Genetic disorder inherited in an autosomal dominant (AD) manner due
to expansion of the cytosine-adenine-guanine (CAG) trinucleotide
repeats in the huntingtin (HTT) gene (or HD or IT15 gene) and is
located on chromosome 4.
The
number of repeats with in the genes correlates with the age of
onset; meaning expanded repeats at earlier age of onset would occur
in greater numbers when compared with later age onset disease.
- Children of an affected parent with Huntington's disease have
~50% risk of developing the condition
- Abnormal expansion of the CAG triplet repeat within the HTT
gene results in abnormal processing of the corresponding Huntingtin
protein, which gradually leads to neuronal damage within the basal
ganglia
- Large CAG expansions produce more widespread injury in the
neurons
Diagnosis is assisted by:
➣ Clinical presentation
➣ Positive family history
➣ Genetic testing for CAG expansion in huntingtin gene
Imaging:
Genetic testing:
- Targeted mutation analysis:
- PCR-based methods detect alleles up to about 115 CAG
repeats
- Southern blot analysis:
- Identification of large expansions which may fail to amplify
well by PCR analysis associated with juvenile-onset HD
- Confirmation of apparent homozygous genotypes obtained by PCR
analysis
Interpretation of genetic testing for CAG
repeats

Genetic counseling:
All
patients or family members should be offered genetic counseling,
but not all patients may want or need genetic testing.
Issues to be addressed are as follows:
Inheritance pattern:
- Each child of an affected individual has a 50% chance of
inheriting the abnormal huntingtin gene
- Inheriting a normal huntingtin gene from the unaffected parent
does not prevent or counteract the disease-causing effects of the
abnormal gene
- Greater expansion with paternal inheritance
Absent family history of HD:
- ~2-5% of all cases develop HD without knowing that they were at
risk
- parent carrying a gene did not live long enough to manifest the
symptoms)
- Non-paternity
Usefulness of genetic testing:
- Diagnostic or confirmatory testing - (if the
clinical suspicion is strong then it is the only diagnostic test
needed)
- Predictive or presymptomatic testing**
(recommended in an individuals with no symptoms, but wishes to know
if he carries the expanded gene). Current implications are that no
cure or treatment to slow down disease progression currently
exists
** May pose potential psychosocial risks and hence often
requires different clinical approach with appropriate
counseling.
- Prenatal testing: Prenatal testing for HD is
possible, and should be performed in conjunction with detailed
genetic counseling
To
date, HD is a universally a fatal disease. Several studies have
investigated potential neuroprotective therapies and many are still
ongoing. However, none of the trials have shown any proven
benefit.
Treatment for HD is largely symptomatic and highly individualized
to help control physical and mental deficits.
Treatment strategies vary over time and from individual to
individual, even within a family.
Always consider non-pharmacological interventions first.
TREATMENT STRATEGY:
- Non-pharmacological
- Pharmacological
Non-pharmacological therapy:
Can be used to assist physical disabilities and mental conditions
and includes:
- Physiotherapy: Improve/maintain posture,
strength, coordination, balance, gait
- Occupational therapy: Assess for safety and
need for assistive devices. Improve ambulation, avoid falls, and
improve nutrition (eating)
- Speech therapy: Improve/maintain speech and
swallowing
- Dietitian: To ensure adequate nutrition
- Psychological therapy: Counsel patient and
family members; assist in coping with skills
- Social work support: Help family prepare for
deteriorating clinical course
- Assist with arrangements for (full time) supervision as
required
- Suggest and assist with identification of alternate living
arrangements (assisted living, nursing home) if required
Pharmacological therapy:
To
date, the only FDA recommended drug for use in HD is tetrabenazine
to treat chorea. There is currently a lack of evidence-based
medicine recommendations due to few class I, randomized controlled
trials (RCTs) of agents for any of the symptoms and thus no
treatment guidelines exist.
The
current choice of agents for any of the motor, psychiatric and
cognitive symptoms relies on expert opinion, physicians' personal
choice and knowledge of an agent balanced against potential
side-effect profile.
For
convenience; therapy is documented according to symptoms during the
disease course.
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Medications for physical symptoms:
Chorea: A prominent movement disorder of HD which
changes overtime, eventually peaks and then begins to decline.
Treatment is initiated when chorea begins to interfere with
voluntary activities like writing, cooking, eating or causes injury
due to fall or accidents. It is worsened by stress, anxiety,
depression and lack of sleep. Not all patients require treatment
and the need has to be balanced against side-effects.
(a) Monoamine depleting agents:
- Tetrabenazine: 25 mg/day PO daily; may increase to TID
(b) Dopamine D2 antagonists:
May treat both chorea and some psychiatric symptoms.
Typical antipsychotics:
- Haloperidol: Start at low dose 0.5-1 mg PO 1
or 2 divided doses, with gradual increase
- Fluphenazine: Start at low dose 0.5-1 mg PO 1
or 2 divided doses, with gradual increase
- Thiothixene hydrochloride: Start with1-2
mg/day PO in 1 or 2 divided doses
- Thioridazine: 10 mg/day PO in 1 or 2 divided
doses
Atypical antipsychotics:
- Risperidone: 0.5-1 mg/day PO in 1 or 2 divided
doses
- Olanzapine: 2.5-5 mg/day PO daily
- Aripiprazole: 10-15 mg/day PO daily
- Quetiapine: 25-50 mg/day PO daily
(c) Amantadine - may be helpful for mild
chorea
(d) Benzodiazepines - see below
Dystonia, rigidity, Parkinsonism and
spasticity:
With
disease progression the clinical phenotype changes from
hyperkinetic to hypokinetic. Thus dystonia may become more evident
with more sustained muscle contractions. Rigidity and parkinsonism
is also evident with advanced disease. In Juvenile onset (due to
the larger number of CAG repeats); this hypokinetic phenotype is
often the presenting feature with parkinsonism, plus spasticity and
cerebellar ataxia.
(a) Benzodiazepines:
- Clonazepam:
- Dose in chorea: 0.5-5 mg/day PO
- Dose in spasticity and stiffness: 10 mg/day PO
increasing up to 60 mg/day in divided doses
- Diazepam:
- For Chorea: 1.25 mg/day in divided doses up to
10 g /day
- Lorazepam: 1-6 mg PO daily in divided
doses
(b) Antispasmodic:
- Baclofen: 10-60 mg PO daily in divided
doses
(c) Alpha 2-adrenergic agonist:
- Tizanidine: 2 mg PO daily, increasing every
weekly up to 12-24 mg,for spasticity with or without baclofen
(d) Antiparkinson drugs:
May also be used (cautiously) to relieve spasticity, rigidity,
dystonia and includes
- Levodopa/carbidopa: 100/25 mg two to three
times per day
(e) Botox: For focal dystonia
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Medications for psychiatric and cognitive
symptoms:
Depression:
(a) Tricyclic antidepressants (TCA):
- Nortriptyline: 10-25 mg PO daily, up to 150-200 mg daily
(b) Selective serotonin reuptake inhibitors
(SSRI):
- Fluoxetine: 10-20 mg PO daily up to 60-80
mg
- Sertraline: 25-50 mg PO daily, up to the max
of 200 mg
- Paroxetine: 10-20 mg PO daily, up to 40-60
mg
(c) Selective norepinephrine reuptake
inhibitors
(SNRI):
- Venlafaxine: Start 25-37.5 mg PO; may increase
up to 225 mg/day in divided doses or once daily (XR)
(d) Others:
- Buproprion: 100-200 mg PO daily in divide
doses, max dose 300-450 mg
Dementia:
No specific treatment. Cholinesterase inhibitors (donepezil,
rivastigmine and galantamine) have been tried, but no proven
benefit.
Violent outbursts/agitation:
(a) Benzodiazepines:
Short acting drugs such as lorazepam may be another good choice,
for the short-term management of agitation
- Lorazepam: 1-2 mg/day PO at bedtime or 2-3
times a day
(b) Neuroleptics/antipsychotics (as above)
Mood stabilizers/mania:
- Valproic acid: 125-250 mg PO BID; increase
dose gradually to effective level or reach a serum concentration of
50-120 mcg/mL or in SI units (400-700 Umol/L); Max. 500-2000 mg PO
BID
- Carbamazepine: 100-200 mg PO daily increase
gradually by 100 mg/day as tolerated to ~1200-1600 mg/day in 2-3
divided doses
- Lithium (particularly if features of bipolar):
Start 900-2100 mg (15-20 mg/kg/day) in 3 divided doses - adjust
dose to target levels range from 0.8-1.2 mmol/L, as needed and
tolerated
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MEDICATIONS:
Antipsychotic agent, Typical
- ➣ Fluphenazine
- ➣ Haloperidol
- ➣ Thiothixene
Potential Mechanism(s):
- Blocks postsynaptic dopaminergic receptors in the brain
- Depresses the release of hypothalamic and hypophyseal
hormones
- Also have weak anticholinergic activity and antiemetic
effect
Doses:
Fluphenazine
Psychosis:
- Start 0.5-2.5 mg PO and increase to 2.5-10 mg/day in divided
dose at 6-8 hrs interval; usual maintenance dose 1-5 mg once daily;
Max. 20-30 mg/day
Chorea:
- Start 0.5-1 mg/day PO; Max. 6-8 mg/day
Haloperidol
Psychosis:
- Start 0.5-2.5 mg PO and increase to 0.5-5 mg PO BID-TID;
maximum usual dose: 20-30 mg/day
Chorea:
- Start 0.5-1 mg/day PO; Max. 6-8 mg/day
Thioridazine
Psychosis:
- 10 mg/day PO in 1 or 2 divided doses
Chorea:
- Start 10 mg/day PO in divided doses; max dose 100 mg/day
Thiothixene
Mild-to-moderate psychosis:
- Start: 5 mg PO BID, increase gradually up to 20-30 mg/day as
required: Max 60 mg/day
Rapid tranquilization of the agitated patient
(administered every 30-60 minutes):
- 5-10 mg PO; average total dose for tranquilization: 15-30
mg
Chorea: 1-2 mg/day PO; max dose upto 10-20
mg/day
Antipsychotic agent, Atypical
- ➣ Aripiprazole
- ➣ Olanzapine
- ➣ Risperidone
- ➣ Quetiapine
Potential Mechanism(s):
- Exact mechanism(s) of action is unknown
- Potent antagonist of serotonin 5-HT2a, dopamine
D2, receptors
- Potentially blocks dopamine transmission and treat chorea and
psychiatric symptoms
Doses:
Aripiprazole
Psychosis:
- 10-15 mg PO once daily; if needed, may increase dose gradually
to maximum of 30 mg PO once daily at minimum of 2 weeks of
interval
Olanzapine
Psychosis:
- 2.5-5 mg PO once daily and increase as tolerated 10 mg PO once
daily within 5-7 days as required; may increase by 5 mg/day at
weekly intervals. Usual maintenance dose 10-20 mg once daily; Max.
15-20 mg/day
- Usual dose in elderly is 1.25-7.5 mg
Risperidone
Psychosis/chorea:
- May begin with 0.5-1 mg PO once or twice daily. Increase
gradually by 1-2 mg/day on a weekly basis to target dose of 4-8 6
mg/day
- For psychosis may increase as tolerated to max. dose of 4-6
mg/day
Quetiapine
Psychosis:
- Start 25 mg PO BID; followed by increments of 25-50 mg daily
divided over 2-3 doses, as tolerated to a target dose of 300-400
mg/day in 2-3 divided doses within 4 days (if needed). May increase
further by 25-50 mg divided BID every 2-3 days if required; usual
maintenance range: 300-800 mg/day
- Hepatic impairment: Initialy 25 mg/day,
increase dose by 25-50 mg/day to effective dose, based on clinical
response and tolerability to patient
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Monoamine depleting agent
Mechanism:
- Reversibly inhibits uptake of monoamine neurotransmitters in
presynaptic vesicles
- Inhibits presynaptic dopamine release and also blocks CNS
dopamine receptors
- Also depletes monoamine stores from nerve terminals
Doses:
Tetrabenazine
Hyperkinetic movement disorders:
- Start 12.5 mg PO BID or TID; may be increased by 12.5 mg/day
every 3-5 days slowly to maximal tolerated and effective dose, if
needed; usual maximum tolerated single dose 25 mg PO in poor
metabolizers
- Daily dosage >100 mg/day are not recommended
- However, some have reported that doses up to 200 mg/day have
been used on rare occasions
Benzodiazepines
- ➣ Clonazepam
- ➣ Diazepam
- ➣ Lorazepam
Mechanism:
- Benzodiazepines bind to the gamma sub-unit of the GABA receptor
and enhance the inhibitory effect of GABA
- Increase the frequency of channel opening events, leads to
- Increase in chloride ion conductance and inhibition of the
action potential
- All benzodiazepines exert five major effects: (i) Anxiolytic
(ii) Hypnotic (iii) Muscle relaxant (iv) Anticonvulsant (v) Amnesia
(transient loss of memory)
Doses:
Clonazepam
Chorea:
- Start 0.5 mg/day PO; may increase to 4 mg/day in divided doses
as tolerated
Spasticity/ rigidity:
- 10 mg/day PO; may increase up to 60 mg/day as needed and
tolerated
Diazepam
Chorea:
- 1.25 mg/day in divided doses up to 20 mg/day in divided
doses
Lorazepam
Chorea:
- 1-6 mg PO daily in divided doses
Violent outbursts/ agitation:
- 1-2 mg/day PO at bedtime or 2-3 times a day
Antispasmodics
Mechanism:
Complete mechanism of action unknown.
Baclofen
- It inhibits both monosynaptic and polysynaptic spinal reflexes,
possibly by hyperpolarization of afferent terminals (resultant
relief of muscle spasticity)
Tizanidine
- It is chemically-related to clonidine and other
α2-adrenergic agonists, which acts as a centrally acting
muscle relaxant with anti-hypertensive properties
- Presumably it reduces spasticity by increasing presynaptic
inhibition of motor neurons
Dose:
Baclofen
Spasticity/ rigidity:
- 10 mg/day PO; may increase up to 60 mg/day as needed and
tolerated
Tizanidine
- 2 mg PO daily at bed time, may increase weekly up to maximum of
12-24 mg/day in divided dose, ( used with or without baclofen)
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Dopaminergic agents
Mechanism:
- Act on dopamine receptors in striatum to modulate basal ganglia
function
- Carbidopa and B benserazide inhibit peripheral
breakdown of Levodopa (L-Dopa) by inhibiting decarboxylation,
thereby increasing availability of L-Dopa to cross the blood brain
barrier (BBB)
- Within the basal ganglia L-Dopa is then converted to
dopamine
Dose:
Levodopa/ carbidopa
- 25/100 mg PO two to three times per day
Glutamate antagonist
Mechanism:
Possibly enhances dopamine action by:
- Blocking the reuptake of dopamine into presynaptic neurons
- Increase dopamine release from presynaptic fibers
- Reduces levodopa-induced dyskinesia by antagonism of NMDA
glutamate receptors
Dose:
Tricyclic antidepressants (TCAs)
Use: Depression
Mechanism:
- Inhibits the presynaptic reuptake of neurotransmitters →
increases synaptic serotonin and/or norepinephrine → potentiates
its effect
- Also has significant anticholinergic properties
Dose:
Nortriptyline
- 10-25 mg PO daily; may increase gradually to 150-200 mg if
needed
Selective serotonin reuptake
inhibitors
- ➣ Fluoxetine
- ➣ Paroxetine
- ➣ Sertraline
Use: Depression
Mechanism:
- Inhibits the presynaptic reuptake of neurotransmitters, in turn
increases synaptic serotonin concentration and potentiates its
effect
- Little effect on the reuptake of norepinephrine or
dopamine
- Does not significantly bind to alpha-adrenergic, histamine, or
cholinergic receptors
Dose:
Fluoxetine
- Start 10 mg PO; may increase to 20 mg after at least 1 week;
Max. 60-80 mg
Paroxetine
- 10 mg PO; may increase to 20 mg after at least 1 week, if well
tolerated; Max. 40-60 mg
Sertraline
- 25-50 mg PO; may increase to 50-100 mg after at least 1 week;
Max. 200 mg
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Serotonin/Norepinephrine reuptake inhibitor
(SNRI)
- ➣ Venlafaxine
- ➣ Duloxetine
- ➣ Nefazodone
Mechanism:
Exact mechanism of action is unknown.
- A potent serotonin and norepinephrine reuptake inhibitor
- Weakly inhibits dopamine reuptake
- Duloxetine has similar affinity to NE and 5-HT receptors (Ki
ratio 9) whereas venlafaxine has a relatively higher binding
affinity to norepinephrine
Dose:
Venlafaxine
- Start 25-37.5 mg PO; may increase up to 225 mg/day
Duloxetine
- Start 30 mg PO daily; may increase 30 mg/week up to 120
mg/day
Nefazodone
Antidepressant, Dopamine reuptake
inhibitor
Mechanism:
Exact mechanism of action is unknown.
- Binds selectively to the dopamine transporter, but its
behavioural effects have often been attributed to its inhibition of
norepinephrine reuptake
- Often acts as nicotinic acetylcholine receptor antagonist
Dose:
Bupropion
- 100-200 mg PO daily in divide doses, max. dose 300-450 mg
Mood stabilizers/Antimanic
- ➣ Valproic acid
- ➣ Carbamazepine
- ➣ Lithium (particularly if features
of bipolar)
Mechanism:
Carbamazepine
- Blocks voltage-gated sodium channels and may potentiate GABA
receptors; decreases synaptic transmission within CNS
Valproic acid (valproate)
- Blocks voltage-gated sodium channels and T-type calcium
channels. Also affects GABA resulting in decreased synaptic
transmission within CNS
Lithium
- Alters sodium transport in nerve and muscle cells and Inhibit
the intracellular formation of cyclic AMP; enhances serotonin
transmission by reducing the activity of post-synaptic serotonin or
5-HT receptors
Use: Acute manias/ mood stabilizers
Dose:
Carbamazepine
- Start 100-200 mg/day; increase dose gradually by 100 mg/day as
tolerated to an effective level or therapeutic level of 5-12
mcg/ml; Max. 1200-1600 mg/day
Valproic acid (valproate)
- Start 125-250 mg PO BID; increase dose gradually to effective
level or reach a blood level of 50-150 mcg/ml; Max. 1000-2000 mg PO
divided BID or TID
Lithium
- Start 900-2100 mg (15-20 mg/kg/day) in 3 divided doses - adjust
dose to target levels range from 0.8-1.2 mmol/L, as needed and
tolerated
- For maintenance therapy, adjust the dose to maintain serum
lithium concentrations between 0.6 and 1 mmol/L; once the patient
is stabilized than change maintenance dosage to once daily
regimen
Renal impairment:
- CrCl 10-50 mL/minute: Administer 50% to 75% of normal dose
- CrCl <10 mL/minute: Administer 25% to 50% of normal
dose