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Huntingtons Disease

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Huntingtons Disease




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 choreic 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 genomic 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 degreesC for 4 minutes, 27 cycles of 1 minute at 94
degreesC and 2 minutes at 67 degreesC, 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
...

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