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.
Genetics
Autosomal dominant inheritance
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. Parents who have 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.
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
Last updated: 05-06-2005 01:27:49
