Huntington's disease

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 about 1/200,000. The causative gene (which is one of the first identified to cause an inherited disease) is located on chromosome 4. The product of this gene is a protein called huntingtin. The continuous accumulation of huntingtin 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 residues in the normal form; the mutated huntingtin causing the disease has more than 40 residues.

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 infintely 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 the demonstration of cell loss, especially in the caudate nucleus, supported by a cranial CT or MRI scan findings. Although dopamine receptor blockers may have restricted benefits, there is no definite treatment for disease.

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, Huntingtion's 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 possibile loss of health insurance as a result.

While theories as to how 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.

Literature :
¹ Proceedings, Volume 99, 5591-5596