Overview

Huntington's disease (HD) is an inherited (autosomally dominant) neurodegenerative disorder characterized by uncontrolled movements (chorea), general motor impairment, dementia, and psychiatric disorders such as depression and obsessive compulsive disorder. HD affects the corpus striatum and cerebral cortex, and currently there is no cure, just treatments for the symptoms of HD. Onset of HD usually occurs from age 30 to 50, and symptoms of the disease progressively worsen over the next one to three decades until death occurs. Death often results from pneumonia, infections, or injuries sustained in falls and other accidents.

After a marker for the HD gene was discovered on chromosome 4 in 1983, the gene itself was isolated, but not until ten years later. The mutation indicative of HD occurs as a polymorphic CAG repeat at the 5'-end of the gene, which is expanded on the HD chromosome. The upper limit of CAG repeats is normally 36; 38 or more repeats are indicative of HD, and the severity of disease is roughly proportional to the number of repeats. The HD gene encodes a 348 kDa protein (named huntingtin), which is not homologous with any other known protein and of which the normal function is still unknown. The repeated CAG sequence in the gene causes an abnormal form of huntingtin to be made; it is the presence of this abnormal form, and not the absence of the normal form, that causes harm in HD.

Prevalence

HD occurs in 4-7 per 100,000 individuals in northern European populations; 3-7 per 100,000 in western European populations; and between 0.1 and 0.38 per 100,000 among Japanese. The uneven distribution of HD is at least partially explained by the distribution of predisposing alleles and haplotypes in the normal population among ethnic groups. For example, the most common alleles in all populations contain 15-20 CAG repeats, but in western European populations the distribution is skewed towards longer alleles. Longer alleles are less common in African and Asian populations, suggesting that the expanded alleles in the disease range arise from longer normal alleles.

Symptoms

Early symptoms of HD are subtle, variable from one person to the next, and can be readily overlooked or misdiagnosed. Researchers at Johns Hopkins University recently reported (Nature 403:544-9, 2000) that movement jerkiness, which characterizes the smoothness and efficiency of motion, is a sensitive indicator of presymptomatic HD progression among HD gene-carriers and subjects with manifest HD. They found that a large percentage of HD gene-carriers displayed elevated jerk even when more than seven years remained until the predicted time of HD onset.

People afflicted with HD may experience early symptoms of mood swings, irritability, apathy, lethargy, depression, or anger. These symptoms may disappear as HD progresses; but sometimes theses symptoms lead to violent outbursts or deep depression.

In most cases HD begins in middle age, but some people develop symptoms prior to age 20. Patients with such early onset (or juvenile) HD may develop seemingly minor movement disorders, such as slowness, rigidity, tremor, or a rapid muscular twitching--symptoms similar to the early signs of Parkinson's disease--but also seizures and mental disabilities.. Juvenile HD symptoms also differ from the chorea that develops in adults with HD. Early onset HD runs it course comparatively faster than adult HD, with death occurring usually in about 10 years.

Typical adult HD has also been seen to develop after age 55. Depression may occur, rather than anger or irritability, during the development of this form of HD, although the patient's memory, reasoning ability, and problem-solving skills may remain sharp early on. In addition, there also are cases where HD develops in elderly people. Called senile chorea, or late-stage HD, this form of the disease is characterized by HD-like symptoms such as chorea, but patients are typically found to lack the indicative CAG repeat, and most of these patients have no family history of the disorder. This leads some researchers to believe that senile chorea results from a different gene mutation altogether.

A rare few individuals suffer from a form of HD known as akinetic-rigid HD, or Westphal HD. Instead of developing chorea, sufferers become rigid and can move very little if at all.

Causes

The genetic mutation that produces HD causes neurons in parts of the brain (mainly the corpus striatum and cerebral cortex,) to degenerate, causing uncontrollable movements, emotional imbalances, and defects in thought, perception, and memory.

It has been suggested that certain neurons become spent as a result of prolonged excitatory neurotransmission, and thus switch from aerobic to anaerobic, glycolytic metabolism, leading to the accretion of lactate.

Other neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis have been shown to have common mechanisms of pathogenicity with HD, and research into treating any one of these usually leads to trials for several. Among the common mechanisms shared by these neurodegenerative diseases is massive cell death (either apoptotic or necrotic), caused by either free radical-induced oxidative stress, mitochondrial dysfunction, excitotoxic processes, or a combination of these.

Treatment

Treating the symptoms

This is no known cure for HD. Patients can only be treated for the symptoms of the disease, with separate focuses on the physical and mental aspects of HD. Even still, treating HD is problematic because of the overall chance of exacerbating dysfunctions or adverse effects.

Chorea

This is especially true when treating chorea, which should be treated only in cases that are severely distressing or disabling. The majority of available antichoreic drugs are dopamine receptor-blocking agents. Tiapride is the antichoreic of choice among antipsychotics as it has better efficacy and fewer adverse effects than the others of its class, and haloperidol may help control hallucinations, delusions, or violent outbursts, but all antipsychotics have the potential to induce Parkinson-like effects. Tetrabenazine is an effective antichoreic drug but is limited by adverse effects (occurring in approximately 80% of patients). Clonazepam may also be used to alleviate choreic movements. Antipsychotics are contraindicated when patients have dystonia, a form of muscular contraction sometimes associated with HD, as it can worsen the condition.

Depression, anxiety, and mood changes

HD patients who suffer from depression may receive fluoxetine, sertraline hydrochloride, nortriptyline, amitriptyline, imipramine, or serotoninergic agents such as fluoxetine and sertraline. The tricyclics (such as nortriptyline and amitriptyline) have the advantage of helping insomnia when given at bedtime, and may prevent weight loss due to the effect they have on stimulating the appetite. The serotonergic drugs are also helpful in patients who exhibit obsessive compulsive disorder. Various tranquilizers can be used to treat anxiety. Lithium, carbamazepine, or valproate may be used for patients who demonstrate pathological excitement or severe mood swings, as can anxiolytics like diazepam, alpralozam, and clonazepam. Patients with impulse control problems may respond to clonidine or propranolol.

Attacking the Cause

Because of the broad array of symptoms that HD patients may develop, the high risk of adverse drug effects, and the relative recentness of the discovery of the HD gene, efforts to understand HD, develop improved techniques and procedures for identifying and diagnosing HD, and find ways of preventing HD, stop its progression, and reverse its effects are spreading over a large array s scientific disciplines.

In the January 1, 2000, issue of The Journal of Neuroscience, Senut et al. report in vivo evidence that polyglutamate tracts themselves can mediate neurodegeneration. Senut's group found that low-level cumulative expression of polyglutamate repeats throughout life did not cause neuronal cell death, but that acute overexpression of polyglutamate was toxic to adult neurons. The rat model Senut's group developed may prove useful in determining the molecular basis of polyglutamate aggregate induction and the mechanism by which such aggregates induce neuronal apoptosis.

Prior research has also suggested that the HD gene product, huntingtin, interacts with other proteins, including huntingtin-associated protein 1 (HAP-1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), apopain, and ubiquitin-conjugating enzyme (hE2-25K). In the presence of calcium, huntingtin also interacts (indirectly) with calmodulin. Among all these interactions, HAP-1 and apopain show huntingtin-specific interactions, while GAPDH interacts with other molecules containing a polyglutamine tract. The interactions of HAP-1, GAPDH, apopain, and calmodulin with huntingtin are stronger when the polyglutamine tract is longer; the dependence on CAG length to the huntingtin-hE2-25K interaction is not as obvious.

Interesting hypotheses have been proposed for each huntingtin-interacting protein. Some reports suggest that more huntingtin-interacting proteins will be identified, but whether any of them actually play a significant role in the disease mechanisms of HD remains to be seen.

In the May 20, 1999, issue of Nature, Robert Friedlander et al. report that progression of HD can be slowed in a mouse model. Dr. Friedlander's group developed a mouse that had defective caspase-1. They found that these mice were resistant to cell death, and furthermore that by mating caspase-1 defective mice with transgenic HD mice resulted in some of the HD mice inheriting the defective caspase-1 enzyme. These double-mutant mice showed some elucidating differences from the regular HD mice. The double-mutant mice had delayed onset of abnormal symptoms, performed better on motor skills tasks, did not lose as much weight, and lived longer than the regular HD mice.

Erich E. Wanker, et al. of the Max-Planck Institute for Molecular Genetics are looking into chemical compounds that inhibit or slow the formation of polyglutamine-containing aggregates among neurons using a simple and sensitive membrane filter assay. The membrane filter assay has been designed to screen, in a reasonable time, chemical libraries (1,500 different chemicals) for compounds that will inhibit huntingtin aggregation in vitro.

Mouse models

Huntingtin is found everywhere in the body but only outside a cell's nucleus. Mice bred to produce no huntingtin fail to develop past a very early embryo stage and quickly die. Huntingtin, it can be concluded, is necessary for life, and investigators can now turn their attention to why the abnormal version of huntingtin damages only certain parts of the brain.

Transgenic mice have been created that develop a neurodegenerative syndrome that closely models HD.

In a report published in the March 2000 Cell (101:57-66), A. Yamamoto and a team from Columbia University in New York describe the creation of a conditional model of HD. By using a tet-regulatable system, Yamamoto's group developed mice that expressing a mutated huntingtin fragment. These mice demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction common to HD. However, the blockade of expression in symptomatic mice led to a disappearance of inclusions and a recovery of the behavioral phenotype.

The goal of B. Leavit and M. Hayden of the University of British Columbia, Vancouver, has been to reproduce an animal model for HD that faithfully replicates the changes seen in humans. Reporting their findings in the May 1999 issue of Neuron, the authors set out to insert the entire HD gene into mice, encompassing large DNA fragments in a yeast artificial chromosome (YAC). The YAC bundle could then be mutated to create the DNA with an expanded CAG repeat length. The YAC-transgenic mice created in this manner express the mutant human huntingtin protein, pass the mutant human gene to their offspring, and develop the features of HD in an age-dependant fashion.

Other Models

Hayden's group has also developed a cell model to assess factors that promote or prevent cell death in HD. In his lab's model, fibroblast cells were damaged by sub-lethal doses of chemicals that only kill cells in the presence of huntingtin. This effect may mimic late-onset HD, in which accumulation of stress or injuries is needed to cause cell death.

Fetal Tissue Research

A relatively new area of research comprises the use of brain tissue grafts to study neurodegenerative disorders. Potentially, HD could be treated by replacing degenerated brain tissue with implants of fresh fetal tissue, taken at the very early stages of development. Comprehensive animal studies will be required to determine whether tissue grafting will be of value in individuals with HD.

In a recently published study by N. Nakao and T. Itakura of Wakayama Medical College in Japan [Prog Neurobiol 61(3):313-338, 2000], embryonic striatal tissue grafting may become a viable strategy to alleviate motor and cognitive disorders in patients with HD where massive degeneration of striatal neurons occurs. The authors found that striatal neurons implanted into the lesioned striatum received major striatal afferents, such as the nigrostriatal dopaminergic inputs, and the glutamatergic afferents from the neocortex and thalamus. They also found that grafted neurons also sent efferents to the primary striatal targets, including the globus pallidus and the entopeduncular nucleus. These connections were found to provide a reversal of lesion-induced alterations in neuronal activities of primary and secondary striatal targets.

Ongoing and Planned Clinical Trials

1. Care HD: CoQ10 and Remacemide evaluation in HD
2. RID-HD: Riluzole Dosing in HD
3. Creatine: Safety, Tolerability and Dose-Finding (Beal, Hersch)
4. Transplants (Europe)
5. US-Venezuela Project
6. Huntington's Study Group's United Huntington's Disease Rating Scale (UHDRS) Data Base
7. PHAROS: Pilot Huntington's At Risk Observational Study
8. Predict-HD: Neurobiologic predictors of HD
9. MAOPS: Modifying Age of Onset Peer Study

Recent Papers

Alexi, T., Borlongan, C.V., Faull, R.L., Williams, C.E., Clark, R.G., Gluckman, P.D., and Hughes, P.E. Neuroprotective strategies for basal ganglia degeneration: Parkinson's and Huntington's diseases. Prog Neurobiol 60(5):409-70, 2000.

Culjkovic, B., Stojkovic, O., Vojvodic, N., Svetel, M., Rakic, L., Romac, S., Kostic, V. Correlation between triplet repeat expansion and computed tomography measures of caudate nuclei atrophy in Huntington's disease. J Neurol 246(11):1090-3, 1999.

De Marchi, N., and Mennella, R. Huntington's disease and its association with psychopathology. Harv Rev Psychiatry 7(5):278-89, 2000.

Etchebehere, E.C., Lima, M.C., Passos, W., Maciel Junior, J.A., Santos, A.O., Ramos, C.D., and Camargo, E.E. Brain SPECT imaging in Huntington's disease before and after therapy with olanzapine. Case report. Arq Neuropsiquiatr 57(3B):863-866, 1999.

Garcia Ruiz, P.J., Gomez Tortosa, E., Sanchez Bernados, V., Rojo, A., Fontan, A., and Garcia de Yebenes, J. Bradykinesia in Huntington's disease. Clin Neuropharmacol 23(1):50-2, 2000.

Guidetti, P., Hemachandra Reddy, P., Tagle, D.A., and Schwarcz, R. Early kynurenergic impairment in Huntington's Disease and in a transgenic animal model. Neurosci Lett 283(3):233-235, 2000.

Hamilton, J.M., Murphy, C., and Paulsen, J.S. Odor detection, learning, and memory in Huntington's disease. J Int Neuropsychol Soc 5(7):609-15, 1999.

Kosinski, C.M., Cha, J.H., Young, A.B., Mangiarini, L., Bates, G., Schiefer, J., and Schwarz, M. Intranuclear inclusions in subtypes of striatal neurons in Huntington's disease transgenic mice. Neuroreport 10(18):3891-3896, 1999.

La Fontaine, M.A., Geddes, J.W., Banks, A., and Butterfield, D.A. 3-Nitropropionic acid induced in vivo protein oxidation in striatal and cortical synaptosomes: insights into Huntington's disease. Brain Res 858(2):356-362, 2000.

Laccone, F., and Christian, W. A recurrent expansion of a maternal allele with 36 CAG repeats causes Huntington disease in two sisters. Am J Hum Genet 66(3):1145-1148, 2000.

Manley, K., Shirley, T.L., Flaherty, L., and Messer, A. Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet 23(4):471-3, 1999.

Menalled, L., Zanjani, H., MacKenzie, L., Koppel, A., Carpenter, E., Zeitlin, S., Chesselet, M.F. Decrease in striatal enkephalin mRNA in mouse models of Huntington's disease. Proc Nat Acad Sci USA 97(6):2898-2903, 2000.

Mizuno, H., Shibayama, H., Tanaka, F., Doyu, M., Sobue, G., Iwata, H., Kobayashi, H., Yamada, K., Iwai, K., Takeuchi, T., Hashimoto, N., Ishihara, R., Ibuki, Y., Ogasawara, S., and Ozeki, M. An autopsy case with clinically and molecular genetically diagnosed Huntington's disease with only minimal nonspecific neuropathological findings. Clin Neuropathol 19(2):94-103, 2000.

Nakao, N., and Itakura, T. Fetal tissue transplants in animal models of Huntington's disease: the effects on damaged neuronal circuitry and behavioral deficits. Prog Neurobiol 61(3):313-338, 2000.

Smith, M.A., Brandt, J., and Shadmehr, R. Motor disorder in Huntington's disease begins as a dysfunction in error feedback control. Nature 403(6769):544-9, 2000.

This article was written by Lynn M. Savage, Managing Editor, D&MD Newsletter

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