Huntington's disease

Huntington's disease
Specialty	Neurology
Frequency	0.0123% (United Kingdom)

Huntington's disease
Specialty	Neurology
Frequency	0.0123% (United Kingdom)

Huntington's disease or Huntington's chorea (HD) is an inherited disorder characterized by abnormal body movements called chorea, and loss of memory. It takes its name from the Ohio physician George Huntington who first described it precisely in 1872. The incidence is 5 to 8 per 100,000.

There is evidence that doctors as far back as the Middle Ages knew of this devastating disease.

Symptoms

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 referring to the lack of development of mental ability rather than loss of it) and an advanced form of rapid jerking called chorea, the Greek word for dance.

The symptoms of Huntington’s disease begin insidiously. One-half to three-fourths of the patients present with abnormal movement or rigidity. The remainder of the patients present with mental status changes, such as irritability, moodiness, or antisocial behavior. All of the patients eventually exhibit chorea, which is jerky, random, uncontrollable, rapid movements. Typically, the abnormal movements begin at the extremities and then later progress.

Huntington's disease 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 in which sufferers find themselves.

Genetics

Huntington's disease is inherited in autosomal dominant fashion, meaning that it is a dominant allele. People with Huntington's disease have a 50% chance of passing the disease to each of their children.

The causative gene HD (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 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 occurring in offspring. A parent who has the disorder has a 50% chance of passing on the gene with each child.

The product of this gene is a 350 kDa 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 fewer than 40 glutamine amino acid residues (encoded by CAG trinucleotide repeats) 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.

Huntington's disease is unusually prevalent 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.

Diagnosis

Symptoms of Huntington's disease begin increasingly early the more glutamines a person carries within the repeating portion of his or her 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).

The diagnosis is established by neurological examination findings and/or 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. Genetically, huntingtin is found on chromosome 4, as are 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 are in involved in energy metabolism.

Survival Rate

It usually takes between 10 to 25 years for the disease to kill someone, and it is invariably fatal. Mortality is due to complications resulting from Huntington's Disease rather than the disease itself. The age of onset of the disease is in the 30s and 40s in most cases.

About 10 percent of Huntington's disease cases occur in people under the age of 20 years and is called juvenile Huntington’s disease. It has an age of onset anywhere between infancy and 20 years of age. The symptoms of juvenile HD are very different from those of adult-onset HD. Individuals with juvenile HD often become stiff or rigid in their movements (instead of having chorea). Any case of HD with an onset before the age of 20 is considered to be the juvenile form.

Symptoms of Huntington’s disease usually occur in patients in their mid 30s to their mid 40s. Death is usually 10 to 20 years after the onset of neurological and psychological impairment. The juvenile form of Huntington’s disease typically presents before the age of 20 and is more rapidly progressive.

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.

There is no treatment to help stop the progression of the disease. Fortunately, there are treatments available to help reduce some symptoms of the disease. Unfortunately, these treatments aggravate other symptoms like bradykinesia and dystonia (very slow movement and stiffness). There are also treatments to control abnormal movements and emotional symptoms like antidepressants, sedatives, and tranquilizers.

Candidate treatments to slow the progression of the disease are in progress although are slow to reach HD sufferers. EPA, an Omega-III fatty acid, has been shown to slow and possibly reverse the progression of the disease. It is currently in FDA clinical trial, as LAX-101, for prescription use. Clinical trials utilize 2 grams per day of EPA. In the United States, it is available over the counter in lower concentrations within Omega-III pills.

Pig cell implants in Huntington's Disease trial: Living Cell Technologies in New Zealand has attempted trials with positive results in primates World health Article but is yet to conduct a human trial.

Ethical aspects

Huntington's disease presents individuals and families with several dilemmas:

• Testing for the presence of the disease
• Whether to have children
• Informing children with an HD positive parent that they are at risk
• Coping with the discovery of the disease in a family member.
• Testing of grandchildren of a sufferer has serious ethical implications if their parent declines testing, a positive result in a grandchild's test automatically diagnoses the parent.
• Coping with the social and personal impacts of significant impairment of memory.

Genetic counseling can provide perspective for those at risk of the disease. Some choose not to undergo HD testing due to numerous concerns (for example, insurability).

For those at risk, or known to have the disease, consideration is necessary prior to having children due to the genetically dominant nature of the disease. In vitro and embryonic genetic screening now make it possible (with 99% certainty) to have an HD-free child; however, the cost of this process can easily reach tens of thousands of dollars.

Parents and grandparents recently discovered to possess the disease are left with the question of when and how to tell their children and grandchildren. It is not unusual for entire segments of a family to become alienated as a result of such information or the withholding of it.

References

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

1. Proceedings, Volume 99, 5591-5596

External links

• Australian Huntington's Disease Association (NSW) Inc.
• Huntington's Disease Lighthouse
• Huntington's Disease Society of America
• Hereditary Disease Foundation
• HDF Everest 2005 Expedition
• Living Cell Technologies
• Huntington Disease; HD (143100), Online Mendelian Inheritance in Man, John Hopkins University
• Stanford University HOPES