Huntington's Disease: Understanding & Treatment

This assignment delves into Huntington's disease, a debilitating neurodegenerative disorder. It examines its genetic basis (HTT gene), pathophysiology (synaptic dysfunction), clinical manifestations (chorea, cognitive decline), and available treatment options. The assignment also highlights the emotional toll on families and discusses ongoing research efforts aimed at developing effective disease-modifying therapies.

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HUNTINGTON’S DISEASE
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Huntington’s Disease
Huntington’s disease (HD) is a dominantly inherited neurogenerative disorder
resulting from the unstable expansion of the CAG trinucleotide in the HTT gene
(Raymond, et al., 2011). The HTT gene serves as an instruction template for the
protein huntingtin. The exact function of huntingtin is, however, unknown but it is
proposed to play a role foetal development before birth, and also has a role in nerve
cells (NIH, 2015). HD is a progressive disorder characterised by unwanted choreatic
movements.
Pathophysiology
The expanded CAG repeat produces an extended polyglutamine tail on the huntingtin
protein, and this causes the protein to cleavage and also generate toxic fragments
(Jankovic & Ashizawa, 2008). The polyglutamine content in the toxic fragments
prompts cross-linking, and this forms aggregates that are resistant to degradation, and
also causes interference with various normal cellular functions, predominantly
mitochondrial energy metabolism, disrupted calcium signalling, abnormal protein
interactions, transcriptional dysregulation of a variety of genes, alterations in axonal
transportation of critical factors, autophagy, and altered proteasomal functioning
(Zuccato, et al., 2010; Johnson & Davidson, 2010). A reduction in the level of wild-
type huntingtin has not shown to be contributing to the disease, it, however, magnifies
the adverse effects of the generated fragments.
The disease primarily affects the striatum, and the clinical presentation is primarily as
a result of the damage (mainly cell loss and gliosis), include behaviour changes,
cognitive impairment, and loss of coordination (Jankovic & Ashizawa, 2008).
Additionally, further pathological changes are also evidenced in several other cortical

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and sub-cortical structures (Rosas, et al., 2008). The hallmark feature of Huntington’s
disease (chorea), results from striatal dysfunction.
This pathological process is the most accepted and as a result, therapeutic
interventions are being designed to improve mitochondrial function, facilitate
retardation of apoptosis, enhance autophagic consumption of mutant proteins, block
the cleavage of huntingtin at the sites that produce the toxic fragments, and also
improve cell-cell interactions (Hannan, 2005).
Existing treatments
1. Drug therapy
Neuroleptics such as haloperidol (typical) and olanzapine (atypical), benzodiazepines
the monoamine-depleting agent tetrabenazine are used to suppress choreic movements
(Huntington Study Group, 2006). While psychiatric disturbances that include
depression are managed using psychotropic and antiepileptic agents (Frank, 2014)
However, pharmacological treatment is only limited to the treatment of signs and
symptoms and cannot change the disease development or progression (Killoran &
Biglan, 2014). Further, chorea may be exacerbated by L-dopa containing compounds
(Warby, et al., 2014)
2. Non-medication interventions
Persons suffering from Huntington’s disease require psychotherapy from a
psychotherapist to help in the management of behavioural problems, help the patient
in developing coping strategies, and also manage the patient’s expectations through
the disease progression. Speech therapy and physical therapy may also be indicated
because HD can impair the control of muscles. A speech therapist will help the patient
improve their ability to speak clearly, or in the use of communication devices.

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Physical therapy will help the patient enhance coordination, balance, flexibility, and
strength.
Persons with HD also require supportive care with special attention to nursing, diet,
special equipment, emotional support, counselling, practical help and relief in forms
such as state and federal benefits (Williams, et al., 2009).
The primary inadequacy of non-pharmacological treatment is that it cannot be used as
the primary treatment in the treatment of HD, but rather as secondary.
3. Surgical treatment
Surgical treatment plays a minimal role in HD. Surgical interventions are basically in
the experimental phase and they include ablative surgery and cell transplantation
(Demeestere & Vandenberghe, 2010). These interventions show some promise but
their efficacy has not been fully demonstrated. The primary advantage of surgical
interventions is the possibility that they can modify the course of the disease. On the
other hand, the primary disadvantage is that these procedures are that for the treatment
of a widespread disease such as Huntington’s disease, the effects of the surgery tend
to be confined to the local region where it is performed (Demeestere &
Vandenberghe, 2010).
The impact on the individual & health system of the disease and treatment
Research on the economic cost of HD has not been well studied. There are only two
notable studies on the same, one being conducted in the US (Divino, et al., 2013), and
another in Europe (Busse, et al., 2011). The authors also claim that the primary cost in
HD is the primary healthcare component. From the two studies, it is evident that the
direct economic burden of the condition is substantial and it increases as the disease
progresses. In 2013, the estimated cost for the treatment of an HD patient was $4,947

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in the early HD stage, and this rises to $22,582 in the late stage, whereas in the UK,
the earliest stages cost approximately £2250 per person and £89 760 in the later stages
(Jones, et al., 2016).
Other than the direct economic cost, HD has a significant impact on both the
individual and their family. The onset of the disease’s signs and symptoms is 35-45
years (Vamos, et al., 2007). This is the period when the family-life cycle is most
complex, as characterised by childbearing and rearing and career development. The
family suffers a great deal of distress and grief in the sense that they have to mourn
those who have passed on and anticipated further losses for those who will die.
Overall burden of disease
It is estimated that 5 to 7 persons per 100,000 are affected by HD in the Western
Countries (Australian Huntington's Disease Association, 2017). This is however not
in the case as some regions of Western Europe have no HD whereas the concentration
is quite high in others as evidenced in Lake Maracaibo in Venezuela where the
prevalence is approximately 700 per 100,000 (Australian Huntington's Disease
Association, 2017). As per the Australian Huntington's Disease Association, in
Australia, approximately 1,800 people have the condition whereas another 9,000 are
at risk. Its prevalence in Australia has been evidenced to increase at 15-20% per
decade (Rawlins, et al., 2016). In the UK, it is estimated that 12 out of every 1000,
000 people are affected (Evans, et al., 2013), whereas in the US, 7 out of every
100,000 persons are at risk of developing the condition (Rawlins, et al., 2016).
According to Rawlins et al., the lowest rates of HD are seen among Asians.

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References
Australian Huntington's Disease Association, 2017. How Common Is Huntington's
Disease (HD)?. [Online]
Available at: https://www.huntingtonsnsw.org.au/information/hd-facts/how-common
[Accessed 18 September 2017].
Busse, M. et al., 2011. Utilisation of Healthcare and Associated Services in
Huntington's disease: a data mining study.. PLoS Curr. , 21(3), p. RRN1206.
Demeestere, J. & Vandenberghe, W., 2010. Experimental Surgical Therapies for
Huntington’s Disease. CNS Neuroscience and Therapeutics, 17(6), pp. 705-713.
Divino, V. et al., 2013. The direct medical costs of Huntington's disease by stage. A
retrospective commercial and Medicaid claims data analysis.. J Med Econ., 16(8), pp.
1043-50.
Evans, S. et al., 2013. Prevalence of adult Huntington's disease in the UK based on
diagnoses recorded in general practice records.. J Neurol Neurosurg Psychiatry,
84(10), pp. 1156-60.
Frank, S., 2014. Treatment of Huntington’s Disease. Neurotherapeutics, 11(1), pp.
153-160.
Hannan, A. J., 2005. Novel therapeutic targets for Huntington's disease.. Expert Opin
Ther Targets., 9(4), pp. 639-50.
Huntington Study Group, 2006. Tetrabenazine as antichorea therapy in Huntington
disease: a randomized controlled trial.. Neurology, 66(3), pp. 366-72.
Jankovic, J. & Ashizawa, T., 2008. Huntington's disease.. In: J. Noweworthy, ed.
Neurological Therapeutics: Principles and Practice. London: Martin Dunitz, pp.
2550-2561.
Johnson, C. D. & Davidson, B. L., 2010. Huntington's disease: progress toward
effective disease-modifying treatments and a cure. Human Molecular Genetics,
19(R1), p. R98–R102.
Jones, C. et al., 2016. The societal cost of Huntington's disease: are we
underestimating the burden?. Eur J Neurol., 23(10), p. 1588–1590.
Killoran, A. & Biglan, K., 2014. Current therapeutic options for Huntington's disease:
good clinical practice versus evidence-based approaches?. Mov Disord, 29(11), pp.
1404-13.
NIH, 2015. HTT gene. [Online]
Available at: https://ghr.nlm.nih.gov/gene/HTT
[Accessed 19 September 2017].

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Rawlins, M. et al., 2016. The Prevalence of Huntington's Disease..
Neuroepidemiology, 46(2), pp. 144-53.
Raymond, L. A. et al., 2011. Pathophysiology of Huntington’s Disease: Time-
Dependent Alterations in Synaptic and Receptor Function. Neuroscience, 15(198), pp.
252-273.
Rosas, H. D. et al., 2008. Cerebral cortex and the clinical expression of Huntington's
disease: complexity and heterogeneity.. Brain, 131(4), pp. 1057-1068.
Vamos, M., Hambridge, J., Edwards, M. & Conaghan, J., 2007. The Impact of
Huntington’s Disease on Family Life. Psychosomatics, 48(5), pp. 400-405.
Warby, S. C., Graham, R. K. & Hayden, M. R., 2014. Huntington Disease. In: R.
Pagon, M. Adam & H. Ardinger, eds. Gene Reviews. Seattle: University pf
Washington.
Williams, J. et al., 2009. The emotional experiences of family carers in Huntington
disease. J Adv Nurs, 65(4), pp. 789-98.
Zuccato, C., Valenza, M. & Cattaneo, E., 2010. Molecular mechanisms and potential
therapeutical targets in Huntington's disease. Physiol Rev., 905(81), pp. 905-981.