1/19. Null alleles at the huntington disease locus: implications for diagnostics and CAG repeat instability.PCR amplification of the CAG repeat in exon 1 of the IT15 gene is routinely undertaken to confirm a clinical diagnosis of huntington disease (HD) and to provide predictive testing for at-risk relatives of affected individuals. Our studies have detected null alleles on the chromosome carrying the expanded repeat in three of 91 apparently unrelated HD families. sequence analysis of these alleles has revealed the same mutation event, leading to the juxtaposition of uninterrupted CAG and CCG repeats. These data suggest that a mutation-prone region exists in the IT15 gene bounded by the CAG and CCG repeats and that caution should be exercised in designing primers that anneal to the region bounded by these repeats. Two of the HD families segregated null alleles with expanded uninterrupted CAG repeats at the lower end of the zone of reduced penetrance. The expanded repeats are meiotically unstable in these families, although this instability is within a small range of repeat lengths. The haplotypes of the disease-causing chromosomes in these two families differ, only one of which is similar to that reported previously as being specific for new HD mutations. Finally, no apparent mitotic instability of the uninterrupted CAG repeat was observed in the brain of one of the HD individuals.- - - - - - - - - - ranking = 1keywords = amplification (Clic here for more details about this article) |
2/19. Polymorphisms in the CAG repeat--a source of error in huntington disease dna testing.Five of 400 patients (1.3%), referred for huntington disease dna testing, demonstrated a single allele on CAG alone, but two alleles when the CAG CCG repeats were measured. The PCR assay failed to detect one allele in the CAG alone assay because of single-base silent polymorphisms in the penultimate or the last CAG repeat. The region around and within the CAG repeat sequence in the huntington disease gene is a hot-spot for dna polymorphisms, which can occur in up to 1% of subjects tested for huntington disease. These polymorphisms may interfere with amplification by PCR, and so have the potential to produce a diagnostic error.- - - - - - - - - - ranking = 1keywords = amplification (Clic here for more details about this article) |
3/19. Preimplantation genetic diagnosis for Huntington's disease with exclusion testing.Huntington's disease is an autosomal dominant, late-onset disorder, for which the gene and the causative mutation have been known since 1993. Some at-risk patients choose for presymptomatic testing and can make reproductive choices accordingly. Others however, prefer not to know their carrier status, but may still wish to prevent the birth of a carrier child. For these patients, exclusion testing after prenatal sampling has been an option for many years. A disadvantage of this test is that unaffected pregnancies may be terminated if the parent at risk (50%) has not inherited the grandparental Huntington gene, leading to serious moral and ethical objections. As an alternative, preimplantation genetic diagnosis (PGD) on embryos obtained in vitro may be proposed, after which only embryos free of risk are replaced. Embryos can then be selected, either by the amplification of the CAG repeat in the embryos without communicating results to the patients (ie non-disclosure testing), which brings its own practical and moral problems, or exclusion testing. We describe here the first PGD cycles for exclusion testing for Huntington's disease in five couples. Three couples have had at least one PGD cycle so far. One pregnancy ensued and a healthy female baby was delivered.- - - - - - - - - - ranking = 1keywords = amplification (Clic here for more details about this article) |
4/19. Long-term treatment of juvenile Huntington's chorea with dipropylacetic acid.Since the proposed mode of action of dipropylacetic acid, an anticonvulsant, is to increase central nervous system gamma-aminobutyric acid levels, we used this agent to treat identical twins with juvenile Huntington's chorea. Their clinical status did not improve immediately after they received dipropylacetic acid. Furthermore, long-term administration (over a year) of high doses of the agent (up to 2,400 mg per day; 92 mg per kilogram per day) did not seem to alter the slow progression of their disease. Prior to treatment with dipropylacetic acid, the twins had normal cerebrospinal fluid gamma-aminobutyric acid levels. In addition, cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid were determined before and after 18 hours of high-dose probenecid. The former showed a normal threefold to fourfold increase after probenecid administration, but homovanillic acid had a distinctly subnormal turnover after probenecid, with only a threefold rather than the normal tenfold increase.- - - - - - - - - - ranking = 0.0041474725490287keywords = acid (Clic here for more details about this article) |
5/19. Juvenile Huntington chorea: clinical, ultrastructural, and biochemical studies.A brain biopsy from a 20-year-old patient whose clinical course was marked by progressive dementia and chorea since age 10 years showed increased amounts of lipofuscin, abnormal mitochondria, and other organelles in cortical neurons, neurites, and astrocytes. Juvenile Huntington chorea was confirmed at autopsy. High levels of three histone-like proteins (molecular weight 10,000 to 16,000) in the microsomal fraction of purified neurons were found by SDS-polyacrylamide gel electrophoresis. fatty acids were abnormal in white matter sphingomyelin. These ultrastructural and biochemical findings conformed to those established in adult Huntington chorea, thus strengthening the concept of a uniform pathologic process in adult and juvenile Huntington diseases in spite of some clinical and histologic differences.- - - - - - - - - - ranking = 0.00034562271241906keywords = acid (Clic here for more details about this article) |
6/19. Huntington's chorea and dimethylaminoethanol (deanol).Huntington's chorea has multiple neurologic and psychiatric manifestations, and its treatment has been the subject of much debate. It appears that no single agent is effective for all patients with chorea. Furthermore, different biochemical substances may be lacking in various Huntington's patients, i.e., gamma aminobutyric acid (GABA) in some, or a deficiency of acetylcholine (ACH) receptors in others. We approach this disease as a possible "spectrum illness," characterized by a relative deficiency of one substance, or a relative excess of another. If patients do not respond to one family of drugs, they may still benefit from a trial with another drug group.- - - - - - - - - - ranking = 0.00034562271241906keywords = acid (Clic here for more details about this article) |
7/19. Long term treatment of huntington disease with L-glutamate and pyridoxine.Decreased levels of gamma aminobutyric acid (GABA) and its synthetic enzyme, glutamic acid decarboxylase, have been found in the brains of patients with huntington disease. In an attempt to augment GABA-mediated neurotransmission, daily doses of 25 gm of L-glutamate (the substrate for glutamic acid decarboxylase) and 500 mg of pyridoxine, its cofactor, were given to five patients with huntington disease. This regimen was continued for 2 years. Assessment of motor and behavioral function indicated no improvement on this regimen.- - - - - - - - - - ranking = 0.0010368681372572keywords = acid (Clic here for more details about this article) |
8/19. myoclonus in adult Huntington's disease.Two brothers with clinically definite adult Huntington's disease developed disabling myoclonus years after the first signs of the disease. Their electroencephalograms were consistent with a primary generalized epilepsy, although neither man had seizures. The myoclonus was controlled with valproic acid therapy.- - - - - - - - - - ranking = 0.00034562271241906keywords = acid (Clic here for more details about this article) |
9/19. Prenatal exclusion testing for huntington disease using the polymerase chain reaction.Prenatal exclusion of huntington disease (HD) may be carried out by analysis of cosegregating dna markers on a first-trimester chorionic villus sample. The conventional Southern blot method is time-consuming and requires microgram quantities of dna and milligram quantities of villus tissue. The use of the polymerase chain reaction (PCR) to amplify genomic dna by a factor of 10(7) or more makes it possible to do analyses on very small samples in a few hours and without recourse to Southern blotting or hybridization with radioactive probes. We report on a fetus at risk of HD; prenatal testing was carried out by using the PCR to amplify a polymorphic dna sequence adjacent to the HD locus. The risk of the fetus inheriting the HD gene could not be excluded and the pregnancy was terminated. This represents an example of gene tracking by using amplification of a restriction fragment length polymorphism at some distance from the relevant mutation.- - - - - - - - - - ranking = 1keywords = amplification (Clic here for more details about this article) |
10/19. brain amino compounds in a Huntington's disease patient on isoniazid therapy.We describe biochemical abnormalities in autopsied brain of a patient with early Huntington's disease (HD) who died of pentobarbital overdosage while under treatment with isoniazid (INH). The brain contained hydrazine, a terminal metabolite of INH, which inhibits gamma-aminobutyric acid (GABA) aminotransferase. GABA content in the basal ganglia was higher than expected for HD, and GABA content was supranormal in some brain regions. Homocarnosine (GABA-histidine) content was greatly elevated in all brain regions, suggesting chronic GABA elevation in life. Therefore, the increase in brain GABA content observed in experimental animals given INH or hydrazine also occurs in human patients.- - - - - - - - - - ranking = 0.00034562271241906keywords = acid (Clic here for more details about this article) |
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