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A case study of Huntington’s disease
Alicia Mangin and Marla Gabriele
Abstract
This case study systematically describes the genetic mutations involved in Huntington’s
disease. It provides basic research on the genes and proteins involved in the trinucleotide
sequence expansion that results in Huntington’s disease. A case study reveals Patients X’s
genetic background, family history, and steps following the prognosis.
Disclaimer
The purpose of the writing is to fulfill course requirements for BB H 411W and to stand as a
personal writing sample, but the findings should not be treated as generalizable research.
Introducing the Disease and Case Study
Huntington’s disease is an autosomal, dominant condition that deteriorates the
brain function of those affected. Typically, the onset for this condition arises between the
ages of 30 and 50, although symptoms can appear even earlier. The disease is recognized
through memory loss, uncontrollable movements, depressive feelings, and altered moods.
Furthermore, in the later stages of Huntington’s disease, those affected lose ability to do
tasks on their own. Biologically, the disease disrupts cells within the basal ganglia. The
mutation of the huntingtin protein ultimately occurs through a gene on chromosome four.
This mutation consists of a trinucleotide repeat expansion of the base sequence CAG,
extending up to more than 40 of these sequences. As a result, those affected by
Huntington’s have an abnormal product of protein that build up in the brain and become
toxic (Louisa, et al., 2015). Studies have shown significant effects on whole-brain volumes,
deterioration with neurophysiological motor tasks, and cognitive functioning in Huntington
carriers (Tabrizi, et al., 2009).
A particular individual, Jared, 35 years old, had been experiencing difficulty walking
and talking and had been showing signs of depression. Jared also had been experiencing
difficulty remembering things that he had done and things that had happened to him. With
Jared’s father having Huntington’s disease, and recognizing these symptoms, he decided to
A case study of Huntington’s disease
Alicia Mangin and Marla Gabriele
have himself checked out by a specialist in the field. Jared had initially been encouraged to
have predictive tests for the HD genetic mutation, but Jared consistently refused because he
wanted to live his life without knowing this information. However, with Jared beginning to
show small deficits in motor functioning, he decided to get the diagnostic test. Upon visiting
a physician, whom specializes in genetic abnormalities, a physical examination was
conducted, followed by neurological and psychological exams. The neurologist asked
questions and ran tests based upon Jared’s reflexes and coordination, as well as his sensory
ability. Furthermore, a psychiatrist analyzed and examined Jared’s judgments and overall
emotional state. Jared’s doctor also ordered a brain-imaging test in order to determine any
changes that may have resulted from Huntington’s disease. The doctors, after recognizing
these symptoms and completing these examinations, ran a genetic test on Jared, confirming
his inheritance of the mutated gene and Huntington’s disease (Pruthi, 2014). The test the
doctor performed used PCR to quantify the number of tandem repeats in the expansion of
Jared’s DNA. As a result, Jared’s doctor explained the implications of the disorder and
provided him with physical and speech therapy to help with his difficulty walking and
talking, along with antidepressant medications to treat his depressive symptoms.
Genetic Description
Huntington’s Disease is a genetic condition inherited by an autosomal, dominant
genetic mutation with a faily late onset (Gusella, et al., 1983). Therefore, those with this
inherited mutation have children before showing any signs of having Huntington’s. This is
why there are family studies available to this degenerative disorder.
A case study of Huntington’s disease
Alicia Mangin and Marla Gabriele
The genetic markers of Huntington’s disease are found on the short arm of
chromosome four, 4p16.3 (Xu, et al., 2009). The nucleotide sequence, cytosine-adenineguanine (C-A-G), genotype repeats are identified in the HD gene, scientifically as IT15,
which proves to be a significant characteristic in patients with Huntington’s disease
phenotype. This gene codes for a protein called the huntingtin protein, and the mutation in
repeats on this gene results in Huntington’s disease, a degenerative disorder. When closely
looking at the HTT gene, the USCS Genome Browser shows a high amount of introns on the
chromosome and the intron density is similar throughout different species. This gene has
ancestral heritability and there are close similarities with other mammals, but closest to
the monkey.
Given that Huntington’s disease is an autosomal dominant genetic disorder, if a
person contains this genetic marker for this disease, they will become symptomatic. The
offspring of one parent with Huntington’s and one parent without have a 50% of inheriting
the genetic mutation and develop the disease (Williams, et al., 2010). Given this high
heritability percentage, there are options for predictive testing to see if a child of a parent
with Huntington’s has the genetic markers for this disease. Predictive testing identifies an
expansion in tandem repeats on the HD gene, specifically the IT15 gene on 4p16.3 of
chromosome 4 (Williams, et al., 2010).
Familial studies compared Family I, with 64 members, eight of which with
Huntington’s Disease (four alive and four deceased), with Family II, having 16 members
and two Huntington’s Disease patients (one alive and one dead). This study looked at the
HD gene (IT15) on chromosome 4 (4p16.3). The CAG repeat on this gene ranges from 6 to
35 tandem repeats (Xu, et al., 2009). According to the American Genetic Association and the
A case study of Huntington’s disease
Alicia Mangin and Marla Gabriele
American Society of Human Genetics, in order to diagnose Huntington’s disease, there must
be more than 40 tandem repeats for the carrier of this mutation to be completely
symptomatic. In these family studies, it found that CAG repeats in HD gene exon 1 was the
most important factor; however, there is a 50% to 70% variance in the size of the tandem
repeats, showing that the size of the repeat is not the single determinant for developing
Huntington’s Disease (Xu, et al., 2009).
In addition to variance in the size of the repeat sequence, studies also examine this
variance in size affecting age-at onset. The cognitive defects and related symptoms occur
usually between 40 and 50 years of age, however; the CAG repeat number accounts for 4270% of the variance in age of onset (Metzger, et al., 2006). Specifically, 52% of the variance
in age-at-onset is due to the effect of the tandem repeats of CAG (Metzger, et al., 2006). A
negative correlation (-0.58) has been proven to be significant (p < 0.01) between age-atonset and mutation size (Simpson, et al., 1993). This significance shows that the greater the
mutation size, meaning more CAG repeats on the gene, relate to a younger age of onset in
Huntington’s Disease patients.
As it is known that the more CAG repeats, the earlier age of onset of Huntington’s
disease, the reasoning for this is relatively unknown. There are few theories that have been
proposed for why this occurs, but more research is needed. One theory proposed for the
CAG repeat and age-of-onset correlation deals with homogeneous nucleation. It is
suggested that polyglutamine sequencing occurs by nucleated growth polymerization. As a
result, predicted aggregation times are approximately the same between repeat-lengthdependent differences and length-dependent age-of-onset, therefore influencing disease
onset (Songming, 2002). Another well-studied theory behind this correlation suggests that
A case study of Huntington’s disease
Alicia Mangin and Marla Gabriele
earlier age-of-onset of Huntington’s disease occurs with more repeats due to DNA repair
mechanisms attempting to correct the mutation. Studies in transgenic mice showed that
oxidation of guanine nucelotides directly lead to neurodegeneration, even death. These
oxidized striatal cells were noted as an important factor of the progress of this disease
(DeLuca, 2008). Further research must be done in order to determine the reasoning behind
the detrimental effects of this gene.
References
DeLuca, G. (2008). A Role for Oxidized DNA Precursors in Huntington's Disease–Like
Striatal Neurodegeneration. Plos Genetics, 10(1).
Gusella, J., Wexler, N., Conneally, P., Naylor, S., Anderson, M., Tanzi, R., et al. (1983). A
polymorphic DNA marker genetically linked to Huntington's disease. Nature, 306,
234-238.
Louisa, S., & Steve, R. (2015). Huntington's Disease. Retrieved November 18, 2015, from
http://learn.genetics.utah.edu/content/disorders/singlegene/hunt/
Metzger, S., Bauer, P., Tomiuk, J., Laccone, F., DiDonato, S., Gellera, et al. (2006). Genetic
analysis of candidate genes modifying the age-at-onset in Huntington’s disease.
Human Genetic, 120(2), 285-292.
Pruthi, S. (2014, July 24). Huntington's disease. Retrieved November 18, 2015, from
http://www.mayoclinic.org/diseases-conditions/huntingtons-disease/basics/testsdiagnosis/con-20030685
Simpson, S., Davidson, M., & Barron, L. (1993). Huntington's disease in Grampian region:
Correlation of the CAG repeat number and the age of onset of the disease. Journal of
Medical Genetics, 30(12), 1014-1017.
Songming, C., et al. (2002). Huntington's disease age-of-onset linked to polyglutamine
aggregation nucleation. PNAS, 99(18), 11884-11889.
Tabrizi, S., Langbehn, D., Leavitt, B., Roos, R., Durr, A., Craufurd, D., et al. (2009). Biological
and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD
study: Cross-sectional analysis of baseline data. The Lancet Neurology, 8(9), 791801.
UCSC Genome Browser: Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM,
A case study of Huntington’s disease
Alicia Mangin and Marla Gabriele
Haussler D. The human genome browser at UCSC. Genome Res. 2002 Jun; 12(6):9961006.
Williams, J., Barnette, J., Reed, D., Sousa, V., Schutte, D., Mcgonigal-Kenney, M., et al. (2010).
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Xu, E., Tang, Y., Li, D., & Jia, J. (2009). Polymorphism of HD and UCHL-1 genes in
Huntington’s disease. Journal of Clinical Neuroscience, 16(11), 1473-1477.