PERSPECTIVES ON HUNTINGTON’S DISEASE
ABSTRACT
Huntington’s disease is a autosomal dominant disease that is characterized by dementia, psychological disturbances and chorea- motorsensory abnormalities. It is a progressive, non-reversible and debilitating disease that affects the brain cells. The Huntington’s Disease gene called huntingtin, is located in chromosome 4. Also called, Huntington’s chorea, it is the first disease mapped using gene markers. This has made it possible for genetic testing to be made available for potential carriers of the gene. Consequently, this has also resulted in depression in populations susceptible to the disease. However, because of its historical value as the first gene mapped disease, more studies are being made to fully understand the pathogenesis of this disease, and in turn, more therapeutic modalities are being explored. The most effective approach seems to be one that is multi-modal, which includes all perspectives relevant to the development and consequently, eventual cure for this debilitating disease.
PERSPECTIVES ON HUNTINGTON’S DISEASE
PERSPECTIVES ON HUNTINGTON’S CHOREA:
NEUROLOGICAL DEGENERATIVE BRAIN DISEASE
INTRODUCTION
Huntington disease (HD), also known as Huntington’s chorea is a neurodegenerative disease that is characterized by the irreversible wasting away of the nerve cells in the brain.
“It is an incurable, adult-onset, autosomal dominant inherited disorder associated with cell loss within a specific subset of neurons in the basal ganglia and cortex. [This disease was]… named after George Huntington, the physician who described it as hereditary chorea in 1872. The name “chorea” comes from the Greek word for “dance” and refers to the incessant quick, jerky, involuntary movements that are characteristic of this condition. Other features of HD include dementia, and behavioral changes.” (Revilla, 2005, 1)
Huntington’s disease is said to be the result to a genetic defect on chromosome number 4. With this defect, there is a repetition of the “cytokine-adenosine-guanine” (CAG) more than the usual number of times. Normally, this section of DNA is repeated 10 to 35 times. But in persons with Huntington’s disease, it is repeated 36 to 120 times. This results in the encoding of a polyglutamine tract in the N-terminus of the protein product called huntingtin.
According to experts, the function of huntingtin is not known. Normally, it is located in the cytoplasm. The association of huntingtin with the cytoplasmic surface of a variety of
PERSPECTIVES ON HUNTINGTON’S DISEASE
Organelles, including transport vesicles, synaptic vesicles, microtubules, and mitochondria, raises the possibility of the occurrence of normal cellular interactions that might be relevant to neurodegeneration. N-terminal fragments of mutant huntingtin accumulate and form inclusions in the cell nucleus in the brains of patients with HD, as well as in various animal and cell models of HD. (Revilla, 2005, 1)
This is further supported by Cepeda et al in an article “The corticostriatal pathway in Huntington’s Disease”:
“The protein coded by the HD gene (huntingtin) is a large protein that is highly conserved and expressed throughout the body. In the brain, it is predominantly found in neurons although recent studies have provided important clues, its exact function still remains a mystery (However, huntingtin is essential for embryogenesis and normal development, and the loss of normal huntingtin function may contribute to the pathogenesis of HD. Increasing normal huntingtin expression improves neuronal survival and attenuates the effects of the mutant protein Huntingtin is a cytoplasmic protein closely associated with vesicle membranes and microtubules, suggesting it may have a role in vesicle trafficking, exocytosis and endocytosis. In addition, its distribution is very similar to that of synaptophysin and it has been shown to associate with various proteins involved in synaptic function. Thus, it is probable that mutant huntingtin causes abnormal synaptic transmission in HD” (Cepeda et al, 2006)
PERSPECTIVES ON HUNTINGTON’S DISEASE
Huntington’s disease is an inherited condition caused by a single abnormal gene. It is an autosomal dominant disease, which means that if one parent carries in, the chances of passing it on to the offspring is immediately 50 %.
It is important to note that HD is the first disease that had been mapped using DNA morphisms in 1983. The actual isolation of the specific gene that caused it happened in 1993. According to the National Genome Research Institute, a collaborative group of 58 researchers in 6 research groups isolated a gene called huntingtin located on chromosome 4p16.3.
NEUROLOGICAL ISSUES
Despite the great leaps that have been made in the understanding of this progressive and debilitating disease, more research is still being undertaken to date.
Leegwater and Cha in their article “The Paradigm of Huntington’s disease: Therapeutic Opportunities in Neurodegeneration” (2004) discusses the salient points in the study of Huntington’s disease, from a neurological perspective. The article goes on to discuss the different mechanism of pathogenesis in HD. The topics on pathogenesis included: excitotoxicity, the “death of neurons as a result of overactivity of glutamate neurotransmission”, apoptosis/caspases or programmed cell death, mitochondrial dysfunction and transcriptional dysregulation. The authors used these concepts to discuss the neurological therapies which can be applied to alleviate the clinical manifestations of Huntington’s disease. The articles goes on to state that
PERSPECTIVES ON HUNTINGTON’S DISEASE
“Examination of human postmortem material as well as informative transgenic animal models has made it clear that although there is a single genetic cause, there are in fact numerous pathologic mechanisms that are unleashed in HD. While the multiplicity of disease mechanisms makes it unlikely that any single therapeutic approach will be successful, this complexity makes credible the idea that combination therapy could be successful. In the future, innovative therapies such as selective disease allele inactivation or neural transplantation are also like to play a valuable role in attacking HD. A combinatorial cocktail approach targeting each of these important mechanisms is likely to yield, at long last, an effective therapy for this dreaded disease.” (Leegwater-Cha and Kim, 2004)
Another article that delves into the neurobiological issues concerning HD is by Cepeda et al in 2007. The article “The Corticostriatal Pathway in Huntington’s Disease” is a review that “summarizes results obtained from genetic HD mouse models concerning various alterations in this pathway” (Cepeda et al, 2 007). This analysis of the general neurological involvement in HD is a very technical paper which discusses the corticostriatal pathway in detail. It initially expounds on the genetic mouse models of HD and follows this with a discussion of the corticostriatal pathway and its target neurons in the striatum”. The article then links the preceding topics with further discourse on Electrophysiology and morphology of the striatum and cortex in mouse models of HD. The other parts of the article contain more technical discussions on Synaptic Plasticity, Selective Neuronal Vulnerability. In the latter part of the paper, there is a recommendation on how to “rescue” synaptic dysfunction in this disease. It can be summarized in these statements:
PERSPECTIVES ON HUNTINGTON’S DISEASE
“It has been generally assumed that treatment of HD should be aimed at reducing glutamate release in the corticostriatal pathway; but as demonstrated, with disease progression, synaptic activity decreases until the striatum becomes functionally disconnected from the cortex. Thus, reducing glutamate release at this stage would not be effective. Furthermore, reducing glutamate release deprives the striatum of important neurotrophic factors. However, reducing glutamate release when the first signs of dysregulation in the corticostriatal pathway occur could be therapeutic.” (Cepeda et al., 2007).
In its conclusion, the article elucidates the findings by stating that the disturbances in cortical function may be indicative of the mechanisms of the cognitive and emotional abnormalities characteristic in Huntington’s disease. It also states that “Alterations in striatal output, in the absence of significant cell loss, will ultimately lead to the disruption of sensorimotor control.” (Cepeda et al, 2007). These observations point out that the interventions in alleviating the clinical manifestations of HD should “target neuronal dysfunction and should be aimed at abnormalities in both cortex and striatum.”
The article is a comprehensive and precise argument that seems to advocate the prioritization of addressing neurological issues in the development of HD in order to arrest it’s progression to sensorimotor and psychological disturbances.
PSYCHOLOGICAL ISSUES OF DIAGNOSIS
According to Revilla (2005) in his article on Huntington’s disease, the estimates of the prevalence of HD in the United States range from 4.1-8.4 per 100,000 people. Internationally, the frequency of HD in different countries varies greatly. A few isolated populations of western
PERSPECTIVES ON HUNTINGTON’S DISEASE
European origin has an unusually high prevalence of HD that appears to have resulted from a founder effect. These include the Lake Maracaibo region in Venezuela (700 per 100,000 people), the island of Mauritius off the South African coast (46 per 100,000 people), and Tasmania (17.4 per 100,000 people). The prevalence in most European countries ranges from 1.63-9.95 per 100,000 people. The prevalence of HD in Finland and Japan is less than 1 per 100,000 people. (Revilla, 2005)
This article also discusses salient points on Huntington’s disease. It states that
“Most studies show a mean age at onset ranging from 35-44 years. However, the range is large and varies from 2 years to older than 80 years. Onset in patients younger than 10 years and in patients older than 70 years is rare. The Venezuelan kindreds manifest an earlier mean age of onset (34.35 y) when compared with Americans (37.47 y) and Canadians (40.36 y). The mean age at death in all major series ranges from 51-57 years, but the range may be broader. Duration of illness varies considerably, with a mean of approximately 19 years. Most patients survive for 10-25 years after the onset of illness (Revilla. 2005)
The article also mentions the occurrence of Juvenile HD which accounts for approximately 5-10% of all affected patients. It is said that inheritance through the father can lead to earlier onset through succeeding generations, a phenomenon termed anticipation. Another point discussed by the article was the importance of CAG repeat length. This correlates inversely with age of onset, and the correlation is stronger when the onset of symptoms occurs earlier. The length of the CAG repeat is the most important factor in determining age of onset of
PERSPECTIVES ON HUNTINGTON’S DISEASE
HD. Revilla further stresses that “both genetic and environmental components account for this variability as substantiated by research done by The US-Venezuela Collaborative Research Project on Venezuelan HD kindreds, the world’s largest genetically related HD community (18,149 individuals spanning 10 generations) since 1979, collecting genetic and clinical data.
Based on the facts on Huntington’s disease diagnosis, several studies were examined by this author in order to learn of the psychological issues involved with this disease.
“Compared with other dominantly inherited genetic traits leading to adult onset disorders, predictive testing for Huntington’s disease has been offered for the longest time.4 Carriers will definitely get the disease—that is, Huntington’s disease confers 100% penetrance, which refers to the proportion of carriers of a genetic alteration who will manifest the effects of it and is equivalent to lifetime incidence. Non-carriers definitely will not develop the disease. (Meier & Dunn, 2000).
From these statements, it is therefore not unlikely that the diagnosis of HD will lead to psychological disturbances that stem from the reception of the diagnosis other than the psychological manifestations associated with the disease process itself.
Meiser and Dunn in 2000 presented a review on the literature regarding the psychological impact of genetic testing for Huntington’s disease. With HD being the first disease that was mapped using genes, genetic testing for this disease had long been made available. The Article discusses the studies made on the psychological impact on the HD gene carriers relating to the increased incidence rate ever since genetic testing was made available. The review reveals that:
“About 10%–20% of people at risk request testing when approached by registries or testing centers. Most of the evidence suggests that non-carriers and carriers differ
PERSPECTIVES ON HUNTINGTON’S DISEASE
Significantly in terms of short term, but not long term, general psychological distress. Adjustment to results was found to depend more on psychological adjustment before testing than the testing result itself”. (Meiser & Dunn, 2000)
The article goes on to recommend that routine assessment of levels of depression and hopelessness be combined with formal assessment tools and referral to clinical psychologist be made , especially for those with high levels of depression, for those considering genetic testing , given the potential resultant psychological disturbance after genetic determination of HD
Meanwhile, Siesling et al in 2000 examined the correlation of diagnosis tools and their accuracy of predicting the development of Huntington’s disease. The study aimed to determine the extent the direct assessment of CAG repeat length has allowed the diagnoses of additional patients, with atypical psychiatric or neurological disease, or those without a family history, that could otherwise not be diagnosed using traditional criteria.”
The study examined 191 patients with suspected HD between July 1993 and January 1996. CAG repeat lengths, family history in the Leiden roster (where all families with HD are traced) were examined. The data was analyzed retrospectively and subdivided into groups, positive, negative and suspect with HD. Patients with expanded CAG repeat were diagnosed with HD. THE family history was compared with repeat length of CAG and the clinical features of HD. In conclusion, it was found that the new approach, using CAG repeat lengths, HD in many more patients could be more accurately predicted than the other methods, even with verification of family history in the Leiden roster. The study states further that since most studies used the older, less accurate methods of determination, it is possible that the prevalence of Hunting ton’s disease has been underestimated.
PERSPECTIVES ON HUNTINGTON’S DISEASE
CONCLUSION
With the preceding studies done in different areas and with varying perspectives on Huntington Disease, it can be surmised that the understanding of this disease ever since it’s discovery in 1872 has widely expanded. Its historical significance as being the first disease with its gene mapped in 1983 has not been lost on the academic community as seen in the proliferation of studies continually made and updated to augment to the existing knowledge on the disease process and its onset. With such enthusiastic pursuit of knowledge in the fields of neurobiology, pharmacology, psychology and genetics, it may not be long until Huntington’s disease will be another first – in reversibility and curability through further research and assiduous experimentation.
PERSPECTIVE ON HUNTINGTON’S DISEASE
REFERENCES:
Cepeda,C. Wu,N. André,V.M., Cummings,D & Levine,M.S.(2007)
“The Corticostriatal Pathway in Huntington’s Disease”. Progressive Neurobiology,81, 253-271.
Curtis,M.A, Penney E.B., Pearson A.G., van Roon-Mom W.M.C., Butterworth N.J., Dragunow,
M., Connor, M. Faull, R.L.M (2003)“Increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain.” Proceedings of the National Academy of Science of USA. , 100, 9023–9027
Leegwater-Kim, J.& Cha,J. (2004) The Paradigm of Huntington’s Disease:
Therapeutic Opportunities in Neurodegeneration. The Journal of the American Society for Experimental NeuroTherapeutics,1, 128–138. Retrieved April 20, 2008 from PubMed Central database.
Meiser,B. & Dunn S.(2000)
“Psychological impact of genetic testing for Huntington’s disease: an update of the literature” Journal of Neurology Neurosurgery and Psychiatry,69, 574–578
S Siesling,M Vegter-van de Vlis,M Losekoot, R D M Belfroid, J A Maat-Kievit,H P H Kremer,
R A C Roos. (2000) “Family history and DNA analysis in patients with suspected Huntington’s disease” Journal of Neurology Neurosurgery and Psychiatry;69:54–5
WebMD,Inc.(2005, December 15) “Huntington’s Disease” by Revilla, F. Retrieved April 20,2008, from http://www.emedicine.com/NEURO/topic81.htm