Huntingtons disease

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 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.