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