Rebecca Meyerson

2. Issues in HD Influencing Disease Management Psychological impact Symptoms develop in mid life Genetic testing affects the entire family Disease affects cognition, personality, and psychiatric/ behavior, therefore may impair decision making

3. Three Domains of HD Behavior/psychiatric features Movement abnormalities Cognitive dysfunction – 60% present with pure motor features – 15% present with pure behavioral illness – 25% present with both motor and behavioral

5. Symptomatic Therapies in HD Utilize an interdisciplinary approach – Primary care provider and neurologist – Psychiatrist/psychologist – Physical therapy/occupational therapy – Speech pathology – Home health nursing/ respite care aids

6. Symptomatic Therapies in HD Education for patient and family Medications Behavioral modification techniques Counseling for coping mechanisms Modification of the home environment to maintain safety Home health care/respite care

7. Behavioral/Psychiatric Features of HD Impulse control Depression – Risk suicide 17 times general population, 7.5% HD patients lives end in suicide Obsessive compulsive features Sleep dysfunction Anxiety/agitation Mania Psychosis Uninhibited behaviors

8. Treatment options SSRI’s SSNRI’s Tricyclic antidepressants Antipsychotic’s (typical) and (atypicals) – Olanzipine – Quitiapine – Clozapine

9. Movement disorder of HD Chorea movements Weight loss due to persistent movement Swallowing difficulties Aspiration pneumonia due to dysphagia Gait impairment due to movements Falls resulting in head trauma or subdural hematoma

11. Treatment options Dopaminergic blockage – Typical antipsychotics (Haloperidol) – Atypical antipsychotics (Clozapine) Dopamine depleting agents (reserpine, tetrabenazine) Benzodiazepines Antiglutamate (NMDA antagonist) – Riluzole – recent study decrease intensity of chorea without improving functional capacity – Remacemide – not effective – Coenzyme Q – not effective

12. Cognitive Dysfunction in HD Variable degree of dementia Safety in the home Driving Activities of daily living Treatment options: nothing beneficial

13. Emerging Treatment for HD understanding the underlying pathophysiology Toxic gain of function from the mutated huntingtin protein – Misfolding and aggregation (form neuronal inclusions) – Abnormal protein interaction – Dysregulation of transcription – Interfere axonal transport and synaptic transmission Mitochondrial dysfunction Excitotoxicity Oxygen free radicals/oxidative stress Microglial activation Accelerated apoptosis

14. Inhibit Huntingtin protein aggregation Small compounds effective in drosophila and HD mice Transglutaminase and protease inhibitors – Minocycline – recently found to be non effective

15. Gene therapy Intracellular antibodies: – express fragments of the antibodies intracellularly to bind to an intracellular target – The intracellular target is specific for the first 17 AA of the Huntingtin protein – blocks aggregation

16. Gene Therapy RNA interference: – Virus vector to introduce an RNA fragment into the cell nucleus – RNA fragment is complementary to the mutant gene for huntingtin – Blocks translation of the mutant gene

17. Neuroprotection Blocking the final common pathway (excitotoxicity, oxidative stress, mitochondrial dysfunction) – Coenzyme Q10: antioxidant, cofactor involved in mitochondrial electron transfer – Remacemide: NMDA receptor antagonist = block excitotoxicity – Minocycline: protease inhibitor, antiapoptotic, antioxidant, anti excitotoxic – Creatine: nutritional supplement which appears to have neuroprotective effect

18. Emerging Therapies for HD Porcine striatal transplantation: no efficacy Fetal cell transplant – intrastriatal transplantation of human striatal neuroblasts: minimal efficacy – 2 HD patients in 1995, and several other small studies – Implanted into the caudate nucleus with striata from 12- 13 week human fetus – Observed for 16-33 months, recent 6 year f/u report – Progression of disease slower in relation to their preoperative state, others no effect – Postmortem showed surviving transplanted cells with typical morphology 18 months after transplant

19. Genetic Counseling in HD Presymptomatic testing – the individual is at risk but has not yet shown symptoms. Labs will not test without genetic counseling Symptomatic testing – the individual displays symptoms of HD, the test is to confirm diagnosis

20. Significance of genetic testing Results determine the future Affects the entire family Confidentiality Insurance

21. Guidelines for Presymptomatic HD DNA testing At risk individuals At least 18 year old Capable to make informed consent Encouraged to have trained support person Test affected relative for accurate diagnosis Counseling before and after testing

22. Genetic Counseling Why the individual wants the test Does the individual understand the significance of the the test Have family members been involved in the decision? What will the individual do with the information – if positive, if negative Is the individual psychologically capable of understanding and coping with this information

23. Guidelines for confirmation of suspected diagnosis of HD Recommended to Not disclose the number of CAG repeats Genetic and psychological counseling recommended, but not mandated as in the presymptomatic cases