2. Huntington´s disease (HD)
It is an autosomal dominant inherited disorder
caused by an abnormality (expansion of a CAG
trinucleotide repeat that codes for a polyglutamine
tract) of the huntingtin gene on chromosome 4.
An autosomal recessive form may also occur.
Huntington disease-like (HDL) disorders are not
associated with an abnormal CAG trinucleotide repeat
number of the huntingtin gene.
Autosomal dominant loci: HDL1 20pter-p12, HDL2 16q24.3
Autosomal recessive forms: HDL3 4p15.3
Katzung, Masters, Trevor. Basic and clinical pharmacology.
3. Huntington´s disease
HD is characterized by progressive
chorea and dementia that usually begin
in adulthood.
The development of chorea seems to be
related to an imbalance of dopamine,
acetylcholine, GABA and perhaps other
neurotransmitters in the basal ganglia.
Chorea results from functional
overactivity in dopaminergic
nigrostriatal pathways.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
5. Huntington´s disease
Drugs that impair dopaminergic
neurotransmission, either by depleting central
monoamines (reserpine, tetrabenazine) or by
blocking dopamine receptors (phenothiazines,
butyrophenones), often alleviate chorea.
Dopamine-like drugs (levodopa) tend to exacerbate
chorea.
Both GABA and enzyme glutamic acid
decarboxylase are markedly reduced in the basal
ganglia of patients with HD.
GABA receptors are usually implicated in
inhibitory pathways.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
6. Huntington´s disease
There is also a significant
decline in concentration
of choline
acetyltransferase
(enzyme that synthesizes
acetylcholine) in the basal
ganglia of these patients.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
7. Pharmacotherapy
Reserpine depletes cerebral dopamine by
preventing intraneuronal storage.
It is introduced in low doses: 0,25 mg daily.
The daily dose is then built up gradually: by
0,25 mg every week.
A daily dose of 2-5 mg is often effective in
suppressing abnormal movements.
Adverse effects: hypotension, depression,
sedation, diarrhea, nasal congestion.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
8. Pharmacotherapy
Tetrabenazine (12,5-50 mg orally three
times daily) resembles reserpine in
depleting cerebral dopamine and has
less adverse effects.
Treatment with postsynaptic
dopamine receptor blockers
(phenothiazines, butyrophenones)
may be also helpful.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
9. Pharmacotherapy
Haloperidol is started in a small dose of
1 mg twice daily.
Dose is increased every 4 days
depending on the response.
If haloperidol is not helpful, treatment
with increasing doses of
perphenazine up to a total of about
20 mg daily sometimes helps.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
10. Pharmacotherapy
Olanzapine may also be useful.
10 mg daily of olanzapine is often
sufficient.
SSRIs (selective serotonin reuptake
inhibitors) may reduce depression,
aggression and agitation.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
11. OTHER FORMS OF CHOREA
Katzung, Masters, Trevor. Basic and clinical pharmacology.
12. Benign hereditary chorea
It is inherited (usually AD) or arises
spontaneously.
Chorea develops in early childhood and does not
progress during adult life.
Dementia does not occur.
In patients with TITF-1 gene mutations, thyroid and
pulmonary abnormalities may also be present:
BRAIN-THYROID-LUNG SYNDROME.
Familial chorea may also occur as part of the
chorea-acanthocytosis syndrome.
Treatment is symptomatic.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
14. Treatment
Treatment of underlying cause:
thyrotoxicosis, polycythemia vera rubra,
systemic lupus erythematosis,
hypocalcemia, hepatic cirrhosis.
Drug-induced chorea is managed by
withdrawal of the offending substance:
levodopa, antimuscarinic drug,
amphetamine, lithium, phenytoin, oral
contraceptive.
Neuroleptic drugs may also produce an
acute or tardive dyskinesia.
Katzung, Masters, Trevor. Basic and clinical pharmacology.
