Publications by authors named "Nancy S Wexler"

25 Publications

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Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington's disease patients.

Sci Rep 2020 11 20;10(1):20295. Epub 2020 Nov 20.

Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.

In Huntington's disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.
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http://dx.doi.org/10.1038/s41598-020-77164-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679413PMC
November 2020

Oligonucleotide Treatment for Huntington's Disease.

N Engl J Med 2019 06 6;380(24):2373-2374. Epub 2019 May 6.

From the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (K.H.F.); and the Departments of Neurology and Psychiatry, College of Physicians and Surgeons, Columbia University and Hereditary Disease Foundation, New York (N.S.W.).

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http://dx.doi.org/10.1056/NEJMe1904861DOI Listing
June 2019

Population-specific genetic modification of Huntington's disease in Venezuela.

PLoS Genet 2018 05 11;14(5):e1007274. Epub 2018 May 11.

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2-21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1, which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.
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http://dx.doi.org/10.1371/journal.pgen.1007274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965898PMC
May 2018

Pope Francis champions Huntington's disease.

Authors:
Nancy S Wexler

Brain 2018 02;141(2):e8

Hereditary Disease Foundation, Columbia University, New York, New York 10032, USA.

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http://dx.doi.org/10.1093/brain/awx322DOI Listing
February 2018

Detection of long repeat expansions from PCR-free whole-genome sequence data.

Genome Res 2017 11 8;27(11):1895-1903. Epub 2017 Sep 8.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London SE5 9RX, United Kingdom.

Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
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http://dx.doi.org/10.1101/gr.225672.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668946PMC
November 2017

Incidence of adult Huntington's disease in the UK: a UK-based primary care study and a systematic review.

BMJ Open 2016 Feb 23;6(2):e009070. Epub 2016 Feb 23.

Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

Objectives: The prevalence of Huntington's disease (HD) recorded in the UK primary care records has increased twofold between 1990 and 2010. This investigation was undertaken to assess whether this might be due to an increased incidence. We have also undertaken a systematic review of published estimates of the incidence of HD.

Setting: Incident patients with a new diagnosis of HD were identified from the primary care records of the Clinical Practice Research Datalink (CPRD). The systematic review included all published estimates of the incidence of HD in defined populations.

Participants: A total of 393 incident cases of HD were identified from the CPRD database between 1990 and 2010 from a total population of 9,282,126 persons.

Primary And Secondary Outcome Measures: The incidence of HD per million person-years was estimated. From the systematic review, the extent of heterogeneity of published estimates of the incidence of HD was examined using the I(2) statistic.

Results: The data showed that the incidence of HD has remained constant between 1990 and 2010 with an overall rate of 7.2 (95% CI 6.5 to 7.9) per million person-years. The systematic review identified 14 independent estimates of incidence with substantial heterogeneity and consistently lower rates reported in studies from East Asia compared with those from Australia, North America and some--though not all--those from Europe. Differences in incidence estimates did not appear to be explained solely by differences in case ascertainment or diagnostic methods.

Conclusions: The rise in the prevalence of diagnosed HD in the UK, between 1990 and 2010, cannot be attributed to an increase in incidence. Globally, estimates of the incidence of HD show evidence of substantial heterogeneity with consistently lower rates in East Asia and parts of Europe. Modifiers may play an important role in determining the vulnerability of different populations to expansions of the HD allele.
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http://dx.doi.org/10.1136/bmjopen-2015-009070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769413PMC
February 2016

The Prevalence of Huntington's Disease.

Neuroepidemiology 2016 30;46(2):144-53. Epub 2016 Jan 30.

Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

Background: Reviews of the epidemiology of Huntington's disease (HD) suggest that its worldwide prevalence varies widely. This review was undertaken to confirm these observations, to assess the extent to which differences in case-ascertainment and/or diagnosis might be responsible, and to investigate whether the prevalence pattern has changed over the past 50 years.

Methods: Eighty two relevant studies were identified from Medline and Embase, previous reviews, scrutiny of references from included and excluded studies and enquiry among those interested in the field.

Results: The lowest rates were among the Asians and the highest among the Caucasians. The differences are not fully explained by varying approaches to case-ascertainment or diagnosis. There was evidence of an increasing prevalence of between 15 and 20% per decade in studies from Australia, North America and Western Europe.

Conclusions: The prevalence of HD varies more than tenfold between different geographical regions. This variation can in part be attributed to differences in case-ascertainment and/or diagnostic criteria, but there is consistent evidence of a lower incidence in Asian populations. There is also evidence that in Australia, North America and in Western Europe (including the United Kingdom), prevalence has increased over the past 50 plus years.
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http://dx.doi.org/10.1159/000443738DOI Listing
October 2016

Paul H. Patterson (October 22, 1943 - June 25, 2014).

J Huntingtons Dis 2014 ;3(3):221-4

Hereditary Disease Foundation, New York, NY, USA and New York State Psychiatric Institute, Departments of Neurology and Psychiatry, Columbia University, New York, NY, USA.

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http://dx.doi.org/10.3233/JHD-149006DOI Listing
February 2016

Aberrantly spliced HTT, a new player in Huntington's disease pathogenesis.

RNA Biol 2013 Nov 11;10(11):1647-52. Epub 2013 Oct 11.

Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology; Cambridge, MA USA.

Huntington's disease (HD) is an adult-onset neurodegenerative disorder caused by a mutated CAG repeat in the huntingtin gene that is translated into an expanded polyglutamine tract. The clinical manifestation of HD is a progressive physical, cognitive, and psychiatric deterioration that is eventually fatal. The mutant huntingtin protein is processed into several smaller fragments, which have been implicated as critical factors in HD pathogenesis. The search for proteases responsible for their production has led to the identification of several cleavage sites on the huntingtin protein. However, the origin of the small N-terminal fragments that are found in HD postmortem brains has remained elusive. Recent mapping of huntingtin fragments in a mouse model demonstrated that the smallest N-terminal fragment is an exon 1 protein. This discovery spurred our hypothesis that mis-splicing as opposed to proteolysis could be generating the smallest huntingtin fragment. We demonstrated that mis-splicing of mutant huntingtin intron 1 does indeed occur and results in a short polyadenylated mRNA, which is translated into an exon 1 protein. The exon 1 protein fragment is highly pathogenic. Transgenic mouse models containing just human huntingtin exon 1 develop a rapid onset of HD-like symptoms. Our finding that a small, mis-spliced HTT transcript and corresponding exon 1 protein are produced in the context of an expanded CAG repeat has unraveled a new molecular mechanism in HD pathogenesis. Here we present detailed models of how mis-splicing could be facilitated, what challenges remain in this model, and implications for therapeutic studies.
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http://dx.doi.org/10.4161/rna.26706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907474PMC
November 2013

Juvenile Huntington's disease: a population-based study using the General Practice Research Database.

BMJ Open 2013 3;3(4). Epub 2013 Apr 3.

Department of Epidemiology, London School of Hygiene and Tropical Medicine, University of London, London, UK.

Background: The juvenile form of Huntington's disease (HD) is a rare disorder. There are no population-based estimates of either its incidence or prevalence in any population in the world. The present study was undertaken to estimate the frequency of juvenile HD in the UK and to examine the range of pharmacological treatments used in its management.

Method: The records of individuals under the age of 21 who had recorded diagnoses of HD were retrieved from the General Practice Research Database from 1990 through 2010. From these data estimates of incidence and prevalence were made as well as the specific treatments used in the treatment of its physical and psychological manifestations.

Results: 12 incident and 21 prevalent patients with juvenile HD were identified. The 21 prevalent cases included the 12 incident cases. The minimum population-based estimate of incidence is 0.70 (95% CI 0.36 to 1.22) per million patient-years. The minimum estimate of prevalence is 6.77/million (95% CI 5.60 to 8.12) per million patient-years. Patients were most frequently prescribed antidepressants, hypnotics, antipsychotics and treatments for motor abnormalities.

Conclusions: In the UK, juvenile HD is an extremely rare and complex disorder. The prescribing data demonstrate that the clinical management of juvenile HD is undertaken with no formal evidence base for the efficacy or safety of the treatments used. Research into the safety and efficacy of appropriate therapies is urgently required to offset the haphazard nature of prescribing. Multinational collaboration will be necessary to enrol sufficient numbers. Exploratory studies, though, should begin now.
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http://dx.doi.org/10.1136/bmjopen-2012-002085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641420PMC
April 2013

Prevalence of adult Huntington's disease in the UK based on diagnoses recorded in general practice records.

J Neurol Neurosurg Psychiatry 2013 Oct 12;84(10):1156-60. Epub 2013 Mar 12.

Department of Epidemiology, London School of Hygiene and Tropical Medicine, University of London, London, UK.

Background And Purpose: The prevalence of Huntington's disease (HD) in the UK is uncertain. Recently, it has been suggested that the prevalence may be substantially greater than previously reported. This study was undertaken to estimate the overall UK prevalence in adults diagnosed with HD, using data from primary care.

Methods: The electronic medical records of patients aged 21 years or more, with recorded diagnoses of HD, were retrieved from the UK's General Practice Research Database. Prevalence was estimated from the number of persons with recorded diagnoses of HD, on 1 July each year, between 1990 and 2010. This number was divided by the total number of persons registered with participating general practices on that same date. These data were also used to estimate both age specific prevalence and prevalence in various regions of the UK.

Results: A total of 1136 patients diagnosed with HD, aged 21 years or more, were identified from the database. The estimated prevalence (expressed per 100 000 population) rose from 5.4 (95% CI 3.8 to 7.5) in 1990 to 12.3 (95% CI 11.2 to 13.5) in 2010. Although an increased prevalence was observed within every age group, the most dramatic was in older patients. Age specific prevalence was highest in the 51-60 year age range (15.8 95% CI 9.0 to 22.3). The prevalence of adult HD was lowest in the London region (5.4 (95% CI 3.0 to 8.9)) and highest in the North East of England (18.3 (95% CI 8.6 to 34.6)) and Scotland (16.1 (95% CI 10.8 to 22.9)).

Conclusions: The prevalence of diagnosed HD is clearly substantially higher in the UK than suggested from previous studies. By extrapolation to the UK as a whole, it is estimated that there are more than 5700 people, aged 21 years or more, with HD. There has also been a surprising doubling of the HD population between 1990 and 2010. Many factors may have caused this increase, including more accurate diagnoses, better and more available therapies and an improved life expectancy, even with HD. There also appears to be a greater willingness to register a diagnosis of HD in patients' electronic medical records. Such a high prevalence of HD requires more ingenuity and responsiveness in its care. How to appropriately care for, and respond to, so many individuals and families coping with the exigencies of HD demands our greatest resolve and imagination.
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http://dx.doi.org/10.1136/jnnp-2012-304636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786631PMC
October 2013

Huntington's disease: advocacy driving science.

Authors:
Nancy S Wexler

Annu Rev Med 2012 ;63:1-22

Columbia University, New York, New York 10032, USA.

My mother, Leonore, was diagnosed with Huntington's disease (HD) in 1968 at age 53. I was 23, my sister Alice 26, and our father, Milton Wexler, 60 years old. The same year, our father created the Hereditary Disease Foundation (HDF), dedicated to finding treatments and cures for HD. HD is an autosomal dominant, neurodegenerative disorder. Alice and I each have a 50% chance of inheriting and dying from the disorder. Over the past 43 years, we have been proud to change the face of science. Through Milton Wexler Interdisciplinary Workshops, judicious funding, and focusing on innovation and creativity, the HDF is an integral partner in key discoveries. The HDF recruited and supported >100 scientists worldwide who worked together as the Huntington's Disease Collaborative Research Group in a successful ten-year search for the HD gene. We found a DNA marker for the HD gene in 1983-the first marker to be found when the chromosomal location was unknown. We isolated the HD gene itself a decade later. These breakthroughs helped launch the Human Genome Project. We supported creating the first mouse model of HD and many other model systems. Currently, we focus on gene silencing, among other approaches, to create new treatments and cures.
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http://dx.doi.org/10.1146/annurev-med-050710-134457DOI Listing
May 2012

Parallel explicit and implicit control of reaching.

PLoS One 2009 Oct 22;4(10):e7557. Epub 2009 Oct 22.

Motor Performance Laboratory, Department of Neurology, Columbia University, New York, New York, United States of America.

Background: Human movement can be guided automatically (implicit control) or attentively (explicit control). Explicit control may be engaged when learning a new movement, while implicit control enables simultaneous execution of multiple actions. Explicit and implicit control can often be assigned arbitrarily: we can simultaneously drive a car and tune the radio, seamlessly allocating implicit or explicit control to either action. This flexibility suggests that sensorimotor signals, including those that encode spatially overlapping perception and behavior, can be accurately segregated to explicit and implicit control processes.

Methodology/principal Findings: We tested human subjects' ability to segregate sensorimotor signals to parallel control processes by requiring dual (explicit and implicit) control of the same reaching movement and testing for interference between these processes. Healthy control subjects were able to engage dual explicit and implicit motor control without degradation of performance compared to explicit or implicit control alone. We then asked whether segregation of explicit and implicit motor control can be selectively disrupted by studying dual-control performance in subjects with no clinically manifest neurologic deficits in the presymptomatic stage of Huntington's disease (HD). These subjects performed successfully under either explicit or implicit control alone, but were impaired in the dual-control condition.

Conclusion/significance: The human nervous system can exert dual control on a single action, and is therefore able to accurately segregate sensorimotor signals to explicit and implicit control. The impairment observed in the presymptomatic stage of HD points to a possible crucial contribution of the striatum to the segregation of sensorimotor signals to multiple control processes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007557PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760763PMC
October 2009

The ups and downs of mutation frequencies during aging can account for the Apert syndrome paternal age effect.

PLoS Genet 2009 Jul 10;5(7):e1000558. Epub 2009 Jul 10.

Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, United States of America.

Apert syndrome is almost always caused by a spontaneous mutation of paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the age of the father (paternal age effect), and this increase is greater than what would be expected based on the greater number of germ-line divisions in older men. We use a highly sensitive PCR assay to measure the frequencies of the two causal mutations in the sperm of over 300 normal donors with a wide range of ages. The mutation frequencies increase with the age of the sperm donors, and this increase is consistent with the increase in the incidence rate. In both the sperm data and the birth data, the increase is non-monotonic. Further, after normalizing for age, the two Apert syndrome mutation frequencies are correlated within individual sperm donors. We consider a mathematical model for germ-line mutation which reproduces many of the attributes of the data. This model, with other evidence, suggests that part of the increase in both the sperm data and the birth data is due to selection for mutated premeiotic cells. It is likely that a number of other genetic diseases have similar features.
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http://dx.doi.org/10.1371/journal.pgen.1000558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700275PMC
July 2009

Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds.

Genet Epidemiol 2008 Jul;32(5):445-53

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

The age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD)=4.29) and 2q35 (LOD=3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD=2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD=3.31 at 5p14 and LOD=3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD.
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http://dx.doi.org/10.1002/gepi.20317DOI Listing
July 2008

Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain.

Hum Mol Genet 2007 May 4;16(10):1133-42. Epub 2007 Apr 4.

Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.
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http://dx.doi.org/10.1093/hmg/ddm054DOI Listing
May 2007

The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset.

Ann Hum Genet 2007 May 19;71(Pt 3):295-301. Epub 2006 Dec 19.

Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA.

Age of onset for Huntington's disease (HD) varies inversely with the length of the disease-causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R-squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two-segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log-transformed age of onset against CAG repeat length reveals this segmental relationship. This two-segment exponential regression on age of onset data increases the adjusted R-squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two-segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) = 11.13, P= 2 x 10(-5)] and in the HD MAPS cohort [F(2, 688) = 38.27, P= 2 x 10(-16)]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult-onset range of CAG repeats than in the juvenile-onset range.
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http://dx.doi.org/10.1111/j.1469-1809.2006.00335.xDOI Listing
May 2007

Regional and cellular gene expression changes in human Huntington's disease brain.

Hum Mol Genet 2006 Mar 8;15(6):965-77. Epub 2006 Feb 8.

Department of Psychological Medicine, Wales College of Medicine and School of Biosciences, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, UK.

Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.
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http://dx.doi.org/10.1093/hmg/ddl013DOI Listing
March 2006

Interrater agreement in the assessment of motor manifestations of Huntington's disease.

Mov Disord 2005 Mar;20(3):293-7

Oregon Health and Science University, Portland, Oregon 97239-3098, USA.

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntington's disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy-five clinicians experienced in the evaluation of patients with early HD and six non-clinicians were shown a videotape compiled from the film archives of the United States-Venezuela Collaborative HD Research Project. Observers were asked to rate a 2-3-minute segment of the motor examination for each of 17 at-risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted kappa statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted kappa = 0.67; standard error (SE) = 0.09). Agreement among the non-clinicians was only fair (weighted kappa = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients.
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http://dx.doi.org/10.1002/mds.20332DOI Listing
March 2005

Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset.

Proc Natl Acad Sci U S A 2004 Mar 1;101(10):3498-503. Epub 2004 Mar 1.

Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation +/- SE) were estimated for sibling (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximately 40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
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http://dx.doi.org/10.1073/pnas.0308679101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC373491PMC
March 2004

Huntington disease expansion mutations in humans can occur before meiosis is completed.

Proc Natl Acad Sci U S A 2003 Jul 11;100(15):8834-8. Epub 2003 Jul 11.

Molecular and Computational Biology Program, University of Southern California, Los Angeles, CA 90089-1340, USA.

Single-molecule DNA analysis of testicular germ cells isolated by laser capture microdissection from two Huntington disease patients showed that trinucleotide repeat expansion mutations were present before the end of the first meiotic division, and some mutations were present even before meiosis began. Most of the larger Huntington disease mutations were found in the postmeiotic cell population, suggesting that expansions may continue to occur during meiosis and/or after meiosis is complete. Defining the germ-line cell compartments where the trinucleotide repeat expansions occur could help to elucidate the underlying mechanisms of instability.
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http://dx.doi.org/10.1073/pnas.1331390100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC166399PMC
July 2003

Candidate DNA replication initiation regions at human trinucleotide repeat disease loci.

Hum Mol Genet 2003 May;12(9):1021-8

Program in Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089-1340, USA.

The positions of DNA replication initiation regions (IRs) at three human trinucleotide repeat (TNR) disease loci were examined in order to characterize the role played by IRs in explaining the known locus-specific variation in TNR instability levels. Using three different normal cell lines, candidate IRs were identified at the HD, SCA-7 and SBMA loci. At each locus the IR is less than 3.6 kb from the CAG/CTG repeat tract. Preliminary studies with a cell line homozygous for an HD disease mutation indicated no change in the position of the candidate IR in spite of the mutation. Comparison with experimental results from model systems suggests that a complex relationship may exist between instability and the proximity and/or orientation of the repeats with respect to an IR.
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http://dx.doi.org/10.1093/hmg/ddg111DOI Listing
May 2003

Case vignette: genetic secrets.

Ethics Behav 1992 ;2(2):129-39

Mrs. Thomas, age 50, became concerned after experiencing intermittent uncontrollable jerky body movements. She contacted her family physician and, following a full diagnostic evaluation, learned that she is experiencing early symptons of Huntington's disease. This illness is a degenerative disease of the central nervous system, which will ultimately lead-to physical incapacity, dementia, and death. The disease is known to be transmitted genetically as an autosomal dominant trait, with the first onset of symptoms usually occurring in middle age. For example, the child of an affected person has a 50% chance of inheriting the gene, and thus the illness, and a 50% chance of passing it on to their children. Mrs. Thomas is unaware of any history of the disease among others in her family; however, her father was an adopted child, who died in an automobile accident at the age of 37 and may well have been a carrier of the gene. It is highly likely that other members of her family, including her siblings and children, may be carriers of the gene and ultimately transmit it to their children before clinical symptoms of the disease develop. Her own son married last year, and her two brothers have children of childbearing age. Genetic screening and counseling are available for those at risk for Huntington's disease; however, Mrs. Thomas does not want to discuss her diagnosis with family members, fearing that they may blame her and that she may lose her job and friends if the information becomes public knowledge. What advice would you give to the health-care providers caring for Mrs. Thomas regarding the assorted rights, duties, and obligations surrounding this situation?
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http://dx.doi.org/10.1207/s15327019eb0202_6DOI Listing
October 1992
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