A. Characteristics

1. Rare autosomal dominant disease with high penetrance
2. Occurs in ~6 per 100,000 white persons, typically >age 35 years
3. Rate is ~0.5 per 100,000 in Japan and most other Asian nations
4. Low overall rate in African populations as well
5. Mutations in Huntingtin gene on chromosome 4p16.3 responsible for disease
6. These mutations lead to inexorable degeneration of the basal ganglia
7. Genetic testing is now available but there are no effective therapies to date
8. Death typically within 15-20 years of diagnosis

B. Symptoms

1. Progressively worsening choreiform movements
   1. Chorea = rapid, distal, jerk-like non-rhythmic movements
   2. Athetosis = slow writhing, snake-like twisting movements; facial grimaces
   3. Early neurologic deficits ± cannot perform rapid finger movements
2. Common Behavioral Difficulties in HD (>50%) [1]
   1. Apathy or lack of initiative
   2. Dysphoria
   3. Irritability
   4. Agitation or anxiety
   5. Poor self-care
   6. Poor judgement
   7. Inflexibility
3. Frequent Behavioral Symptoms (20-50%) [1]
   1. Depression (high incidence of suicide)
   2. Disinhibition
   3. Euphoria
   4. Aggression
4. Delusions or compulsions are uncommon
5. Dementia - worsening mental status
6. Differential Diagnosis of Choreoathetotic Movement Disorders
   1. Thyrotoxicosis
   2. Post-hemiplegic athetosis
   3. Senile Chorea
   4. Sydenham's Chorea
   5. Lesch-Nyhan Syndrome (children)

C. Pathology
[Figure] "Corpus Striatum"

1. Large ventricles
2. Atrophy of gyri, widening of sulci
3. Shrunken Caudate and Putamen (Striatum)
4. Neuronal Destruction
   1. Enkephalin - neurons
   2. Substance P - neurons
   3. GABA
   4. Acetylcholine (mild decrease)
5. Dopaminergic neurons are spared

D. Pathophysiology [3,4]

1. Inherited Neurodegenerative Disease
   1. Expansion of CAG trinucleotide repeats in huntingtin protein
   2. Normally, huntingtin has <34 CAG repeats (range 11-34)
   3. Incomplete penetrance of disease occurs with 35-40 repeats
   4. In symptomatic Huntington's chorea, there are >40 CAG repeats in huntingtin gene
   5. CAG codes for polyglutamine
   6. Polyglutamine tract of excess size leads to aggregation of mutant proteins
   7. These aggregants lead to protobrifbrils, fibrils, aggregation foci, and visible aggregates
   8. Visible aggregates lead to cellular dysfunction, apoptosis of neurons, eventual symptoms
   9. Thus, Huntington's due to is a toxic gain-of-function mutation
2. Huntingtin Protein
   1. Function is unknown, but widely expressed and required in embryogenesis
   2. Found at higher levels in brain and testes, lower levels in heart, liver and lungs
   3. Abnormal protein accumulation and degradation due to elongated polyglutamine stretches
   4. Abnormal huntingtin protein is not metabolized properly by the proteasome
   5. Huntingtin, ubiquitin, and other proteins are abnormally transported to the nucleus in HD
   6. In addition, abnormal oxidative phosphorylation has been found
3. Neurons destined to die develop intranunclear inclusions [3]
   1. Intranuclear inclusions in HD believed to result from abberrant protein breakdown
   2. These inclusions contain the abnormal huntingtin protein and other proteins
   3. Ubiquitin and other proteasome proteins are also found
   4. Nuclear deposits of these proteins are only found in affected neurons
   5. These neurons undergo programmed cell death (apoptosis)
   6. Upregulation of caspase 1 early, then caspase 3 has been documented
   7. This leads to activation of caspases 8 and 9, and cytochrome c release, then apoptosis
4. Other neurodegenerative diseases with polyglutamine repeats have similar inclusion bodies
5. Other diseases caused by expanded CAG trinucleotide repeats
   1. Huntington's Disease
   2. Dentatorubropallido-Luysian Atrophy
   3. Spinobulbar Muscular Atrophy (Kennedy's Disease)
   4. Spinocerebellar Ataxias types 1, 2, 3, 6, 7, 12, 17

E. Treatment

1. There is no specific tredatment for this disease
2. Chorea Treatment
   1. Dopamine blockers may be beneficial, especially in early stages
   2. Haloperidol (Haldol®) - iniate carefully, then dose 1-4mg qid
   3. Chlorpromazine (Thorazine®) - suggested dose 50mg tid
   4. Amantadine - especially in early disease
   5. Levetiracetam (Keppra®) - antiseizure agent, 500mg po bid up to maximum 1500mg bid
3. Treatment of Depression
   1. Serotonin selective reuptake inhibitors (SSRI) - paroxetine, sertraline
   2. Tricyclic antidepressant agents (TCA)
4. Miscellaneous Agents
   1. Propranolol (Inderal®) - high doses for action tremor
   2. Dantrolene (Dantrium) - chorea associated with hemiatrophy
5. Fetal Neural Implantation [5]
   1. Human fetal neuroblasts grafted into right striatum initially
   2. One year later, grafts into left striatum
   3. Increased metabolic activity (PET scans) in 3 of 5 grafted patients
   4. This increased activity correlated with maintained or improved motor / cognitive functions
6. Counselling

References

1. Walker FO. 2007. Lancet. 369(9557):218
2. Martin JB. 1999. NEJM. 340(25):1970
3. Friedlander RM. 2003. NEJM. 348(14):1365
4. Bates G. 2003. Lancet. 361(9369):1642
5. Bachoud-Levi AC, Remy P, Ngyuyen JP, et al. 2000. Lancet. 356(9246):1975