Huntington's disease or Huntington's chorea is an inherited disorder characterized by abnormal body movements called chorea, and loss of memory. The incidence is 5 to 8 per 100,000.

Short Summary

Huntington's disease is inherited in the autosomal dominant fashion, meaning that it is on a dominant allele and offspring of carriers have a 50% chance of inheriting the disease. (Crossing of a heterozygote with a homozygous recessive partner.) Symptoms of the disorder include loss of cognitive ability (thinking, speaking), changes in personality, jerking movements of the face and body in general and unsteady walking. These symptoms develop into dementia and cognitive decline (not mental retardation which is an older term refering to the lack of development of mental ability rather than loss of it.) and an advanced form of jerking called Chorea, the Greek word for dance. It usually takes between 10-25 years for the disease to kill someone, and it is fatal 100% of the time. The disease is onset in the 30’s and 40’s in most cases, however there is an early childhood form that starts at the age of 2. Victims of this form rarely reach adulthood. One interesting fact about the disease is that it contributes to a chemical imbalance that leads many victims to commit suicide. This is also believed in part to be a result of the position sufferers find themselves in. Another interesting fact about the disease is that its origin is being traced back to a woman in the small Venezuelan fishing village of Barranquitas. Families there have a high presence of the disease and geneticists and doctors view this community as invaluable in the research of the disease.

Genetics

The causative gene (one of the first identified to cause an inherited disease) is located on chromosome 4. Huntington's disease is inherited in an autosomal dominant fashion. The autosomal dominant fashion means that the a recipient of the gene only needs one allele to inherit the disease. Most genetic diseases are autosomal recessive meaning that they need two alleles to inherit the disease. The dominant nature of Huntington's disease increases the chance of the disease occuring in offspring. A parent who has the disorder have a 50% chance of passing on the gene with each child.

The product of this gene is a 350KDa cytoplasmic protein called huntingtin. The continuous aggregation of huntingtin molecules in neuronal cells gives rise to cell death, especially in the frontal lobes and the basal ganglia (mainly in the caudate nucleus) by some unknown mechanism. Huntingtin has a characteristic sequence of 40 or fewer glutamine (CAG amino acid) residues in the normal form; the mutated huntingtin causing the disease has more than 40 residues. The severity of the disease is proportional to the number of extra residues.

While theories as to how the mutation brings about disease remain diverse and speculative, researchers have identified many specific subcellular abnormalities associated with the mutant protein, as well as unusual properties of the protein in vitro. Just as one example, in 2001, Max Perutz discovered that the glutamine residues form a nanotube¹ in vitro, and the mutated forms are long enough in principle to pierce cell membranes.

Diagnosis

Symptoms of Huntington's disease onset increasingly early the more glutamines a person carries within the repeating portion of their mutant huntingtin proteins. This number increases as the disease gene is passed on, so that the age of onset decreases with successive generations (although not infinitely early, since patients with childhood symptoms tend not to have children themselves). Currently most Huntington's patients start to show symptoms in the 4th decade of life. These symptoms include the loss of cognitive abilities, changes in personality, quick jerking movements of face and body (i.e. chorea) and unsteadiness of gait. The diagnosis is established by neurological examination findings and demonstration of cell loss, especially in the caudate nucleus, supported by a cranial CT or MRI scan findings.

Pathology

Degeneration of the caudate and the putamen (striatum) can be found. There is also neuronal loss and astrogliosis, as well as loss of medium spiny neurons, a GABAergic result. Intranuclear inclusions that stain for ubiquitin and huntingtin can be seen, as well as huntingtin in cortical neurites. Genetics, huntingtin is found on chromosome 4, as do CAG repeats. It is suspected that the cross-linking of huntingtin results in aggregates which are toxic, and can lead to dysfunction of the proteosome system. This mitochondrial dysfunction can lead to excitotoxicity and oxidative stress.

Linkage between CAG repeats (huntingtin) and mitochondrial failure, however, is far from clear. There is some evidence that aggregates may trap critical enzymes that in involved in energy metabolism.

Treatment and prevention

Although dopamine receptor blockers may have restricted benefits, there is no definite treatment for disease. In 2004 it was found that a simple sugar called trehalose can alleviate symptoms in genetically modified mice, giving hope for a treatment.

Ethical aspects

Unlike many hereditary illnesses, the alleles that cause Huntington's disease are dominant--meaning that having one parent with the disease guarantees offspring a 50% chance of inheriting it--and disease alleles are fatal in 100% of individuals that inherit them. Genetic testing can identify these individuals even before symptoms are present.

Because of these aspects, Huntington's disease raises many of the most pressing issues of bioethics. Disease carriers must contemplate whether to have children. Children of carriers must contemplate whether to have themselves genetically tested, despite absence of a cure and the possible loss of health insurance as a result. Genetic counseling is recommended for family members to help review the benefits and drawbacks of testing.

References

Neural Diseases Lecture Handout: Oct, 28th, 2004. Dr. Norenberg, University of Miami

1. Proceedings, Volume 99, 5591-5596

External Links

1. Australian Huntington's Disease Association (NSW) Inc. AHDA(NSW) (http://www.ahdansw.asn.au)