Huntington's Disease

Huntington's Disease (HD) is an inherited, slowly progressive brain disorder leading to deterioration of motor control, memory loss and eventual dementia, and a variety of emotional and psychiatric problems. Sometimes, relatively subtle symptoms may precede, by several years, the disease onset.

HD affects 1 in 10,000 people. ^[1] The disease is always fatal. On average, those afflicted with it live for 16 years after the time when onset of the disease is recognized (diagnosed).

While some of the symptoms and complications of Huntington's Disease can be treated, so far there is no way to halt or slow the ravages of this illness. However, there is an active, collaborative effort of top researchers and clinicians around the world to test various medications which might be able to stop or at least slow deterioration.

Signs and Symptoms

HD is best known for a striking disorder of voluntary and involuntary movements. In the past, it was known as "Huntington's Chorea' because many people with it have small flickering and twisting movements (called chorea). This name has been changed because some people with Huntington's Disease never have chorea, but rather have marked awkwardness, stiffness, slowness and rigidity. All people with HD who live to the late stages of the disease develop these latter problems, as well as swallowing difficulties. The dementia can be severe, but for many years those with H.D. can follow what is going on and can understand language.

Psychiatric signs and symptoms, such as depression, obsessive–compulsive disorder, psychosis, apathy, substance abuse and paranoia are much more common than in the general population. Many of these conditions can be treated ^[2]

Other Names

"Huntington's Chorea", "hereditary chorea", "Huntington's disease"

Types

There are two forms of the disease: a juvenile form, which appears before age 20, and an adult-onset form, for which the age of onset peaks at around 35-50 years. Early onset is associated with more rapid progression and more severe symptoms.

An inverse correlation was shown to exist between the length of the CAG repeats and the age of onet ^[3].

Causes

Huntington's disease (HD) is caused by an defective gene inherited from a parent. The gene is located on chromosome 4, and was discovered as the result of decades of effort by many researchers, most notably the HD Collaborative research group. This culminated in the final detection of the affected gene in the labs of Marcy MacDonald, James Gusella and colleagues in 1983. This gene is present in its normal form in all humans, but was not known to exist until the defective variant which produces Huntington's Disease was discovered.

The normal "huntington" gene produces a large protein found in organisms from yeast to humans. In HD, this gene is defective in that it contains a trinucleotide repeat that is expanded and unstable Cell 1993; 72:971-983</ref>,

Although both the normal and abnormal huntingin gene is expressed throughout the brain, the earliest and most pronounced changes in HD occur in the neostriatum ^[4]. The caudate and putamen are most damaged, with marked neuronal loss ^[5].

History

A family practitioner, George Huntington M.D., published a remarkably accurate description of this condition in 1872 ^[6]. The disease bears his name based on this description. However, in 1841 Charles Oscar Waters wrote a letter containing a clear-cut report on the condition to a colleague (published in 1842).

Research

Recent discoveries

A common theme among neurodegenerative diseases is that there is a some kind of "nucleating protein" which aggregates within specific areas of the brain. There is debate as to whether the aggregates cause disease, or are simply an attempt by brain cells to sequester bad proteins. If the former is true, then therapy should be aimed at disaggregating the bad protein. If the latter is true, then therapy should be focused on helping the brain to inactivate the free-floating bad proteins. A recent advance in the understanding of Huntington disease (HD) suggests that the free-floating form of the protein may be the culprit, lending support to the idea that other neurodegenerative diseases like Alzheimer's and Parkinson's may also be caused by soluble proteins rather than the aggregates that we neuropathologists focus on under the microscope.

Scientists have known for some time that HD is associated with a mutation in the protein huntingtin on chromosome 4. But, since huntingtin is present throughout the brain, why does neurodegeneration in HD take place predominantly in an area of the brain called the striatum? Solomon H. Snyder and his team at Johns Hopkins University, in the June 5, 2009 issue of the journal Science, show that damage in HD takes place because of the interaction of mutant huntingtin with a second protein, known as Rhes^[7]. It turns out that Rhes is a protein that resides specifically in the striatum, thus explaining the anatomic specificity of neurodegeneration in HD. Snyder and colleagues go on to show that cells in culture tend to sequester mutant huntingtin into an aggregate. But in the presence of Rhes, mutatant huntingtin cannot aggregate, suggesting that the soluble form of the bad protein is what causes damage.

An Associated Press article about the discovery posted on Forbes.com quotes Walter J. Koroshetz of NIH's National Institute of Neurological Disorders and Stroke as follows regarding the implications of this new study: "The answers in one disease may have implications for another... There's been people on both sides of the fence. This story plays to the role of the aggregates as not being the major problem but the soluble protein as being the major problem."

The first HD animal model involved the expression of the first 63 amino acids of huntingtin containing 115-116 glutamines ^[8].

Current research

Clinical Trials

Interesting Facts

Other Resources

References

External Links

Diagnosis

Treatment

Prevention

References

1. ↑ Bates G et al. (Eds; 2002) Huntington's Disease. New York: Oxford University Press
2. ↑ Folstein S et al. Mosby Year Book 1993
3. ↑ M. Duyao, C. Ambrose, R. Myers, A. Novelletto, F. Persichetti, M. Frontali, S. Folstein, C. Ross, M. Franz and M. Abbott et al., Trinucleotide repeat length instability and age of onset in Huntington's disease, Nat. Genet. 4 (1993), pp. 387–392
4. ↑ Hersch S, Ferrante R. Neuropathology and pathophysiology of Huntington's disease. Movement disorders. In: Neurologic principles and practice. Watts R, Koller W. (editors). New York: McGraw-Hill; 1997. pp. 503-526
5. ↑ DJ Galas and SJ McCormack. An Historical Perspective on Genomic Technologies. Curr Issues Mol Biol. 2003 Oct;5(4):123-7. Review. 12921227 Abstract |
6. ↑ Huntington, G. (1872) On Chorea. In Medical and Surgical Reporter, vol. 26, pp. 320–321, Philadelphia. full text
7. ↑ Subramaniam S, Sixt KM, Barrow R, Snyder SH. Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity. Science 5 June 2009: Vol. 324. no. 5932, pp. 1327 - 1330
8. ↑ Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996; 87:493-506