Order this document
Am J Med Genet 1999 Nov 26;87(3):245-50
MTA POTE Clinical Genetics Research Group at the University Medical School of Pecs, Pecs, Hungary.
In apparently healthy, unrelated Hungarians we examined triplet repeat length polymorphism at Huntington disease (HD), spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA-1), dentatorubral-pallidoluysian atrophy (DRPLA), and myotonic dystrophy (MD) loci. The distribution of alleles of the SCA-1 locus was markedly different compared with Asians and Caucasian samples examined by Watkins WS, Bamshad M, and Jorde LB [1995: Hum Mol Genet 4:1485-1491]. The unimodal distribution of peaks was shifted towards the shorter repeats on the average with 4-5 repeats. Alleles under 21 repeats at the SBMA locus were significantly less frequent in Hungarians than in Asians and Caucasians. We also found significant difference in the distribution of DRPLA allele size at repeat length over 15 repeats; these alleles were less frequent in Hungarians compared with Asians and Caucasians. No significant differences were found in alleles at the MD and also at the HD loci compared with the other groups. These findings suggest that these trinucleotide sites in combination with other markers are particularly useful for determination of the genetic origin of a population, if they can be compared with similar subset of data of other populations. The present results could not confirm the large genetic distance between Hungarian and Oriental races and the relatively short distance between Hungarian and other European populations suggested in earlier reports [Czeizel A, Benkmann H-G, Goedde HW, editors. 1991: Genetics of the Hungarian population. Budapest: Akademiai Kiado. p 82-334]. Copyright 1999 Wiley-Liss, Inc.
PMID: 10564878, UI: 20033397
Other Formats: Links:
Neuropathol Appl Neurobiol 1999 Oct;25(5):351-62
University of Cambridge, Cambridge, UK. SD19@cam.ac.uk
Over the last decade, neural transplantation has progressed from being an experimental technique for studying regeneration and plasticity in the brain to clinical trials of reconstructive surgery in human neurodegenerative disease. Whereas clear evidence is only available at present for the viability of this technique in Parkinson's disease, applications to several other diseases, including Huntington's disease, multiple sclerosis, spinal cord injury, and chronic pain are currently under active consideration. It is clear that the techniques of transplantation can be functionally viable under certain well-defined biological circumstances, but significant problems remain in the availability of suitable donor tissues and defining the optimal conditions for reliable survival of the implanted cells. If we are to obtain improved reliability of the present techniques or identify suitable alternatives, we need a better understanding of the conditions for the survival and integration of grafts into the host brain, and the mechanisms by which they influence host function. In this review I consider the nature of the structural reconstruction required to achieve repair in animal models of Parkinson's and Huntington's diseases, contrasting the replacement of deficient neurochemicals within the striatum in the former case, and the need for reconstruction of input and output connections of the striatal circuitry in the latter.
Publication Types:
PMID: 10564524, UI: 20032058
Nat Cell Biol 1999 Jun;1(2):E44-5
PMID: 10559896, UI: 20032736
Fed Regist 1999 Feb 1;64(20):4884-5
The inventions listed below are owned by agencies of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.
PMID: 10557611, UI: 99603336
Nervenarzt 1999 Oct;70(10):878-88
Neurologische Klinik, Medizinische Fakultat der RWTH, Aachen.
Huntington's disease (HD) is member of a growing family of neurodegenerative diseases which are caused by a CAG-Triplet expansion in the coding region of their respective genes. The results of the research of the last years is very suggestive of a common pathomechanisms of all these diseases even though their clinical appearance may be quite different. The development of new animal models by transferring the human gene defect into the mouse genome has led to the finding of so-called intranuclear inclusion bodies. This new observation allowed to come closer to solving the problem how this genetic defect causes neurodegeneration. Recent studies on transgenic HD mice could also demonstrate a possible connection between the genetic defect and glutamate exitotoxicity in the neurodegenerative process of HD which had been emphasized by earlier animal models of the disease. Transgenic animal models of HD will have an important impact on the understanding of the disease mechanisms and may contribute to a faster development and testing of new therapeutic approaches.
PMID: 10554779, UI: 20022430
J Prof Nurs 1999 Sep-Oct;15(5):313-24
University of Pennsylvania, Philadelphia, USA.
Genetics plays a role in every disease, yet few health care providers understand basic genetic principles or the science underlying the genetic testing process. An understanding of the science behind genetic advances is necessary, and it is equally important for health professionals to have an understanding of the complex nature of genetic testing for individuals and their families. Much of the debate about the psychological effects of genetic testing has occurred in the absence of empirical data on diseases for which predictive testing has only recently emerged. This article will review selected literature on genetic testing and its implications for the individual and the family. The responses of families and individuals to the diagnosis of a genetic disease will be reviewed, and Huntington disease will be used as the paradigm for examining issues related to genetic testing for adult-onset cancers. Literature addressing the response to genetic susceptibility for adult-onset cancers and the implications of testing children also will be explored. Finally, identification of emerging issues relevant to genetic screening will provide a framework for identifying needed nursing research in genetic testing for adult-onset cancer risk.
PMID: 10554472, UI: 20022123
Eur J Nucl Med 1999 Nov;26(11):1458-64
University of Manitoba, Winnipeg, Canada.
Huntington disease (HD) is characterized by severe abnormalities in neurotransmitter concentrations and neuroreceptor density. Quantitative changes in dopamine D(2) receptors occur in the early stages of HD and may be detectable with functional neuroimaging techniques. The aim of this study was to determine whether dopamine D(2) receptor imaging with single-photon emission tomography (SPET) identifies preclinical abnormalities in HD. The study population comprised 32 subjects from families affected by HD: 11 were genetically normal while 21 were genetically positive for HD (seven asymptomatic, six early, three moderate and five advanced findings). Disease severity was determined using a standardized quantitative neurological examination (QNE) and the mini-mental status examination (MMSE). Subjects underwent brain SPET imaging 120 min following intravenous injection of iodine-123 epidepride. Ratios of target (striatal) to nontarget (occipital or whole-brain) uptake were calculated from the reconstructed image data. Striatum to occiput and striatum to whole-brain count ratios correlated negatively with disease stage (P=0.002 and P=0.0002) and QNE (P<0. 002 and P=0.0002), and positively with the MMSE (P=0.001 and P<0. 001). Uptake was significantly reduced in the moderate-advanced subjects but was still normal for the asymptomatic and early symptomatic stages. It is concluded that reductions in striatal dopamine D(2) receptor density can be detected with (123)I epidepride at moderate or advanced stages of HD. In contrast to other reports, we could not identify abnormalities in clinically unaffected or early stages of HD.
PMID: 10552088, UI: 20020064
J Neurochem 1999 Nov;73(5):2018-27
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294-0017, USA.
The polyglutamine-expanded N-terminal region of mutant huntingtin causes neurodegeneration in Huntington's disease (HD). Neuronal intranuclear and cytosolic inclusions composed of mutant huntingtin are found in brains of HD patients. Because tissue transglutaminase cross-links proteins into filamentous aggregates and polypeptide-bound glutamines are primary determining factors for tissue transglutaminase-catalyzed reactions, it has been hypothesized that tissue transglutaminase may contribute to the formation of these aggregates. In this report immunohistochemical and biochemical methods were used to demonstrate that tissue transglutaminase expression and transglutaminase activity are elevated in HD brains in a grade-dependent manner. In the striatum, tissue transglutaminase activity was significantly increased in the grade 3 HD cases compared with controls. When normalized to the neuronal marker calbindin D28k, immunoblot analysis revealed that in the striatum the levels of tissue transglutaminase were significantly increased in all HD cases compared with controls. Immunohistochemical staining of the HD striatum revealed that tissue transglutaminase immunoreactivity was markedly increased in all grades as compared with controls. In the superior frontal cortex, tissue transglutaminase activity was significantly higher in all HD cases as compared with controls. Quantitative analysis of immunoblots demonstrated that tissue transglutaminase levels were elevated in HD grades 2 and 3 cases. Tissue transglutaminase immunoreactivity within the superior frontal neocortex was also greater in all the HD cases compared with controls. These data clearly indicate that tissue transglutaminase is elevated in HD brain and may play a role in the disease process.
PMID: 10537061, UI: 20005453
Epidemiology 1999 Nov;10(6):706-10
Department of Clinical Epidemiology, Leiden University Medical Center, The Netherlands.
To estimate the impact of the Huntington gene on mortality, we studied ten families with Huntington disease, whose records started before 1800. We investigated mortality from 1800 to 1997 in 257 carriers of the Huntington gene and 474 potential carriers. Follow-up extended from age 20 years to the date of death or end-of-study date. The observed deaths were compared with those expected on the basis of the general population, adjusted for sex, age, and calendar time. To study the influence of the family and parental transmission, we calculated hazard ratios adjusted for sex, probability of carrying the gene, and year of birth. In 25,013 person-years, 420 deaths occurred, whereas 278 deaths were expected [standardized mortality ratio = 1.5; 95% confidence interval (CI) = 1.4-1.7]. Excess mortality was confined to ages 40-70 years (standardized mortality ratio = 2.2; 95% CI = 1.9-2.4). To study the evolution of mortality over time in this age group, we calculated absolute mortality rates per calendar period. From 1800 onward, mortality rates in the general population continuously declined, but among the families with Huntington disease this decline was absent. There were only small differences in risk between families, and the relative risk for paternal over maternal transmission was 1.2 (95% CI = 0.9-1.5). Our main finding is that persons who carry the Huntington gene and reach middle age have not benefited from advances in medical care and overall increase in life expectancy.
PMID: 10535784, UI: 20004442
Neurology 1999 Oct 22;53(7):1605-6
Department of Neuroscience, University Hospital, Uppsala, Sweden. joakim.tedroff@swipnet.se
PMID: 10534281, UI: 20001848
J Neurosci Res 1999 Nov 15;58(4):515-32
Mental Retardation Research Center, University of California at Los Angeles, 90095, USA. mlevine@mednet.ucla.edu
We used two mouse models of Huntington's disease (HD) to examine changes in glutamate receptor sensitivity and striatal electrophysiology. One model, a transgenic, consisted of mice expressing exon 1 of the human HD gene and carrying 141-157 CAG repeat sequences (R6/2 line). The second model, a CAG repeat "knockin," consisted of mice with different lengths of CAG repeats (CAG71 and CAG94 repeats). The effects of glutamate receptor activation were examined by visualizing neurons in brain slices with infrared videomicroscopy and differential interference contrast optics to determine changes in somatic area (cell swelling). Striatal and cortical neurons in both models (R6/2 and CAG94) displayed more rapid and increased swelling to N-methyl-D-aspartate (NMDA) than those in controls. This effect was specific as there were no consistent group differences after exposure to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate (KA). Intracellular recordings revealed that resting membrane potentials (RMPs) in the R6/2 transgenics were significantly more depolarized than those in their respective controls. RMPs in CAG94 mice also were more depolarized than those in CAG71 mice or their controls in a subset of striatal neurons. Confirming previous results, R6/2 mice expressed behavioral abnormalities and nuclear inclusions. However, CAG71 and CAG94 knockins did not, suggesting that increased sensitivity to NMDA may occur early in the disease process. These findings imply that NMDA antagonists or compounds that alter sensitivity of NMDA receptors may be useful in the treatment of HD. Copyright 1999 Wiley-Liss, Inc.
PMID: 10533044, UI: 20004645
J Med Genet 1999 Oct;36(10):739-46
Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, UK.
Huntington's disease (HD) is thought to show true dominance, since subjects with two mutant alleles have been reported to have similar ages at onset of disease compared to heterozygous sibs. We have investigated this phenomenon using a cell culture model. Protein aggregate formation was used as an indicator for pathology, as intraneuronal huntingtin inclusions are associated with pathology in vitro and in vivo. We showed that cytoplasmic and nuclear aggregates are formed by constructs comprising part of exon 1 of huntingtin with 41, 51, 66, or 72 CAG repeats, in a rate that correlates with repeat number. No inclusions were seen with 21 CAG repeat constructs. Mutant and wild type huntingtin fragments can be sequestered into inclusions seeded by a mutant huntingtin. Wild type huntingtin did not enhance or interfere with protein aggregation. The rate of protein aggregation was dose dependent for all mutant constructs tested. These experiments suggested a model for the dominance observed in HD; the decrease in the age at onset of a mutant homozygote may be small compared to the variance in the age at onset for that specific repeat number in heterozygotes. Our experiments also provide a model, which may explain the different repeat size ranges seen in patients and healthy controls for the different polyglutamine diseases.
PMID: 10528852, UI: 99456120
Am J Med Genet 1999 Nov 5;87(1):91-2
PMID: 10528258, UI: 99458591
Neurobiol Dis 1999 Oct;6(5):364-75
Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, Massachusetts, 02129, USA.
Huntington's disease (HD) is caused by an expanded glutamine tract, which confers a novel aggregation-promoting property on the 350-kDa huntingtin protein. Using specific antibodies, we have probed the structure of the polyglutamine segment in mutant huntingtin complexes formed in cell culture from either truncated or full-length protein. Complexes formed by a mutant amino terminal fragment most frequently entail a change in conformation that eliminates reactivity with the polyglutamine-specific mAb 1F8, coincident with production of insoluble aggregate. By contrast, complexes formed by the full-length mutant protein remain soluble and are invariably 1F8-reactive, indicating a soluble polyglutamine conformation. Therefore, aggregates in HD may form by different biochemical mechanisms that invoke different possibilities for the pathogenic process. If pathogenesis is triggered by a truncated fragment, it probably involves the formation of an insoluble aggregate. However, the observation of soluble complexes in which an HD-specific pathogenic conformation of the glutamine tract remains accessible suggests that pathogenesis could also be triggered at the level of full-length huntingtin by abnormal aggregation with normal or abnormal protein partners. Copyright 1999 Academic Press.
PMID: 10527804, UI: 99459105
Neuropsychology 1999 Oct;13(4):525-31
Department of Psychology, York University, Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada. jbr@yorku.ca
Two characteristics of word-list generation performance are forming clusters (i.e., contiguous words from the same subcategory) and switching among them. Patients with frontal lobe pathology show reduced switching on letter-cued word generation tasks, and clustering has been associated with temporal lobe functioning. Letter-cued word generation was examined in 72 patients with Huntington's disease (HD) and 41 healthy participants of equivalent age and education. As predicted, the patients showed reduced switching but normal clustering. In addition, switching but not clustering correlated inversely with disease severity, as measured by both movement and mental status scales. Furthermore, 5-year longitudinal analysis revealed a monotonic decrease in switching over time, whereas clustering performance remained stable. Control participants performed uniformly over time on both measures. These results are consistent with a progressive reduction in cognitive flexibility attributed to disruption of frontal-subcortical circuits secondary to neostriatal pathology in HD.
PMID: 10527060, UI: 99454184
Neurology 1999 Oct 12;53(6):1330-2
Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Huntington's disease (HD) is attributed to a triplet CAG repeat mutation, and about half of the variation in onset age can be explained by the size of the repeat expansion. Recently, a TAA repeat polymorphism in close linkage to the kainate receptor, GluR6, was reported related to onset age in HD. We examined this polymorphism in 258 unrelated HD-affected persons (172 from a clinic sample and 86 from a postmortem series). This study confirms that the 155 allele is associated with younger onset age of HD and suggests that it is in linkage disequilibrium with a variant of the GluR6 gene or another gene in this region.
Comments:
PMID: 10522893, UI: 99450728
Nervenarzt 1999 Sep;70(9):842-6
Psychiatrische Universitatsklinik Zurich.
We report on a female inpatient who at the age of 47 years presented depressive and anxiety symptoms and alcohol abuse and who suffered from cognitive, personality, and discrete movement disturbances later on. In the course of the long-term psychotherapy which was supported by the technique of creative drawings previously forgotten memories of a very severe sexual abuse in childhood emerged. The recovery of these memories was followed by an intensification of the anxiety which lead to several psychiatric rehospitalizations. During the last hospital stay the diagnosis of Huntington's chorea was verified explaining well the rich psychopathology of the patient. The recollections of sexual abuse were for the most part qualified as a false memory syndrome. In addition to other factors the chorea-inherent cognitive impairment will have contributed to the occurrence of false memory syndrome. The new diagnosis dictated a change of the therapeutic procedure which, at least in the medium-term, proved to be successful.
PMID: 10522255, UI: 99451753
Arch Neurol 1999 Oct;56(10):1248-52
Department of Neurology, University of Miami, Fla. 33136, USA. ksharma@med.miami.edu
OBJECTIVE: To examine the autonomic nervous system functions in patients with Huntington disease. BACKGROUND: Although patients with Huntington disease frequently experience vegetative symptoms, it is not clear if there is dysfunction of the autonomic nervous system. METHODS: Sympathetic skin response (SSR) latency and amplitude from both palms and soles and R-R (heart rate) interval variation (RRIV) at rest and during the Valsalva maneuver were examined in 22 patients and 21 age-matched controls. Unified Huntington's Disease Rating Scale scores were determined in all the patients. RESULTS: Our data are reported as means +/- SEMs. The SSR latencies in patients (mean palm latency, 1835.8+/-110.7 milliseconds; mean sole latency, 2625.3+/-226.9 milliseconds) were prolonged compared with controls (mean palm latency, 1359.5+/-28 milliseconds [P<.01]); mean sole latency, 2038.1+/-44.9 milliseconds [P<.01]) and amplitudes in patients (mean amplitude, 1063.1+/-237.7 microV) were smaller compared with controls (mean amplitude, 1846.3+/-251.2 microV [P<.05]). The RRIV in patients both at rest (mean RRIV in patients, 3.7%+/-0.4% vs. controls, 9.7%+/-0.6% [P<.01]) and during the Valsalva maneuver (mean RRIV in patients, 6.3%+/-1.6% vs. controls, 14.5%+/-1.2% [P<.01]) was lower compared with controls. Furthermore, the prolonged SSR latencies, smaller amplitudes, and lower RRIV in patients compared with controls closely correlated with the various components of the Unified Huntington's Disease Rating Scale scores (total behavior score and SSR latency, R = 0.6 [P<.01]; total behavior score and SSR amplitude, R = -0.5 [P<.05]; total behavior score and RRIV, R = -0.4 [P<.05]; verbal fluency and SSR latency, R = -0.5 [P<.05]; verbal fluency and SSR amplitude, R = 0.5 [P<.05], verbal fluency and RRIV, R = 0.5 [P<.05]; total functional capacity and SSR latency, R = -0.6 [P<.01]; total functional capacity and SSR amplitude, R = 0.5 [P<.05]). CONCLUSION: These results suggest that there is autonomic nervous system dysfunction in patients with Huntington disease.
PMID: 10520941, UI: 99449251
Genet Epidemiol 1999 Nov;17(4):237-52
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44109, USA. cordell@darwin.cwru.edu
Linkage disequilibrium mapping exploits the fact that at genetic markers close enough to a disease locus on a particular chromosome, we expect to find an association between the disease and marker alleles. Furthermore, the magnitude of the association is expected to follow a unimodal curve when plotted against location, with the peak at the disease location. In practice, for real data, we usually see deviations from such a curve due to other influences such as evolutionary variability, mutation, and selection. Here we propose fitting a quadratic curve to data of this nature, estimating the location of the disease locus by the point at which the curve is maximum. A key feature of our method is the use of transformations of both location and disequilibrium, so that departures from a unimodal curve are incorporated by fitting the curve not to the original location and disequilibrium values but to the transformed values. In addition, we estimate the covariances between the disequilibrium values at linked loci using either a multinomial approximation or a bootstrap procedure. The location estimate from our method is the ratio of two quantities that, in large samples, are normally distributed, and so we use Fieller's theorem to obtain a confidence interval for the disease gene location. We successfully apply our method to data from several published studies in which the true disease gene location is known. Copyright 1999 Wiley-Liss, Inc.
PMID: 10520208, UI: 99452784
Prog Neurobiol 1999 Dec;59(5):427-68
URA CEA CNRS 2210, Service Hospitalier Frederic Joliot, Orsay, France. brouille@shfj.cea.fr
Huntington's disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder characterized by involuntary choreiform movements, cognitive decline and a progressive neuronal degeneration primarily affecting the striatum. There is at present no effective therapy against this disorder. The gene responsible for the disease (IT15) has been cloned and the molecular defect identified as an expanded polyglutamine tract in the N-terminal region of a protein of unknown function, named huntingtin (The Huntington's Disease Collaborative Research Group, 1993. Cell 72, 971-983). An intense, search for the cell pathology attached to this molecular defect is currently under way [see Sharp and Ross (1996, Neurobiol. Dis. 3, 3-15) for review]. Huntingtin interacts with a number of proteins, some of which have well identified functions, and it has thus been suggested that alterations in glycolysis, vesicle trafficking or apoptosis play a role in the physiopathology of HD. On the other hand data derived from positron emission tomography (PET), magnetic resonance spectroscopy and post-mortem biochemical evidence for a defect in succinate oxidation have suggested the implication of a primary impairment of mitochondrial energy metabolism. All these hypotheses are not necessarily to be opposed and recent findings indicate that the HD mutation could possibly directly alter mitochondrial functions which would in turn activate apoptotic pathways. To test this mitochondrial hypothesis, we studied the effects in rodents and non-human primates of a chronic blockade of succinate oxidation by systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP). Extensive behavioural and neuropathological evaluations showed that a partial but prolonged energy impairment induced by 3NP is sufficient to replicate most of the clinical and pathophysiological hallmarks of HD, including spontaneous choreiform and dystonic movements, frontal-type cognitive deficits, and progressive heterogeneous striatal degeneration at least partially by apoptosis. 3NP produces the preferential degeneration of the medium-sized spiny GABAergic neurons with a relative sparing of interneurons and afferents, as was observed in HD striatum. The present manuscript reviews the different aspects of this neurotoxic treatment in rodents and non-human primates, and its interest as a phenotypic model of HD to understand the degenerative process of HD and test new therapeutic strategies.
PMID: 10515664, UI: 99443687
the above reports in Macintosh PC UNIX Text HTML format documents on this page through Loansome Doc
