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Huntington's Background Huntington's disease is inherited as an autosomal dominant disease
that gives rise to progressive, elective (localized) neural cell death associated with
choleric movements (uncontrollable movements of the arms, legs, and face) and dementia.
It is one of the more common inherited brain disorders. About 25,000 Americans have it
and another 60,000 or so will carry the defective gene and will develop the disorder as
they age. Physical deterioration occurs over a period of 10 to 20 years, usually
beginning in a person's 30's or 40's. The gene is dominant and thus does not skip
generations. Having the gene means a 92 percent chance of getting the disease. The
disease is associated with increases in the length of a CAG triplet repeat present in a
gene called 'huntington' located on chromosome 4. The classic signs of Huntington disease
are progressive chorea, rigidity, and dementia, frequently associated with seizures.
Studies & Research Studies were done to determine if somatic mtDNA (mitochondria DNA)
mutations might contribute to the neurodegeneration observed in Huntington's disease.
Part of the research was to analyze cerebral deletion levels in the temporal and frontal
lobes. Research hypothesis: HD patients have significantly higher mtDNA deletionlevels
than agematched controls in the frontal and temporal lobes of the cortex. To test the
hypothesis, the amount of mtDNA deletion in 22 HD patients brains was examined by serial
dilution-polymerase chain reaction (PCR) and compared the results with mtDNA deletion
levels in 25 aged matched controls. Brain tissues from three cortical regions were taken
during an autopsy (from the 22 HD symptomatic HD patients): frontal lobe, temporal lobe
and occipital lobe, and putamen. Molecular analyses were performed on genetic DNA
isolated from 200 mg of frozen brain regions as described above. The HD diagnosis was
confirmed in patients by PCR amplification of the trinucleotide repeat in the IT 15 gene.
One group was screened with primers that included polymorphism and the other was screened
without the polymorphism. After heating the reaction to 94 degrees C for 4 minutes, 27
cycles of 1 minute at 94 degreesC and 2 minutes at 67 degrees C, tests were performed.
The PCR products were settled on 8% polyacrylamide gels. The mtDNA deletion levels were
quantitated relative to the total mtDNA levels by the dilution-PCR method. When the
percentage of the mtDNA deletion relative to total mtDNA was used as a marker of mtDNA
damage, most regions of the brain accrued a very small amount of mtDNA damage before age
75. Cortical regions accrued 1 to 2% deletion levels between ages 80-90, and the putamen
accrued up to 12% of this deletion after age 80. The study presented evidence that HD
patients have much higher mtDNA deletionlevels than agematched controls in the frontal
and temporal lobes of the cortex. Temporal lobe mtDNA deletion levels were 11 fold higher
in HD patients than in controls, whereas the frontal lobe deletion levels were fivefold
higher in HD patients than in controls. There was no statistically significant difference
in the average mtDNA deletion levels between HD patients and controls in the occipital
lobe and the putamen. The increase in mtDNA deletion levels found in HD frontal and
temporal lobes suggests that HD patients have an increase mtDNA somatic mutation rate.
Could the increased rate be from a direct consequence of the expanded trinucleotide
repeat of the HD gene, or is it from an indirect consequence? Whatever the origin of the
deletion, these observations are consistent with the hypothesis: That the accumulation of
somatic mtDNA mutations erodes the energy capacity of the brain, resulting in the
neuronal loss and symptoms when energy output declines below tissue expression
thresholds. (Neurology, October 95) Treatments Researchers have identified a key protein
that causes the advancement of Huntington's after following up on the discovery two years
ago of the gene that causes this disorder. Shortly after the Huntington's gene was
identified, researchers found the protein it produces, a larger than normal molecule they
called huntingtin that was unlike any protein previously identified. The question that
they did not know was what either the healthy huntingtin protein or its aberrant form
does in a cell. Recently, a team from Johns Hopkins University found a second protein
called HAP-1, that attaches to the huntingtin molecule only in the brain. The
characteristics of this second protein has an interesting feature- it binds much more
tightly to defective huntingtin than to the healthy from, and it appears that this
tightly bound complex causes damage to brain cells. Researchers are hoping to find simple
drugs that can weaken this binding, thereby preventing the disease to progress any
further. In other Huntington-related research, scientists have found where huntingtin
protein is localized in nerve cells, a step closer to discovering its contribution toward
Huntington's. A French team reported that they have developed an antibody that attaches
itself to the defective protein in Huntington's and four other inherited diseases. This
finding may lead to identifying the defects in a variety of others unexplained disorders.
The identification of the gene an the huntingtin protein promised to be a major
breakthrough in tracing the causes of Huntington's, but that promise has so far been
delayed. The protein of Huntington is unlike any other protein known making it difficult
for researchers to guess its role in a healthy cell. However, this has not stopped
researchers from trying to find a possible cure for HD. Effects on Society By finding
possible drugs to weaken the binding of the HAP-1 protein, researchers can provide
society an incredibly sophisticated, but quick and easy wasy to screen for new
treatments. One of the biggest arguments for genetic testing, even when there isn't any
cure or treatment to offer the patient, is financial planning. If you know that you're
probably going to be disabled and unable to work before reaching 50, you can plan for it.
But what if your income doesn't allow for it? This demonstrates the importance for
continuous research on HD. Overview of the Two Articles Both articles concentrate on HD's
protein causing affect. There is no doubt between the two that HD is an inherited
mutation. The Neurology articles explains how HD patients have much higher deletion
levels than agematched controls in the frontal and temporal lobes of the cortex, whereas
the article from Times Medical Writer focuses on a possible treatment resulting from a
finding of a second protein called HAP-1, that binds itself to the huntingtin molecule
only in the brain. Both conclude that HD is a mutation that causes damage to brain cells
further in a person's life.
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