Neuroscience. Huntington’s Disease Epidemiology

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Table of Contents

Introduction
Prevalence
Symptoms
Causes
Pathophysiology
Diagnostic strategies
Treatment of Huntington’s disease
Conclusion – Future Trends
Bibliography

Introduction

Huntington’s disease is a hereditary, acute disorder of the central nervous system usually beginning in middle age and characterized by involuntary muscular movements and progressive intellectual deterioration (Harper et al, 1988). It was formerly called Huntington’s chorea and confused with chorea or St. Vitus’s dance, which is not hereditary. HD attacks the cells of the basal ganglia, clusters of nerve tissue deep within the brain that govern coordination and the cerebral cortex (Harper et al, 1988).

The disease sets in suddenly and progresses steadily and no treatment has yet been found for this fatal disease. Huntington’s disease can be defined as a neurodegenerative disorder that is characterized by movement disorders and progressive dementia. George Sumner Huntington (1973) was the first person to give a clear, concise, and accessible report on what was to become the standard description of the disease, and therefore the disease is named after him (Harper et al, 1988).

Prevalence

Huntington’s disease is a relatively rare disorder. Epidemiological assessment is complicated by the fact that it is extremely rare in many regions but unusually frequent in others. Its worldwide prevalence rate is estimated to be five cases per 100,000 persons. Its incidence rate is estimated to be 3.4 cases per 1 million persons each year (CUSO, 2002). In certain regions of the world, notably the Lake Maracaibo region of Venezuela, the prevalence rate is extremely high, affecting up to 700 people per 100,000 persons (CUSO, 2002). Between 1968 and 1974 it was estimated that HD accounted for 1.15 deaths per 1 million persons in the United States per year. It is estimated that 25,000 Americans now suffer from this disorder and another 125,000 Americans are thought to be at risk of developing the disease (CUSO, 2002).

Symptoms

Huntington’s disease has symptoms of three types: movement, cognitive, and emotions. Different people are affected to different levels by this disease. Some symptoms of Huntington’s disease are mood swings, involuntary movement, impaired judgment, an inability to control impulses, severe weight loss, difficulty with memory, organizing, and planning (Goolkasian, 2001). Psychiatric disturbances range from personality changes involving apathy and irritability to bipolar or schizophreniform illness.

Motor manifestations include flicking movements of the extremities, a lilting gait, and motor persistence (inability to sustain a motor act such as tongue protrusion). The most prominent signs of Huntington’s disease (HD) are the choreic movements. In Greek, chorea means “dance” and this term is used because of the involuntary movements of those afflicted with HD (Knight, 1992). The continuous involuntary movement that is a symptom of the disease resembles the movements of a dance.

Huntington observed that the disease begins with the “irregular and spasmodic action of certain muscles as of the face, arms, etc.” The initial symptoms of HD are personality and behavioral changes and involuntary movements (CUSO, 1990). As HD progresses, the involuntary movements become more intense, crippling the patient. Young patients who are afflicted with this disease experience slowed movement and rigidity. In the later stages of the disease, memory and other cognitive abilities are affected.

Patients can lose their mental stability and memory (dementia). Overall there is a slow and steady decline in the health of the afflicted person leading to his death about14 19 years after the onset of the disease (CUSO, 2002).

Huntington also remarked on “a tendency to that insanity that leads to suicide” as one of the prime features of the disease (Knight, 1992). This has been confirmed by research studies that show the suicide rate is four times higher among people with Huntington’s disease than among the general population. (Farrer, 1986). Some people undergo severe depression after being diagnosed with the fatal Huntington’s disease (M. F. Folstein, S. E. Folstein, & McHugh, 1979). According to a study by Lieberman et al. (1979) dementia and psychosis were more common in Huntington’s than Parkinson’s disease.

Causes

Huntington’s disease is mostly inherited and caused by a genetic disorder. A single defective gene appears to be responsible for HD. According to Trottier et al (1995), Huntington’s disease (HD) results from the expansion of a polyglutamine encoding CAG repeat in a gene of unknown function. Zuccato et al (2001) have expanded the research on this gene of unknown function. They explain that Huntingtin is a 350-kilodalton protein of unknown function that is mutated in Huntington’s disease (HD) acquiring a toxic gain of function that is harmful to striatal neurons in the brain.

However, Zuccato et al (2001) point out that the loss of a beneficial activity of wild-type huntingtin may also cause the death of striatal neurons. Because HD is a genetic disorder, any child of a parent with HD has a 50 percent risk of inheriting the gene and succumbing to the disease.

In 1983 Gusella et al. (1983) reported in Science that the HD gene could be localized to a polymorphic DNA marker, G8, on the distal arm of chromosome 4 (Knight, 1992). The genetic mutation that occurs in gene IT-15, located on chromosome 4, alters the Huntington protein, which is present in all human beings and causes Huntington’s disease. How the mutation of gene IT-15 alters the function of the protein is not well understood (Swierzewski, 2000).

With advances in molecular genetics, the location of the HD gene has been traced to chromosome 4 (Harper et al, 1988). Although the gene itself has not been identified, knowledge of its location has important practical implications – a person or fetus carrying the HD gene may be identified before the onset of the disease. Researchers are attempting to determine the gene’s function and eventually develop an effective treatment for HD.

Pathophysiology

The brains of persons with HD appear shrunken at autopsy. There is generalized cortical atrophy, particularly of the frontal and occipital lobes. At death, the basal ganglia are found to weigh about 50% of normal, and total brain weight is reduced by about 20% (Bird, 1978). The cortex is reduced in thickness and atrophy is particularly evident in layers 3, 5, and 6 (Knight, 1992). There is extensive nerve cell death in certain regions of the brain, including the striatum and the cerebral cortex.

A study by Vonsattel et al (1985) showed that in postmortem brain specimens from 163 clinically diagnosed cases of Huntington’s disease (HD) the striatum exhibited severe neuropathological involvement. The abnormal movement associated with HD is attributed to loss of nerve cells in the striatum; dementia is attributed to a loss in other regions. The nerve cell loss associated with HD results in a profound decrease in certain brain chemicals, including GABA (gamma-aminobutyric acid) and acetylcholine. However, the reason behind nerve cell death has not yet been scientifically explained.

Diagnostic strategies

Diagnosis of HD is based on a thorough personal and family medical history, physical examination including a neurological exam, and a series of laboratory tests. Genetic testing involves taking a blood sample for DNA analysis to determine whether the distinct mutation for Huntington’s disease has occurred in gene IT-15 (Swierzewski, 2000). A sample of DNA also may be required from a closely related affected relative, ideally a parent.

Persons who test positive and are considering pregnancy are advised to seek genetic counseling before they conceive. Presymptomatic testing can be performed on adults, children, and even fetuses in the womb (Swierzewski, 2000). Genetic testing of a fetus holds special challenges and risks, and some testing facilities choose not to do it. At-risk couples wanting to have children may choose to undergo in vitro fertilization with preimplantation screening. In this procedure, embryos produced from the couple’s sperm and eggs are screened to identify one that is free of the HD mutation, which is then implanted in the woman’s uterus (Swierzewski, 2000).

Computed Tomography (CT scan) is a painless diagnostic procedure that produces computer-generated images of the brain’s internal structures. Patients with HD often show shrinkage in two areas of the brain – the caudate nuclei and putamen – and enlargement of cavities within the brain called ventricles. The presence of these structural changes is not conclusive for Huntington’s disease nor does their absence rule it out. However, CT scans combined with other procedures such as magnetic resonance imaging (MRI scan) and/or positron emission tomography (PET scan) can be a helpful diagnostic tool, especially when evaluated in the context of family history and clinical symptoms.

Testing can be done most effectively when the whole family cooperates because, for diagnostic tests to be accurate, chromosomal material from several affected and unaffected family members must be collected. For couples, where one spouse may be affected, there are decisions to be made about whether to have children and/or test fetal material for transmission of the defective genetic attributes. Thus, diagnostic strategies need to consider the mental stress the patient undergoes during the process of diagnosis.

Treatment of Huntington’s disease

Since most patients with HD have inherited the abnormal gene from a parent, preventive measures may be taken to reduce the number of abnormal genes transmitted. Until recently, the only way to achieve this was by limiting the family size of those at risk (Harper et al, 1988). HD is a disease that is quite difficult to treat because of its rarity. Moreover, by nature of the disease, those who are afflicted are also cognitively and emotionally unstable, making it very difficult to treat them at nursing or group homes. Sometimes younger people with HD are denied healthcare as most nursing homes cater only to the elderly population.

Today, people with HD are given symptomatic treatment. They are not treated for the disease itself. While there is no cure, research has shown that providing a conducive environment can reduce symptomatic suffering of the patient and minimize the impact of symptoms and greatly improve quality of life. Exercises, adaptive equipment, medication, and high-calorie diets can all help. It is important to have staff who are trained to understand the symptoms and deal with them effectively. The greatest challenge in treating people with HD is that sometimes symptoms are interrelated. It is not enough to treat individual symptoms. HD is a holistic disease that affects both the mind and the body. Hence any treatment should consider both the physical and mental aspects of the disease (Goolkasian, 2001).

Treatment for HD is aimed at minimizing the abnormal movements and mental problems associated with the disease. In their normal state, nerve cells that degenerate in HD may suppress the activity of other dopamine-producing nerve cells.

Destruction of the former may lead to excessive and uncontrolled dopamine production, causing the involuntary movements typical of HD. Drug therapy aimed at blocking the action of dopamine is employed to suppress involuntary movements. This therapy produces undesirable side-effects, however, including sedation, depression, and severe limitation of movement. Drugs are also used to help control the mental changes associated with HD. None of these drug therapies is adequate for the treatment of HD, and none prevents the progression of the disease.

Conclusion – Future Trends

Neural grafting is a new method of treating HD that is being studied using animal research (CUSO, 1992). It is based on the possibility of replacing degenerated cells or replenishing certain brain chemicals. More research may be done regarding HD and other neurological disorders to study the functions of the basal ganglia and cerebral cortex. Neuropsychological studies have found several interesting double dissociations between HD and other chronic neurological conditions (Knight, 1992). Compared to Korsakoff patients, Huntington’s disease patients appear to have more difficulty acquiring new skills, particularly in the perceptual-motor domain.

HD patients have particular problems on tasks requiring personal or egocentric spatial orientation and in this respect, they differ from Alzheimer patients. The fact that HD has psychosocial consequences and that the whole family is affected by a positive diagnosis has important implications for clinicians. More work needs to be done in the area of improving the family and work environment of the patients. More research must be conducted to find out the link between the nature of the cognitive deficits associated with HD and structural changes in the brain. Comparative neuropsychological studies can be both informative and heuristic and are likely to yield further insights into the study and treatment of HD in the future.

Bibliography

Book Sources

CUSO (Congress of the United States Office of) (2002). Neural grafting: repairing the brain and spinal cord. Congress of the United States Office of. The Minerva Group, Inc.

Knight, G. Robert (1992). The Neuropsychology of Degenerative Brain Diseases. Lawrence Erlbaum Associates. Hillsdale, NJ.

Journal Articles

Bird E. D. (1978). The brain in Huntington’s chorea. Psychological Medicine. Volume 8. pp. 357-360.

Creighton et al (2003). Predictive, prenatal and diagnostic genetic testing for Huntington’s disease: the experience in Canada from 1987 to 2000. Clinical Genetics. Volume 63, Issue 6. pp. 462-475.

Farrer, A. Lindsay (1986). “Suicide and Attempted suicide in Huntington’s disease: Implications for preclinical testing of persons at risk”. 42 Am. J. Med. Genet. Volume 504. pp. 499-507.

Folstein S. E.; Folstein M. F.; & McHugh P. R. (1979). Psychiatric syndromes in Huntington’s disease. Advances in neurology. Vol. 23, pp. 281-189.

Goolkasian, Virginia (2001). Delving into Huntington’s Disease. USA Today. Volume: 130. Issue: 2676. pp. 34.

Gusella J. F.; Wexler N. S.; Conneally P. M.; Naylor S. L.; Anderson M. A.; Tanzi R. E.; Watkins P. C.; Ottina K.; Wallace M. R.; Sakaguchi A. Y.; Young A. B.; Shoulson I.; Bonilla E., & Martin J. B. ( 1983). A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. Volume 306. pp. 234-238.

Harper P. S; Quarrell, O.W.J. ; Youngman, S.; Hodgson, S. V.; McLaren L. A. and Cassiman J. J. (1988). Huntington’s Disease: Prediction and Prevention. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. Volume 319. No. 1194. pp. 285-298.

Lieberman A.; Dziatolowski M.; Neophytides A.; Kupersmith M.; Aleksic S.; Serby M.; Korein J.; & Goldstein H. (1979). Dementias of Huntington’s and Parkinson’s diseases. Advances in neurology. Vol. 23, pp. 273-289.

Trottier et al (1995). Cellular localization of the Huntington’s disease protein and discrimination of the normal and mutated form. Nature Genetics. Volume 10. 1995. pp. 104-110.

Vonsattel et al (1985). Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol. Volume 44. Issue 6. pp. 559-77.

Zuccato et al (2001). Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington’s Disease. Science. Volume 293. Issue 5529. pp. 493-498.

Other Sources

Swierzewski, J. Stanley (2000). Huntington’s Disease. Neurology Channel. Web.

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