NEUROGENERATIVE

DISORDERS: DISCUSSING
HUNTINGTON’S DISEASE
AND ITS POSSIBLE
TREATMENTS

Student Name: Nanou Maria

Neptun Code: CLHW6H

Course Name: Biological Basic Knowledge II

Course Code: PSZI1004

Word Count: 1,694

2021/2022/2
Table of Contents
Introduction ......................................................................................... 2

Huntington ‘s disease ........................................................................... 2

Aetiology .......................................................................................... 3

Diagnosis .......................................................................................... 3

Research .............................................................................................. 4

Promising treatments ........................................................................... 4

Biomarkers ....................................................................................... 5

Stem cells ......................................................................................... 6

Brain Development ........................................................................... 6

Summary ............................................................................................. 7

Works Cited ......................................................................................... 8

Introduction
Degenerative nerve diseases pose a daunting threat to the health of many people,
especially elders, reporting higher numbers constantly. These, primarily, age
dependent diseases are diverse in their pathophysiology affecting the body’s cognitive
abilities and activities such as balance, breathing, movement, talking and even heart
functions (Gitler, Dhillon, & Shorter, 2017).

Some examples of neurodegenerative diseases are Parkinson’s disease,

Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS) etc. and their causes can
vary (Roos, 2010). Nevertheless, the majority of these illnesses originate from genetics
or medical conditions such as alcoholism, tumour, or stroke. Other times, rarer, these
disorders can be attributed to toxins, chemicals, or viruses (University of Utah Health
Communications, 2022).

Mouse, fruit flies, nematode worms and even baker’ yeast have been employed in
order to study degenerative nerve diseases. However, in order to provide effective
treatment to such complex diseases further understanding is needed. Lamentably, even
the existing treatments do not cure the patients from their disorder, but they only
improve the symptoms, alleviate pain, and enhance mobility (Gitler, Dhillon, &
Shorter, 2017).

One of the many inherited neurodegenerative disorders is Huntington’s disease, rare

but dominant disease for which researchers are constantly attempting to find a treatment
for.

Huntington ‘s disease
As aforementioned Huntington’s disease, - or else HD-, is not frequent and a rather
dominant illness causing the progressive degeneration of nerve cells in various
locations in the brain causing impairment in movement such as unwanted choreatic
movements and impeding cognitive abilities whilst also resulting in psychiatric
disturbance (Roos, 2010). Other less known features of HD are involuntary weight
loss, circadian rhythm disturbances and autonomic nervous system dysfunction (Anil,
Mason, & Barker, 2020).
 ‘’When HD develops, you do no longer always see motor, mental, and behavioral
signs all at once,” states Meghan Zorn, currently under the tenure of co-directing at
the University of Utah Huntington's Disease Center of Excellence (University of Utah
Health Communications, 2022). It is worth highlighting that even though the
predisposition for the disease is encoded on one’s DNA the onset of the symptoms can
appear around the age thirty to fifty with fully penetrance at the age of sixty-five
(Roos, 2010).

Aetiology
As aforementioned, the disorder passes through families, and it is monogenic and
fully penetrant. The cause of this HD is the misfolding of a protein, caused by CAG
triplet repeat expansion in Huntingtin protein (HTT), the short arm of chromosome
4p16.3 in the Huntingtine gene, which encodes an elongated polyglutamine stretch in
HTT (Gitler, Dhillon, & Shorter, 2017). Furthermore, the huntingtin protein is very
large and serves many functions, but in people with HD, a DNA error causes the
protein to aggregate in protein clumps in the brain cells, causing them to become
damaged and die (Roos, 2010).

Huntington's disease is associated with thirty-six or more repeats. If the number of

copies surpasses forty, there will be definite clinical manifestations. The age range of
thirty-six to thirty-nine results in either an incomplete penetrance of the disease or an
extremely late onset. The range of twenty-nine to thirty-five alleles, known as
intermediate alleles, is unstable, which means that these alleles are susceptible to
changes during reproduction. Copying the gene may result in errors and, in most cases,
elongation rather than shortening. This phenomenon is observed in the male
reproductive line (Anil, Mason, & Barker, 2020).

Huntington’s disease is characterized by autosomal dominance meaning that if one

biological parent carries this abnormal gene it is enough to cause it to the offspring
(University of Utah Health Communications, 2022).

Diagnosis
A diagnosis from a person with a parent proven with HD is based on clinical
symptoms. Currently, the way diagnosis is conducted is through DNA determination,
displaying, as aforementioned, a CAG-repeat of at least thirty-six on the huntingtin
gene on chromosome 4. The clinical criteria that are currently required for a diagnosis
are motor alterations with or without psychiatric or intellectual changes (Roos, 2010).

Research
It is worth mentioning that a study was carried out in 2020 comparing thirty people
that were diagnosed either early in life or later on. The researchers compared disease
progression between the two groups, and it was found that complete motor defects,
impairments of mouth and throat movements, and bradykinesia progressed more
rapidly in early-onset patients. Interestingly, no variations have been determined
withinside the development of cognitive impairments or practical disability among
groups (Abdullah, 2020).

In another study, it was found that there is a correlation between the amount of
leisure time someone has and the severity of the symptoms of HD. To elaborate,
investigators found that spending more time in leisure activities, something that
contributes to one’s preservation of their cognitive abilities is associated with lesser
cognitive and functional decline in people with early manifestation of Huntington’s
disease. These findings, to cite the researchers, characterize that recreational activities
“make contributions to the increase of a selected cognitive reserve that modulates the
negative impact of brain impairment on cognition and independence in day by day
life’’ (Figueiredo, 2022).

Another study coordinated in 2021, highlighted that in asymptomatic patients’ time

perception, in contrast to symptomatic patients in early stages, is not altered or
impaired. A total of 70 participants took part in the study, 25 while being on the early
stages of HD, 20 being pre-Huntington and the rest 25 comprised the control group.
Overall results showed an imperative deficit in the time domain for Huntington's
patients (Bryson, 2022)

Promising treatments
According to recent international research conducted by Erin Furr Stimming, MD,
researcher at UT Health Houston, who was principal investigator for the KINECT-HD
 Huntington Study Group, a new drug has conclusively demonstrated helpful in the
treatment of a movement disorder typically associated with Huntington's disease
(Henderson, 2022).

It was reported that valbenazine, a selective vesicular monamine transporter 2

(VMAT2) inhibitor not yet approved by the United States Food and Drug
Administration, is designed specifically for Huntington's disease and that it was safe
and effective when provided as a once-daily treatment for chorea, - involuntary,
irregular movement, and the cardinal motor feature in Huntington's disease-, in
patients with Huntington's disease (Shasteen, 2022).

Another treatment under consideration focusing on gene therapy is the drug AMT-
130, infusing it into the patient’s brain. AMT-130 consists of a small part of artificial
genetic fabric referred to as microRNA (miRNA) that may bind to the messenger
molecule sporting the genetic facts vital to make huntingtin protein and mark it for
degradation. This outcomes withinside the reduced manufacturing of the ordinary
huntingtin protein, the underlying motive of Huntington’s disease (Shapiro, 2022).

Biomarkers
Since the gene was localized in 1983 and particularly after 1993, researchers have
been focusing on finding a therapy regarding the pathophysiological pathway while at
the same time focusing on biomarkers (Anil, Mason, & Barker, 2020).

Biomarkers comprise biological changes in an individual that are able to diagnose

and even predict a disease whilst monitoring it as well. Several international studies
have been focusing on identifying and validating biomarkers for HD (National Institute
of Neurological Disorders and Stroke, 2020). One of the aims of PREDICT-HD is to
see if the clinical course corresponded with changes in brain scan images or chemical
changes in blood, urine, or cerebrospinal fluid. Furthermore, another target would be
identifying measurable changes in personality, mood, and cognition that occur prior to
the onset of motor symptoms of HD (Roos, 2010).
 A related NINDS-funded (National Institute of Neurological Disorders and Stroke)
study seeks to identify additional human genetic factors that influence the disease's
progression. Locating genetic variants that decelerate or accelerate disease progression
holds the promise of providing important new targets for disease intervention and
therapy (National Institute of Neurological Disorders and Stroke, 2020).

Stem cells
Another possible treatment being under consideration and development are stem
cells. Scientists can take adult blood or skin cells and revert them to a pluripotent state
(known as iPS cells), from which they can become nearly all of the body's cells.
Researchers are employing cultures of these cell lines (produced from individuals with
HD who donated skin and blood samples for research) to explain why neurons
malfunction and die in HD, as well as to speedily test prospective future drugs through
a NINDS-funded consortium. Another method could be to mobilize stem cells that are
already present and capable of migrating into damaged tissue (National Institute of
Neurological Disorders and Stroke, 2020).

Brain Development
Changes in brain development may play a significant role in HD. Huntington is
displayed throughout life and during embryogenesis. Animal studies have revealed
that the standard HD gene is essential for brain development. Adults who hold the
mutant HD gene but have not yet developed symptoms have noticeable changes in
their brain structure, even up to 20 years prior to actual clinical diagnosis (Gitler,
Dhillon, & Shorter, 2017).

A NINDS-funded study is examining brain functioning in children, adolescents,

and young adults up to the age of 30 who are at likelihood of developing HD because
a parent or grandparent has the disease. The goal of this study is to spot potential HD
effects throughout the final stages of brain development (National Institute of
Neurological Disorders and Stroke, 2020).

Participants having the elongated gene will be evaluated by being compared to

those carrying the gene but have CAG repeats of 39 or less, as well as those who do not
have a family history of HD. Brain structure and/or function modifications in the gene-
elongated group may indicate a developmental element in HD (Gitler, Dhillon, &
Shorter, 2017).

Summary

Huntington’s disease affects people severely leading them, eventually to their

death. However, treatment is still under process with no drug in existence being able
to completely eradicate the illness, only to alleviate for a reduced amount of time,
some physical symptoms.

An optimised understanding of the pathophysiology will almost certainly

contribute to the development of drugs to intervene in the pathological process. Drugs
that can decelerate, delay, or make the disease's onset come at a halt are being pursued.
The second concern is the hunt for reliable, early-detection, and clinically significant
markers for the onset of the disease's end course.

It is also worth mentioning that Huntington’s disease, as proven by aforementioned

studies might be based on genetic modifiers however, environmental factors can
contribute greatly to the way the disease progresses and can also show another path to
scientists for possible effective treatment.
Works Cited
Abdullah, A. (2020), Late-onset Huntington’s Has Fewer Motor Defects, Similar
Cognitive Progression, Study Shows, retrieved from HUNTINGTON'S
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Anil, M., Mason, S., & Barker, R. (2020), The Clinical Features and Progression of
Late-Onset Versus Younger-Onset in an Adult Cohort of Huntington’s Disease
Patients, Journal of Huntington's Disease .
Bryson, S. (2022), Time Perception Impaired – but Only in Patients With Early
Symptoms, retrieved from HUNTINGTON'S DISEDASZE NEWS:
https://huntingtonsdiseasenews.com/2022/03/29/time-perception-impaired-
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Figueiredo, M. (2022), Leisure Time Helps Preserve Cognition, Function in Early
Huntington’s, retrieved from HUNTINGTON'S DISEASE NEWS:
https://huntingtonsdiseasenews.com/2022/02/22/leisure-time-helps-preserve-
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Gitler, A., Dhillon, P., & Shorter, J. (2017), Neurodegenerative disease: models,
mechanisms, and a newhope, The Company of Biologists.
Henderson, E. (2022), New drug shows promise in treating a movement disorder
associated with Huntington's disease, retrieved from Medical Life Sciences:
https://www.news-medical.net/news/20220413/New-drug-shows-promise-in-
treating-a-movement-disorder-associated-with-Huntingtons-disease.aspx.
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Hope Through Research, retrieved from National Institute of Neurological
Disorders and Stroke: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-
Education/Hope-Through-Research/Huntingtons-Disease-Hope-Through#7c.
Roos, R. A. (2010), Huntington’s disease: a clinical review, Orphanet Journal of Rare
Disease.
Shapiro, L. (2022), First 2 Groups Enrolled in Phase 1/2 Trial of Gene Therapy AMT-
130, retrieved from HUNTINGTON'S DISEASE NEWS:
https://huntingtonsdiseasenews.com/2022/03/22/amt-130-trial-huntingtons-
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Shasteen, H. (2022), Phase III Results Set Neurocrine Up for Huntington's Disease
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https://www.biospace.com/article/neurocrine-presents-positive-data-for-
treatment-targeting-chorea-associated-with-huntington-s-disease/.

University of Utah Health Communications. (2022), HUNTINGTON’S DISEASE:

WHO WILL INHERIT THE GENE?, retrieved from University of Utah Health
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