Domina Petric, MD Huntington´s disease

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.

Katzung, Masters, Trevor. Basic and clinical pharmacology. 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.

Katzung, Masters, Trevor. Basic and clinical pharmacology. Huntington´s disease There may be increased responsiveness of postsynaptic dopamine receptors or deficiency of a neurotransmitter that normally antagonizes dopamine. Katzung, Masters, Trevor. Basic and clinical pharmacology.

Katzung, Masters, Trevor. Basic and clinical pharmacology. 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.

Katzung, Masters, Trevor. Basic and clinical pharmacology. 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.

Katzung, Masters, Trevor. Basic and clinical pharmacology. 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.

Katzung, Masters, Trevor. Basic and clinical pharmacology. 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.

Katzung, Masters, Trevor. Basic and clinical pharmacology. 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.

Katzung, Masters, Trevor. Basic and clinical pharmacology. 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.

Katzung, Masters, Trevor. Basic and clinical pharmacology. Other forms of chorea Katzung, Masters, Trevor. Basic and clinical pharmacology.

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.

Chorea-acanthocytosis syndrome Orolingual tics Vocalizations Cognitive changes Seizures Peripheral neuropathy Muscle atrophy Normal serum β-lipoproteins Katzung, Masters, Trevor. Basic and clinical pharmacology.

Katzung, Masters, Trevor. Basic and clinical pharmacology. 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.

Image source: http://philahomeopathy.com Chorea Image source: http://philahomeopathy.com Katzung, Masters, Trevor. Basic and clinical pharmacology.

Treatment: haloperidol, perphenazine or other dopamine-blocking drugs. Katzung, Masters, Trevor. Basic and clinical pharmacology. Ballismus Treatment: haloperidol, perphenazine or other dopamine-blocking drugs. MedFriendly.com