1. Genetics of Brain Disease: Huntington’s
Disease and Autism
Daniel Solis
Genetic cause of Huntington’s disease & Autism & results on connectomic
patterns
Association studies (single nucleotide polymorphisms or genes associated)
Causative gene for Huntington’s disease and prospective treatments or cure
The field of genomics has been increasing in both ease and cost of sequencing
genomes. Due to this, several neural disorders such as Huntington’s disease and
autism have been linked to certain genetic abnormalities. In the diseases mentioned,
these genetic abnormalities have, in the case of Huntington’s disease, been
discovered or, in the case of autism, remain a part of the neuropathology that still
needs further elucidation.
Key words: genomics, Huntington’s disease, autism, connectomics
Introduction
Huntington’s disease affects “more than a quarter of a million Americans”
indiscriminately through genetics directly by the disease or indirectly as a carrier. It
is a “devastating, hereditary, and degenerative brain disorder” with one symptom
treatment, Xenazine. These symptoms include “affected cognitive ability or
mobility… depression, mood swings, forgetfulness, clumsiness, involuntary
twitching and lack of coordination.” Eventually, death arises from complications of
these symptoms. 10 to 25 years later. These symptoms usually arise in mid-age,
“between the ages of 30 and 50” due to a certain trinucleotide repeat CAG of over
35+ times in a gene HTT which causes accumulation of given protein. This gene was
located in 1993 as the HD gene, and genetic testing can determine whether that
gene is present which will indicate an onset of the disease (Huntington's Disease
Society of America, 2014).
Autism is a neurodevelopmental disease that occurs in early brain development and
is observed through characterization of difficulties in “social interaction, verbal and
nonverbal communication and repetitive behaviors.” Currently, there is no medical
detection or cure; although, scientists have “identified a number of rare gene
changes associated with autism.” Any particular genetic cause is attributable to “15
percent of cases”, but most cases are a combination of these “risk genes and
environmental factors”. With 100 genes or gene changes leading to an increased risk
for autism, there is speculation that genetics are not the only factor in the
2. development of autism. Even though the connectomics of the brain is abnormal after
the development of the brain, there are “environmental stressors” that work in
conjunction with genetic predisposition to influence that abnormal development
caused by autism spectrum disorder (Autism Speaks, 2014).
Huntington’s Disease
As an inherited neurodegenerative disorder, it is an autosomal dominant; through
its 100% penetrance, it is prevalent in roughly “1/10,000 people.” Connectomes are
affected by the pathology of disease that causes a certain protein to have extremely
long “poly q’s” which act as loose protective ends of a protein. These extremely long
“poly “q’s” entangle and cause the proteins to become connected to each other. This
causes neuronal loss and gliosis which “diffuses cortical changes, and is primarily
frontal.” This neuronal loss is selective towards affecting “medium spiny neurons
that utilize (GABA). Because of this inhibitory neuron destruction, impulses are left
to easily propagate to other cells and cause one of the symptoms of the disease (U.S.
National Library of Medicine, 2013).
Figure 1 Poly Q CAG Lengths
,Figure 2 Results of Huntington's disease
3. Figure 3 Histogram of CAG Repeat Size in a Population
Huntington’s disease contains a genetic mutation in chromosome 4 section p16.3.
The genetic mutation has a very low spontaneous mutation rate meaning that it is
most likely to stay. Dubbed the IT15, it demonstrates “universal expression in
multiple tissues” with a “new class of protein important to neuronal function”,
huntingtin. Huntingtin is normally localized in cytoplasm but in Huntington’s
disease, the poly q’s entangle and allow the protein to entangle in neuronal
intranuclear inclusions with another protein called ubiquitin. This leads to a
hypothesis in the pathophysiology side of an excitotoxic theory. The proteins act to
impair mitochondrial energy metabolism that leads to decreased neuronal
sensitivity to endogenous glutamate that leads to a gradual loss of neurons.
Likewise, there is a theory that there is a weak excitotoxic hypothesis and in
contrast to the excitotoxic theory, this theory hypothesizes a more domino effect
such as through inhibition of different enzymes that disrupts neuronal activity.
Genetic linkage is found at “4p16, 6p21-23, and 6q24-26. At these points,
therapeutic intervention is being studied. (U.S. National Library of Medicine, 2013).
Autism
Within the umbrella of autism spectrum disorder (ASD), there are multiple genetic
causes that are facilitated by the environment to express pathological effect. These
range from oxytocin receptor genes in the Chinese Han populations to Glyoxalase I
more common in boys to 15q11-q13 duplication syndrome and Williams-Beuren-
region duplication syndrome to deletions such as in 16p11.2 or 1q21.
As there are many genetic factors that have been associated with autism, their
heritable nature is a concern for the continuation of the disorder. These “autism
loci” are identified but not explained in their role as genetic risk factors. A much
easier and more yielding focus of the research is to determine neurodevelopmental
4. pathways that are disrupted instead of the little predictive value that a focus
discloses. These foci cause genomic disorders that result in connectomic disorders
through frame-shifts or missense in single nucleotide changes. Some recurrent copy
number variants associated with autism, but are not limited to just autism, are
located on chromosomes 1, 7, 15-17, and 22 ranging from 600 kilobases to 9
megabases. Some single gene variants associated with autism, but not limited to just
autism, are located in genes such as AHI1, NF1, and SHANK3. (Weiss, 2009)
Figure 4 Genetic Variation on Neurobiological Endophenotypes
Conclusion
In Huntington’s disease, although the genetic factor has been identified, there is just
a symptomatic treatment fro the chorea. Xenazine addresses uncontrolled muscle
movements. Current treatment methods involve gene therapy through capsules
implanted into the cerebral cavity.
In regards to autism, heritability has been shown, as causation although the specific
genetic risk factors have not been explanatory. They have been correlated to autism
however such as in the case of the Oxytocin Receptor Gene, which creates receptors
that influences neuronal physiology through peptides such as oxytocin and
vasopressin.
For future study, therapeutical methods must be researched and clinically tested for
addressing Huntington’s disease. Population-based research and study of
neurobiological endophenotypes would elucidate critical neurobiological pathways
that can be addressed through medicinal methods to treat autism. Both of these
methods focus on the genetic aspect to be preventative to the damage to the
connectome.
5. Works Cited
Autism Speaks. (2014). What is Autism. Retrieved 7 27, 2014, from Autism Speaks:
http://www.autismspeaks.org/what-autism
Huntington's Disease Society of America. (2014). What is Huntington's Disease.
Retrieved 7 27, 2014, from HSDA: http://www.hdsa.org/about/our-
mission/what-is-hd.html
Mohammed A. Junaid, D. K. (2006, Feb 3). Proteomic Studies Identified a Single
Nucleotide Polymorphism in Glyoxalase I as Autism Susceptibility Factor.
NIHPA Author Manucripts: PMC1360505 .
Suping Wu, M. J. (2005). Positive Association of the Oxytocin Receptor Gene (OXTR)
with Autism in the Chinese Han Population . Biological Psychiatry , 58 (1), 74-
77.
U.S. National Library of Medicine. (2013, 6). Huntington Disease. Retrieved 7 27,
2014, from Genetics Home Reference:
http://ghr.nlm.nih.gov/condition/huntington-disease
Weiss, L. A. (2009). Autism genetics: emerging data from genome-wide copy number
and single nucleotide polymorphism scans. Expert Reviews , pp. 1-9.