Huntington’s DiseaseHuntington’s Disease

Disease Management: current and emerging treatment

Rebecca Meyerson

Issues in HD Influencing Issues in HD Influencing Disease ManagementDisease Management

Psychological impactSymptoms develop in mid lifeGenetic testing affects the entire familyDisease affects cognition, personality, and

psychiatric/ behavior, therefore may impair decision making

Three Domains of HDThree Domains of HD

Behavior/psychiatric featuresMovement abnormalitiesCognitive dysfunction

– 60% present with pure motor features– 15% present with pure behavioral illness– 25% present with both motor and behavioral

Symptomatic Therapies in HDSymptomatic 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

Symptomatic Therapies in HDSymptomatic Therapies in HD

Education for patient and familyMedicationsBehavioral modification techniquesCounseling for coping mechanismsModification of the home environment to

maintain safetyHome health care/respite care

Behavioral/Psychiatric Behavioral/Psychiatric Features of HDFeatures 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

Treatment optionsTreatment options

SSRI’s SSNRI’sTricyclic antidepressantsAntipsychotic’s (typical) and (atypicals)

– Olanzipine– Quitiapine– Clozapine

Movement disorder of HDMovement disorder of HD

Chorea movementsWeight loss due to persistent movementSwallowing difficultiesAspiration pneumonia due to dysphagiaGait impairment due to movementsFalls resulting in head trauma or subdural

hematoma

Treatment optionsTreatment 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

Cognitive Dysfunction in HDCognitive Dysfunction in HD

Variable degree of dementiaSafety in the homeDrivingActivities of daily living

Treatment options: nothing beneficial

Emerging Treatment for HDEmerging Treatment for HDunderstanding the underlying understanding the underlying

pathophysiologypathophysiology

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

Inhibit Huntingtin protein Inhibit Huntingtin protein aggregationaggregation

Small compounds effective in drosophila and HD mice

Transglutaminase and protease inhibitors– Minocycline – recently found to be non

effective

Gene therapyGene 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

Gene TherapyGene 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

NeuroprotectionNeuroprotection

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

Emerging Therapies for HDEmerging 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

Genetic Counseling in HDGenetic 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

Significance of genetic testingSignificance of genetic testing

Results determine the futureAffects the entire familyConfidentialityInsurance

Guidelines for Guidelines for Presymptomatic HD DNA Presymptomatic HD DNA

testingtestingAt risk individualsAt least 18 year oldCapable to make informed consentEncouraged to have trained support personTest affected relative for accurate diagnosisCounseling before and after testing

Genetic CounselingGenetic 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

Guidelines for confirmation of Guidelines for confirmation of suspected diagnosis of HDsuspected 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