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  • 1.
    Alafuzoff, I
    et al.
    Karaolinska institutet.
    Almqvist, E
    Adolfsson, R
    Lake, S
    Wallace, W
    Greenberg, D A
    Winblad, B
    A comparison of multiplex and simplex families with Alzheimer's disease/senile dementia of Alzheimer type within a well defined population.1994In: Journal of neural transmission. Parkinson's disease and dementia section, ISSN 0936-3076, Vol. 7, no 1, p. 61-72Article in journal (Refereed)
    Abstract [en]

    A study was made on 150 clinically demented patients presenting at autopsy at Umeå University Hospital in Sweden. In 90 of the cases dementia was considered to be primary in nature and of these forty six per cent (41 cases), fulfilled both the clinical and histopathological criteria for the diagnosis of Alzheimer's disease/Senile dementia of Alzheimer type (AD/SDAT). The families of these 41 AD/SDAT cases were then studied, and a family history obtained through interviews with multiple family informants and from civil and medical records. Additional diseased family members suffering from progressive dementia (multiplex families) were observed in 12 probands out of 41 (29%). Multiplex families exhibited similar clinical and histopathological characteristics as simplex families containing a single affected individual. The secondary cases in the multiplex families exhibited similar demographic and clinical characteristics as the probands. 39% of the multiplex and 14% of the simplex cases had an early age of onset of the disease, that was under 65 years. The overall prevalence of progressive dementia disorders in the 41 families was 5.9%. The prevalence of a progressive dementia disorder was 11% in the multiplex families (14% for the early onset cases) and 3.5% in the simplex families (2% for the early onset cases). The prevalence of progressive dementia disorder for family members who had passed the mean age of the onset of the disease for their family, was 45% for multiplex and 18% for simplex families. Furthermore the incidence rate for dementia was significantly higher (p < 0.005) in multiplex families (5.5 per 1,000 person years) when compared to simplex families (2.5 per 1,000 person years). No differences could be seen in parental age at birth of the diseased when comparing the two sets of families. However in multiplex families the duration of the disease was significantly (p < 0.025) shorter, in subjects with parental age at birth over 35 years compared to those with a parental age under 35 years. The multiplex families contained significantly (p < 0.025) larger sibships; and showed a significantly lower age of onset for the disease (p < 0.001), and a significantly longer duration of disease (p < 0.05) compared to the simplex families. A significant intra familial correlation of age at disease onset was observed in both sets of the families.

  • 2.
    Almqvist, E
    et al.
    Kanada.
    Adam, S
    Bloch, M
    Fuller, A
    Welch, P
    Eisenberg, D
    Whelan, D
    Macgregor, D
    Meschino, W
    Hayden, M R
    Risk reversals in predictive testing for Huntington disease.1997In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 61, no 4, p. 945-52Article in journal (Refereed)
    Abstract [en]

    The first predictive testing for Huntington disease (HD) was based on analysis of linked polymorphic DNA markers to estimate the likelihood of inheriting the mutation for HD. Limits to accuracy included recombination between the DNA markers and the mutation, pedigree structure, and whether DNA samples were available from family members. With direct tests for the HD mutation, we have assessed the accuracy of results obtained by linkage approaches when requested to do so by the test individuals. For six such individuals, there was significant disparity between the tests. Three went from a decreased risk to an increased risk, while in another three the risk was decreased. Knowledge of the potential reasons for these changes in results and impact of these risk reversals on both patients and the counseling team can assist in the development of strategies for the prevention and, where necessary, management of a risk reversal in any predictive testing program.

  • 3.
    Almqvist, E
    et al.
    Karolinska institutet.
    Andrew, S
    Theilmann, J
    Goldberg, P
    Zeisler, J
    Drugge, U
    Grandell, U
    Tapper-Persson, M
    Winblad, B
    Hayden, M
    Geographical distribution of haplotypes in Swedish families with Huntington's disease.1994In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 94, no 2, p. 124-8Article in journal (Refereed)
    Abstract [en]

    This study was planned to determine the number of origins of the mutation underlying Huntington's disease (HD) in Sweden. Haplotypes were constructed for 23 different HD families, using six different polymorphisms [(CCG)n, GT70, 674, BS1, E2 and 4.2], including two within the gene. In addition, extensive genealogical investigations were performed, and the geographical origin of the haplotypes was studied. Ten different haplotypes were observed suggesting multiple origins for the HD mutation in Sweden. Analysis of the two polymorphic markers within the HD gene (the CCG repeat and GT70) indicates that there are at least three origins for the HD mutation in Sweden. One of these haplotypes (7/A) accounts for 89% of the families, suggesting that the majority of the Swedish HD families are related through a single HD mutation of ancient origin. Furthermore, three of the families that were previously considered to be unrelated could be traced to a common ancestor in the 15th century, a finding that is consistent with this hypothesis.

  • 4.
    Almqvist, E
    et al.
    Karolinska institutet.
    Lake, S
    Axelman, K
    Johansson, K
    Winblad, B
    Screening of amyloid precursor protein gene mutation (APP 717 Val-->Ile) in Swedish families with Alzheimer's disease.1993In: Journal of neural transmission. Parkinson's disease and dementia section, ISSN 0936-3076, Vol. 6, no 2, p. 151-6Article in journal (Refereed)
    Abstract [en]

    Screening for the APP 717 Val-->Ile mutation in the amyloid precursor protein (APP) gene in 34 Swedish families with familial Alzheimer's disease (FAD), 16 sporadic cases of Alzheimer's disease and five patients with Down's syndrome (DS) failed to identify further cases of the mutation. These results suggests that the mutation is rare among Swedish families with Alzheimer's disease. In addition, we summarize present reports of the frequency of the mutation.

  • 5.
    Almqvist, E
    et al.
    Kanada.
    Spence, N
    Nichol, K
    Andrew, S E
    Vesa, J
    Peltonen, L
    Anvret, M
    Goto, J
    Kanazawa, I
    Goldberg, Y P
    Ancestral differences in the distribution of the delta 2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes: insights into the genetic evolution of Huntington disease.1995In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 4, no 2, p. 207-14Article in journal (Refereed)
    Abstract [en]

    This study addresses genetic factors associated with normal variation of the CAG repeat in the Huntington disease (HD) gene. To achieve this, we have studied patterns of variation of three trinucleotide repeats in the HD gene including the CAG and adjacent CCG repeats as well as a GAG polymorphism at residue 2642 (delta 2642). We have previously demonstrated that variation in the CCG repeat is associated with variation of the CAG repeat length on normal chromosomes. Here we show that differences in the GAG trinucleotide polymorphism at residue 2642 is also significantly correlated with CAG size on normal chromosomes. The B allele which is associated with higher CAG repeat lengths on normal chromosomes is markedly enriched on affected chromosomes. Furthermore, this glutamic acid polymorphism shows significant variation in different ancestries and is absent in chromosomes of Japanese, Black and Chinese descent. Haplotype analysis of both the CCG and delta 2642 polymorphisms have indicated that both are independently associated with differences in CAG length on normal chromosomes. These findings lead to a model for the genetic evolution of new mutations for HD preferentially occurring on normal chromosomes with higher CAG repeat lengths and a CCG repeat length of seven and/or a deletion of the glutamic acid residue at delta 2642. This study also provides additional evidence for genetic contributions to demographic differences in prevalence rates for HD.

  • 6.
    Almqvist, E W
    et al.
    Kanada.
    Bloch, M
    Brinkman, R
    Craufurd, D
    Hayden, M R
    A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease.1999In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 64, no 5, p. 1293-304Article in journal (Refereed)
    Abstract [en]

    Prior to the implementation of predictive-testing programs for Huntington disease (HD), significant concern was raised concerning the likelihood of catastrophic events (CEs), particularly in those persons receiving an increased-risk result. We have investigated the frequency of CEs-that is, suicide, suicide attempt, and psychiatric hospitalization-after an HD predictive-testing result, through questionnaires sent to predictive-testing centers worldwide. A total of 44 persons (0.97%) in a cohort of 4,527 test participants had a CE: 5 successful suicides, 21 suicide attempts, and 18 hospitalizations for psychiatric reasons. All persons committing suicide had signs of HD, whereas 11 (52.4%) of 21 persons attempting suicide and 8 (44.4%) of 18 who had a psychiatric hospitalization were symptomatic. A total of 11 (84.6%) of 13 asymptomatic persons who experienced a CE during the first year after HD predictive testing received an increased-risk result. Factors associated with an increased risk of a CE included (a) a psychiatric history </=5 years prior to testing and (b) unemployed status. The frequency of CEs did not differ between those persons receiving results of predictive testing through linkage analysis in whom there was only changes in direction of risk and those persons receiving definitive results after analysis for the mutation underlying HD. These findings provide insights into the frequency, associated factors, and timing of CEs in a worldwide cohort of persons receiving predictive-testing results and, as such, highlight persons for whom ongoing support may be beneficial.

  • 7.
    Almqvist, E W
    et al.
    Kanada.
    Brinkman, R R
    Wiggins, S
    Hayden, M R
    Psychological consequences and predictors of adverse events in the first 5 years after predictive testing for Huntington's disease.2003In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 64, no 4, p. 300-9Article in journal (Refereed)
    Abstract [en]

    The promise of genetic medicine is to provide information, based on genotype, to persons not yet sick about their risk of future illness. However, little is known of the long-term psychological effects for asymptomatic persons learning their risk of having a serious disease. Predictive genetic testing for Huntington's disease (HD) has been offered for the longest time for any disease. In the present study, the psychological consequences of predictive testing were assessed prospectively in individuals at risk for HD during seven visits over 5 years. Questionnaires of standard measures of psychological distress (the General Severity Index of the Symptom Check List-90-Revised), depression (the Beck Depression Inventory), and general well-being (the General Well-Being Scale) were administered to the participants. A significant reduction in psychological distress was observed for both result groups throughout 2 years (p < 0.001) and at 5 years (p = 0.002). Despite the overall improvement of the psychological well-being, 6.9% (14 of 202) of the participants experienced an adverse event during the first 2 years after predictive testing that was clinically significant. The frequency of all defined adverse events in the participants was 21.8%, with higher frequency in the increased risk group (p = 0.03) and most occurring within 12 months of receiving results.

  • 8.
    Almqvist, E W
    et al.
    Kanada.
    Elterman, D S
    MacLeod, P M
    Hayden, M R
    High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia.2001In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 60, no 3, p. 198-205Article in journal (Refereed)
    Abstract [en]

    The advent of the direct mutation test for Huntington disease (HD) has made it possible to identify a previously unrecognized symptomatic population of HD, including those with an atypical presentation or patients without a family history of HD. The present study investigated the uptake of this test in the province of British Columbia (BC), Canada and assessed the incidence rate and rate of identification of new mutations for HD. All symptomatic individuals residing in BC who were referred for the genetic test for HD between 1993 and 2000 (n=205) were analyzed for CAG expansion, baseline demographics and clinical data, and a family history of HD. A total of 141 (or 68.8%) had a CAG expansion > or =36. Of these, almost one-quarter (24.1%) did not have a family history of HD. An extensive chart review revealed that 11 patients (or 7.8%) had reliable information on both parents (who lived well into old age) and therefore possibly could represent new mutations for HD. This indicates a three to four times higher new mutation rate than previously reported. Our findings also show that the yearly incidence rate for HD was 6.9 per million, which is two times higher than previous incidence studies performed prior to the identification of the HD mutation. We also identified five persons with a clinical presentation of HD but without CAG expansion (genocopies) (2.4%).

  • 9.
    Andrew, S E
    et al.
    Kanada.
    Goldberg, Y P
    Kremer, B
    Squitieri, F
    Theilmann, J
    Zeisler, J
    Telenius, H
    Adam, S
    Almquist, E
    Anvret, M
    Huntington disease without CAG expansion: phenocopies or errors in assignment?1994In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 54, no 5, p. 852-63Article in journal (Refereed)
    Abstract [en]

    Huntington disease (HD) has been shown to be associated with an expanded CAG repeat within a novel gene on 4p16.3 (IT15). A total of 30 of 1,022 affected persons (2.9% of our cohort) did not have an expanded CAG in the disease range. The reasons for not observing expansion in affected individuals are important for determining the sensitivity of using repeat length both for diagnosis of affected patients and for predictive testing programs and may have biological relevance for the understanding of the molecular mechanism underlying HD. Here we show that the majority (18) of the individuals with normal sized alleles represent misdiagnosis, sample mix-up, or clerical error. The remaining 12 patients represent possible phenocopies for HD. In at least four cases, family studies of these phenocopies excluded 4p16.3 as the region responsible for the phenotype. Mutations in the HD gene that are other than CAG expansion have not been excluded for the remaining eight cases; however, in as many as seven of these persons, retrospective review of these patients' clinical features identified characteristics not typical for HD. This study shows that on rare occasions mutations in other, as-yet-undefined genes can present with a clinical phenotype very similar to that of HD.

  • 10.
    Andrew, S
    et al.
    Kanada.
    Theilmann, J
    Almqvist, E
    Norremolle, A
    Lucotte, G
    Anvret, M
    Sorensen, S A
    Turpin, J C
    Hayden, M R
    DNA analysis of distinct populations suggests multiple origins for the mutation causing Huntington disease.1993In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 43, no 6, p. 286-94Article in journal (Refereed)
    Abstract [en]

    Results of association studies can be significantly biased if the ancestry of the control population is not similar to that of the affected population. One approach to overcome such a bias is to use distinct populations where controls and affected individuals are likely to be of similar descent. We have examined homogeneous populations of French, Danish and Swedish ancestry for nonrandom allelic association between Huntington disease (HD) and several markers previously shown to be in association with HD. No evidence for nonrandom allelic association between HD and these markers was shown in these populations. The demonstration of association in a United Kingdom (UK) sample of similar size, and lack of significant differences in allele frequencies between the French, Danish, Swedish and UK populations suggested that the absence of association was not predominantly a consequence of allele frequencies or sample size. To investigate further the number of potential HD chromosomes, DNA haplotypes were constructed for the Danish, French, Swedish and UK populations. The minimum of two HD haplotypes observed in each of the French, Danish and Swedish populations, compared to the one haplotype in the UK population of a similar size, is an important factor accounting for the absence of association between HD and the DNA markers in these populations. Furthermore, these data are in favour of multiple independent origins for the mutation causing HD.

  • 11.
    Aylward, E H
    et al.
    USA.
    Rosenblatt, A
    Field, K
    Yallapragada, V
    Kieburtz, K
    McDermott, M
    Raymond, L A
    Almqvist, E W
    Hayden, M
    Ross, C A
    Caudate volume as an outcome measure in clinical trials for Huntington's disease: a pilot study.2003In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 62, no 2, p. 137-41Article in journal (Refereed)
    Abstract [en]

    Previous research has demonstrated that longitudinal change in caudate volume could be observed over a period of 3 years in subjects with Huntington's disease (HD). The current pilot study was designed to determine whether measurement of caudate change on magnetic resonance imaging (MRI) is a feasible and valid outcome measure in an actual clinical trial situation. We measured caudate volumes on pre- and post-treatment MRI scans from 19 patients at two sites who were participating in CARE-HD (Co-enzyme Q10 and Remacemide: Evaluation in Huntington's Disease), a 30-month clinical trial of remacemide and co-enzyme Q(10) in symptomatic patients with HD. Results from this pilot study indicated that decrease in caudate volume was significant over time. Power analysis indicated that relatively small numbers of subjects would be needed in clinical trials using caudate volume as an outcome measure. Advantages and disadvantages of using MRI caudate volume as an outcome measure are presented. We recommend the adoption of quantitative neuroimaging of caudate volume as an outcome measure in future clinical trials for treatments of HD.

  • 12.
    Brinkman, R R
    et al.
    Kanada.
    Mezei, M M
    Theilmann, J
    Almqvist, E
    Hayden, M R
    The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size.1997In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 60, no 5, p. 1202-10Article in journal (Refereed)
    Abstract [en]

    Prior studies describing the relationship between CAG size and the age at onset of Huntington disease (HD) have focused on affected persons. To further define the relationship between CAG repeat size and age at onset of HD, we now have analyzed a large cohort of affected and asymptomatic at-risk persons with CAG expansion. This cohort numbered 1,049 persons, including 321 at-risk and 728 affected individuals with a CAG size of 29-121 repeats. Kaplan-Meier analysis has provided curves for determining the likelihood of onset at a given age, for each CAG repeat length in the 39-50 range. The curves were significantly different (P < .0005), with relatively narrow 95% confidence intervals (95% CI) (+/-10%). Penetrance of the mutation for HD also was examined. Although complete penetrance of HD was observed for CAG sizes of > or = 42, only a proportion of those with a CAG repeat length of 36-41 showed signs or symptoms of HD within a normal life span. These data provide information concerning the likelihood of being affected, by a specific age, with a particular CAG size, and they may be useful in predictive-testing programs and for the design of clinical trials for persons at increased risk for HD.

  • 13.
    Bruland, O
    et al.
    Norge.
    Almqvist, E W
    Goldberg, Y P
    Boman, H
    Hayden, M R
    Knappskog, P M
    Accurate determination of the number of CAG repeats in the Huntington disease gene using a sequence-specific internal DNA standard.1999In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 55, no 3, p. 198-202Article in journal (Refereed)
    Abstract [en]

    We have developed a sequence-specific internal DNA size standard for the accurate determination of the number of CAG repeats in the Huntington disease (HD) gene by cloning key fragments (between 15 and 64 CAG repeats) of the HD gene. These fragments, pooled to produce a sequence-specific DNA ladder, enabled us to observe the true number of CAG repeats directly, with no need for calculations. Comparison of the calculated numbers of CAG repeats in the HD gene using this sequence-specific DNA standard with a commercially available standard (GENESCAN-500 TAMRA) showed that the latter underestimated the number of CAG repeats by three when analyzed by capillary electrophoresis on the ABI 310 Genetic Analyzer (POP4 polymer). In contrast, the use of the same standard overestimated the number of CAG repeats by one when the samples were analyzed by denaturing polyacrylamide electrophoresis on ABI 377 DNA Sequencer (6% denaturing polyacrylamide gel). This suggests that our sequence-specific standard provides greater accuracy for the determination of the true number of CAG repeats in the HD gene than commercially available standards. The sequence-specific standard can be radioactively labeled and successfully replace conventional DNA size standards when analyzing polymerase chain reaction (PCR)-amplified HD alleles by denaturing polyacrylamide electrophoresis.

  • 14.
    Chong, S S
    et al.
    USA.
    Almqvist, E
    Telenius, H
    LaTray, L
    Nichol, K
    Bourdelat-Parks, B
    Goldberg, Y P
    Haddad, B R
    Richards, F
    Sillence, D
    Greenberg, C R
    Ives, E
    Van den Engh, G
    Hughes, M R
    Hayden, M R
    Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses.1997In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 6, no 2, p. 301-9Article in journal (Refereed)
    Abstract [en]

    New mutations for Huntington disease (HD) arise from intermediate alleles (IAs) with between 29 and 35 CAG repeats that expand on transmission through the paternal germline to 36 CAGs or greater. Using single sperm analysis, we have assessed CAG mutation frequencies for four IAs in families with sporadic HD (IANM) and IAs ascertained from the general population (IAGP) by analyzing 1161 single sperm from three persons. We show that IANM are more unstable than IAGP with identical size and sequence. Furthermore, comparison of different sized IAs and IAs with different sequences between the CAG and the adjacent CCG tracts indicates that DNA sequence is a major influence on CAG stability. These studies provide estimates of the likelihood of expansion of IANM and IAGP to > or = 36 CAG repeats for these individuals. For an IA with a CAG of 35 in this family with sporadic HD, the likelihood for siblings to inherit a recurrent mutation > or = 36 CAG is approximately 10%. For IAGP of a similar size, the risk of inheriting an expanded allele of > or = 36 CAG through the paternal germline is approximately 6%. These risk estimates are higher than previously reported and provide additional information for counselling in these families. Further studies on persons with IAs will be needed to determine whether these results can be generalized to other families.

  • 15.
    Creighton, S
    et al.
    Kanada.
    Almqvist, E W
    MacGregor, D
    Fernandez, B
    Hogg, H
    Beis, J
    Welch, J P
    Riddell, C
    Lokkesmoe, R
    Khalifa, M
    MacKenzie, J
    Sajoo, A
    Farrell, S
    Robert, F
    Shugar, A
    Summers, A
    Meschino, W
    Allingham-Hawkins, D
    Chiu, T
    Hunter, A
    Allanson, J
    Hare, H
    Schween, J
    Collins, L
    Sanders, S
    Greenberg, C
    Cardwell, S
    Lemire, E
    MacLeod, P
    Hayden, M R
    Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000.2003In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 63, no 6, p. 462-75Article in journal (Refereed)
    Abstract [en]

    Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.

  • 16.
    Djoussé, L
    et al.
    USA.
    Knowlton, B
    Hayden, M
    Almqvist, E W
    Brinkman, R
    Ross, C
    Margolis, R
    Rosenblatt, A
    Durr, A
    Dode, C
    Morrison, P J
    Novelletto, A
    Frontali, M
    Trent, R J A
    McCusker, E
    Gómez-Tortosa, E
    Mayo, D
    Jones, R
    Zanko, A
    Nance, M
    Abramson, R
    Suchowersky, O
    Paulsen, J
    Harrison, M
    Yang, Q
    Cupples, L A
    Gusella, J F
    MacDonald, M E
    Myers, R H
    Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease.2003In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 119A, no 3, p. 279-82Article in journal (Refereed)
    Abstract [en]

    Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

  • 17.
    Djoussé, Luc
    et al.
    USA.
    Knowlton, Beth
    Hayden, Michael R
    Almqvist, Elisabeth W
    Brinkman, Ryan R
    Ross, Christopher A
    Margolis, Russel L
    Rosenblatt, Adam
    Durr, Alexandra
    Dode, Catherine
    Morrison, Patrick J
    Novelletto, Andrea
    Frontali, Marina
    Trent, Ronald J A
    McCusker, Elizabeth
    Gómez-Tortosa, Estrella
    Mayo Cabrero, David
    Jones, Randi
    Zanko, Andrea
    Nance, Martha
    Abramson, Ruth K
    Suchowersky, Oksana
    Paulsen, Jane S
    Harrison, Madaline B
    Yang, Qiong
    Cupples, L Adrienne
    Mysore, Jayalakshmi
    Gusella, James F
    MacDonald, Marcy E
    Myers, Richard H
    Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16.2004In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 5, no 2, p. 109-14Article in journal (Refereed)
    Abstract [en]

    Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Delta2642 (within the HD coding sequence), and BJ56 ( D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Delta2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.

  • 18.
    Ewertzon, Mats
    et al.
    Ersta Sköndal Bräcke University College, Department of Health Care Sciences.
    Alvariza, Anette
    Ersta Sköndal Bräcke University College, Department of Health Care Sciences, Palliative Research Centre, PRC. Capio Palliativ vård Dalen, Stockholm.
    Winnberg, Elisabeth
    Ersta Sköndal Bräcke University College, Department of Health Care Sciences.
    Leksell, Janeth
    Högskolan Dalarna, Uppsala universitet.
    Andershed, Birgitta
    Norge.
    Goliath, Ida
    Karolinska institutet, Ersta sjukhus.
    Momeni, Pardis
    Ersta Sköndal Bräcke University College, Department of Health Care Sciences.
    Kneck, Åsa
    Ersta Sköndal Bräcke University College, Department of Health Care Sciences.
    Skott, Maria
    Karolinska institutet, Norra Stockholms psykiatri Stockholms läns landsting.
    Årestedt, Kristofer
    Linnéuniversitetet, Linköpings universitet, Länssjukhuset i Kalmar.
    Adaptation and evaluation of the Family Involvement and Alienation Questionnaire for use in the care of older people, psychiatric care, palliative care and diabetes care.2018In: Journal of Advanced Nursing, ISSN 0309-2402, E-ISSN 1365-2648, Vol. 74, no 8, p. 1839-1850Article in journal (Refereed)
    Abstract [en]

    AIM: To adapt the Family Involvement and Alienation Questionnaire for use in the care of older people, psychiatric care, palliative care and diabetes care and to evaluate its validity and reliability.

    BACKGROUND: Involvement in the professional care has proven to be important for family members. However, they have described feelings of alienation in relation to how they experienced the professionals' approach. To explore this issue, a broad instrument that can be used in different care contexts is needed.

    DESIGN: A psychometric evaluation study, with a cross-sectional design.

    METHOD: The content validity of the Family Involvement and Alienation Questionnaire was evaluated during 2014 by cognitive interviews with 15 family members to adults in different care contexts. Psychometric evaluation was then conducted (2015-2016). A sample of 325 family members participated, 103 of whom in a test-retest evaluation. Both parametric and non-parametric methods were used.

    RESULTS: The content validity revealed that the questionnaire was generally understood and considered to be relevant and retrievable by family members in the contexts of the care of older people, psychiatric care, palliative care and diabetes care. Furthermore, the Family Involvement and Alienation Questionnaire (Revised), demonstrated satisfactory psychometric properties in terms of data quality, homogeneity, unidimensionality (factor structure), internal consistency and test-retest reliability.

    CONCLUSION: The study provides evidence that the Family Involvement and Alienation Questionnaire (Revised) is reliable and valid for use in further research and in quality assessment in the contexts of the care of older people, psychiatric care, palliative care and diabetes care. This article is protected by copyright. All rights reserved.

  • 19.
    Falush, D
    et al.
    Japan.
    Almqvist, E W
    Brinkmann, R R
    Iwasa, Y
    Hayden, M R
    Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases.2001In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 68, no 2, p. 373-85Article in journal (Refereed)
    Abstract [en]

    We describe a new approach for analysis of the epidemiology of progressive genetic disorders that quantifies the rate of progression of the disease in the population by measuring the mutational flow. The framework is applied to Huntington disease (HD), a dominant neurological disorder caused by the expansion of a CAG-trinucleotide sequence to >35 repeats. The disease is 100% penetrant in individuals with > or = 42 repeats. Measurement of the flow from disease alleles provides a minimum estimate of the flow in the whole population and implies that the new mutation rate for HD in each generation is > or = 10% of currently known cases (95% confidence limits 6%-14%). Analysis of the pattern of flow demonstrates systematic underascertainment for repeat lengths <44. Ascertainment falls to <50% for individuals with 40 repeats and to <5% for individuals with 36-38 repeats. Clinicians should not assume that HD is rare outside known pedigrees or that most cases have onset at age <50 years.

  • 20.
    Goellner, G M
    et al.
    USA.
    Tester, D
    Thibodeau, S
    Almqvist, E
    Goldberg, Y P
    Hayden, M R
    McMurray, C T
    Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer.1997In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 60, no 4, p. 879-90Article in journal (Refereed)
    Abstract [en]

    Two recent lines of evidence raise the possibility that instability in germ-line or somatic cells arises by a common mechanism that involves defective mismatch repair. Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD). Furthermore, both germ-line and somatic-cell instability are likely to be mitotic defects, the former occurring early in embryogenesis. To test the hypothesis that defective repair is a common prerequisite for instability, we have utilized two disease groups that represent different instability "conditions." Germ-line instability within simple tandem repeats (STR) at 10 loci in 29 HD families were compared with somatic instability at the same loci in 26 colon cancer (CC) patients with identified or suspected defects in mismatch-repair enzymes. HD is known to be caused by expansion within the CAG repeat of the locus, but the extent or pattern of STR instability outside this region has not been examined systematically. We find a distinctly different pattern of STR mutation in the two disease groups, suggesting different mechanisms. Instability in HD is generally confined to a single locus, whereas instability is widespread for the same loci in CC. Our data do not support a causative role for defective mismatch-repair enzymes in instability associated with HD; rather, our data are consistent with a model in which DNA structure may inhibit normal mismatch repair at the expansion site.

  • 21.
    Goldberg, Y P
    et al.
    Kanada.
    McMurray, C T
    Zeisler, J
    Almqvist, E
    Sillence, D
    Richards, F
    Gacy, A M
    Buchanan, J
    Telenius, H
    Hayden, M R
    Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population.1995In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 4, no 10, p. 1911-8Article in journal (Refereed)
    Abstract [en]

    We have directly compared intergenerational stability of intermediate alleles (IAs) derived from new mutation families (IANM) for Huntington disease (HD) with IAs in the general population (IAGP) which occur in approximately 1 in 50 persons. Analysis of meiotic events in blood and sperm reveals that IANM are significantly more unstable than IAGP despite similar size. However, for both IANM and IAGP CAG changes were small and risks for inheriting an expansion into the HD affected range were low. Sequence analysis reveals that the CAG tract is generally interrupted by a penultimate CAA in IAGP, IANM and alleles in the affected range. In one new mutation family, however, two A-->G mutations result in a pure CAG tract which is associated with very marked instability. These mutations alter the predicted DNA hairpin structure with a predicted increase in the likelihood of large expansion, supporting the model that hairpin loop formation plays an important role in trinucleotide instability.

  • 22. Hagberg, Anette
    et al.
    Bui, The-Hung
    Winnberg, Elisabeth
    Ersta Sköndal University College, Department of Health Care Sciences.
    More appreciation of life or regretting the test? Experiences of living as a mutation carrier of Huntington's disease2011In: Journal of Genetic Counseling, ISSN 1059-7700, E-ISSN 1573-3599, Vol. 20, no 1, p. 70-79Article in journal (Refereed)
    Abstract [en]

    Little is known about how the knowledge of being a mutation carrier for Huntington's disease (HD) influences lives, emotionally and socially. In this qualitative study 10 interviews were conducted to explore the long term (>5 years) experiences of being a mutation carrier. The results showed a broad variety of both positive and negative impact on the carriers' lives. The most prominent positive changes reported were a greater appreciation of life and a tendency to bring the family closer together. On the other hand, some participants expressed decisional regrets and discussed the negative impact this knowledge had on their psychological well-being. The knowledge variously served as either a motivator or an obstacle in pursuing further education, career or investment in personal health. Deeper understanding of people's reactions to the certainty of knowing they will become affected with HD is essential for the genetic counseling team in order to provide appropriate support.

  • 23.
    Holmgren, G
    et al.
    Department of: Clinical Genetics, University Hospital, Umeå, Sweden..
    Almqvist, E W
    Anvret, M
    Conneally, M
    Hobbs, W
    Mattsson, B
    Wahlström, J
    Winblad, B
    Gusella, J F
    Linkage of G8 (D4S10) in two Swedish families with Huntington's disease.1987In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 32, no 5, p. 289-94Article in journal (Refereed)
    Abstract [en]

    Two Swedish families with Huntington's disease (HD) have been investigated for linkage with G8 (D4S10). In one family from northern Sweden (Family 1) 48 family members were examined, and in another family from the southwestern part of Sweden (Family 2) 14 family members were examined. The lod scores were 1.531 for Family 1 and 2.057 for Family 2, and the combined lod score was 3.59. The HD gene was segregating with the haplotype C in Family 1 and with haplotype A in Family 2. The predictive value of the test was obvious. Before the testing with the G8 probe, 84.2% of the family members in Family 1 had a theoretical risk of 25% or 50% of having the HD gene. After the testing with the G8 probe, only 23.7% of the family members remained at the same risk, and it could also be certified that 63.2% had no or little risk of having the HD gene. Only one asymptomatic person was predicted to have HD.

  • 24.
    Karlstedt, M
    et al.
    Karolinska institutet.
    Fereshtehnejad, S M
    Karolinska institutet.
    Winnberg, Elisabeth
    Ersta Sköndal University College, Department of Health Care Sciences.
    Aarsland, D
    Karolinska institutet.
    Lökk, J
    Karolinska institutet.
    Psychometric properties of the mutuality scale in Swedish dyads with Parkinson's disease.2017In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 136, no 2, p. 122-128Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The 15-item mutuality scale (MS) has been used in several neurological conditions assessing the quality of relationship associations with negative effects of the caregiving situation. The aim of this study was to translate the original MS into Swedish and assess its psychometric properties in Parkinson's disease (PD).

    MATERIALS AND METHODS: Following the forward-backward translation method, the scale was evaluated regarding linguistic correctness at a conceptual level and user-friendliness. The scale was filled out by a sample of 50 care dyads where one was having PD. Scale assumptions and scale structure were evaluated using floor/ceiling effect and principal component analyses (PCA) with promax rotation. Internal consistency was evaluated using Cronbach's alpha and mean inter-item correlation coefficients.

    RESULTS: The Swedish MS was evaluated as user-friendly and relevant by the participants. The scale demonstrated no floor/ceiling effect and showed high internal consistency (α≥0.93) with a mean inter-item correlation coefficient of ≥0.5. Through the PCA, a two factor solution emerged, which accounted for 67% and 64% of the variance of the MS score by PD-partners and PD-patients, respectively. However, some variables were complex and discarded in the final solution.

    CONCLUSION: Our findings provide initial support of the Swedish MS as a user-friendly and useful instrument with acceptable psychometric properties even though more research is needed to evaluate the existence of subscales.

  • 25.
    Kremer, B
    et al.
    Kanada.
    Almqvist, E
    Theilmann, J
    Spence, N
    Telenius, H
    Goldberg, Y P
    Hayden, M R
    Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes.1995In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 57, no 2, p. 343-50Article in journal (Refereed)
    Abstract [en]

    A total of 254 affected parent-child pairs with Huntington disease (HD) and 440 parent-child pairs with CAG size in the normal range were assessed to determine the nature and frequency of intergenerational CAG changes in the HD gene. Intergenerational CAG changes are extremely rare (3/440 [0.68%]) on normal chromosomes. In contrast, on HD chromosomes, changes in CAG size occur in approximately 70% of meioses on HD chromosomes, with expansions accounting for 73% of these changes. These intergenerational CAG changes make a significant but minor contribution to changes in age at onset (r2 = .19). The size of the CAG repeat influenced larger intergenerational expansions (> 7 CAG repeats), but the likelihood of smaller expansions or contractions was not influenced by CAG size. Large expansions (> 7 CAG repeats) occur almost exclusively through paternal transmission (0.96%; P < 10(-7)), while offspring of affected mothers are more likely to show no change (P = .01) or contractions in CAG size (P = .002). This study demonstrates that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene. Similar paternal sex effects are seen in the evolution of new mutations for HD from intermediate alleles and for large expansions on affected chromosomes. Affected mothers almost never transmit a significantly expanded CAG repeat, despite the fact that many have similar large-sized alleles, compared with affected fathers. The sex-dependent effects of major expansion and contractions of the CAG repeat in the HD gene implicate different effects of gametogenesis, in males versus females, on intergenerational CAG repeat stability.

  • 26.
    Kremer, B
    et al.
    Kanada.
    Clark, C M
    Almqvist, E W
    Raymond, L A
    Graf, P
    Jacova, C
    Mezei, M
    Hardy, M A
    Snow, B
    Martin, W
    Hayden, M R
    Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial.1999In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 53, no 5, p. 1000-11Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD).

    BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo.

    METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included.

    RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected.

    CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.

  • 27.
    Kremer, B
    et al.
    Kanada.
    Goldberg, P
    Andrew, S E
    Theilmann, J
    Telenius, H
    Zeisler, J
    Squitieri, F
    Lin, B
    Bassett, A
    Almqvist, E
    A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats.1994In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 330, no 20, p. 1401-6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Huntington's disease is associated with an expanded sequence of CAG repeats in a gene on chromosome 4p16.3. However, neither the sensitivity of expanded CAG repeats in affected persons of different ethnic origins nor the specificity of such repeats for Huntington's disease as compared with other neuropsychiatric disorders has been determined.

    METHODS: We studied 1007 patients with diagnosed Huntington's disease from 565 families and 43 national and ethnic groups. In addition, the length of the CAG repeat was determined in 113 control subjects with a family history of Alzheimer's disease (44 patients), schizophrenia (39), major depression (16), senile chorea (5), benign hereditary chorea (5), neuroacanthocytosis (2), and dentatorubropallidoluysian atrophy (2). The number of CAG repeats was also assessed in 1595 control chromosomes, with the size of adjacent polymorphic CCG trinucleotide repeats taken into account.

    RESULTS: Of 1007 patients with signs and symptoms compatible with a diagnosis of Huntington's disease, 995 had an expanded CAG repeat that included from 36 to 121 repeats (median, 44) (sensitivity, 98.8 percent; 95 percent confidence interval, 97.7 to 99.4 percent). There were no significant differences among national and ethnic groups in the number of repeats. No CAG expansion was found in the 110 control subjects with other neuropsychiatric disorders (specificity, 100 percent; 95 percent confidence interval, 95.2 to 100 percent). In 1581 of the 1595 control chromosomes (99.1 percent), the number of CAG repeats ranged from 10 to 29 (median, 18). In 12 control chromosomes (0.75 percent), intermediate-sized CAG sequences with 30 to 35 repeats were found, and 2 normal chromosomes unexpectedly had expanded CAG sequences, of 39 and 37 repeats.

    CONCLUSIONS: CAG trinucleotide expansion is the molecular basis of Huntington's disease worldwide and is a highly sensitive and specific marker for inheritance of the disease mutation.

  • 28.
    Langbehn, D R
    et al.
    USA.
    Brinkman, R R
    Falush, D
    Paulsen, J S
    Hayden, M R
    A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length.2004In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 65, no 4, p. 267-77Article in journal (Refereed)
    Abstract [en]

    Huntington's disease (HD) is a neurodegenerative disorder caused by an unstable CAG repeat. For patients at risk, participating in predictive testing and learning of having CAG expansion, a major unanswered question shifts from "Will I get HD?" to "When will it manifest?" Using the largest cohort of HD patients analyzed to date (2913 individuals from 40 centers worldwide), we developed a parametric survival model based on CAG repeat length to predict the probability of neurological disease onset (based on motor neurological symptoms rather than psychiatric onset) at different ages for individual patients. We provide estimated probabilities of onset associated with CAG repeats between 36 and 56 for individuals of any age with narrow confidence intervals. For example, our model predicts a 91% chance that a 40-year-old individual with 42 repeats will have onset by the age of 65, with a 95% confidence interval from 90 to 93%. This model also defines the variability in HD onset that is not attributable to CAG length and provides information concerning CAG-related penetrance rates.

  • 29.
    Lannfelt, L
    et al.
    Karolinska institutet.
    Viitanen, M
    Johansson, K
    Axelman, K
    Lilius, L
    Almqvist, E
    Winblad, B
    Low frequency of the APP 670/671 mutation in familial Alzheimer's disease in Sweden.1993In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 153, no 1, p. 85-7Article in journal (Refereed)
    Abstract [en]

    Molecular genetic studies have identified disease-causing mutations at codon 717 of the amyloid protein precursor gene in families with early-onset Alzheimer's disease. Recently, we reported a new mutation at codon 670/671 in a large Swedish family with Alzheimer's disease. The mutation results in two amino acid changes at the N-terminal of the beta-amyloid region. In the present study, we screened for the APP 670/671 mutation in sufferers from 31 other Swedish families with Alzheimer's disease using PCR and restriction enzyme digestion. The mutation was found only in the family previously reported and not in any other family. It is concluded that this mutation is a rare cause of familial Alzheimer's disease in Sweden.

  • 30.
    Li, Jian-Liang
    et al.
    USA.
    Hayden, Michael R
    Almqvist, Elisabeth W
    Brinkman, Ryan R
    Durr, Alexandra
    Dodé, Catherine
    Morrison, Patrick J
    Suchowersky, Oksana
    Ross, Christopher A
    Margolis, Russell L
    Rosenblatt, Adam
    Gómez-Tortosa, Estrella
    Cabrero, David Mayo
    Novelletto, Andrea
    Frontali, Marina
    Nance, Martha
    Trent, Ronald J A
    McCusker, Elizabeth
    Jones, Randi
    Paulsen, Jane S
    Harrison, Madeline
    Zanko, Andrea
    Abramson, Ruth K
    Russ, Ana L
    Knowlton, Beth
    Djoussé, Luc
    Mysore, Jayalakshmi S
    Tariot, Suzanne
    Gusella, Michael F
    Wheeler, Vanessa C
    Atwood, Larry D
    Cupples, L Adrienne
    Saint-Hilaire, Marie
    Cha, Jang-Ho J
    Hersch, Steven M
    Koroshetz, Walter J
    Gusella, James F
    MacDonald, Marcy E
    Myers, Richard H
    A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study.2003In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 73, no 3, p. 682-7Article in journal (Refereed)
    Abstract [en]

    Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21-23 (LOD=2.29), and 6q24-26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.

  • 31. Marder, K
    et al.
    Zhao, H
    Eberly, S
    Tanner, C M
    Oakes, D
    Shoulson, I
    Dietary intake in adults at risk for Huntington disease: analysis of PHAROS research participants.2009In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 73, no 5, p. 385-92Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine caloric intake, dietary composition, and body mass index (BMI) in participants in the Prospective Huntington At Risk Observational Study (PHAROS).

    METHODS: Caloric intake and macronutrient composition were measured using the National Cancer Institute Food Frequency Questionnaire (FFQ) in 652 participants at risk for Huntington disease (HD) who did not meet clinical criteria for HD. Logistic regression was used to examine the relationship between macronutrients, BMI, caloric intake, and genetic status (CAG <37 vs CAG > or =37), adjusting for age, gender, and education. Linear regression was used to determine the relationship between caloric intake, BMI, and CAG repeat length.

    RESULTS: A total of 435 participants with CAG <37 and 217 with CAG > or =37 completed the FFQ. Individuals in the CAG > or =37 group had a twofold odds of being represented in the second, third, or fourth quartile of caloric intake compared to the lowest quartile adjusted for age, gender, education, and BMI. This relationship was attenuated in the highest quartile when additionally adjusted for total motor score. In subjects with CAG > or =37, higher caloric intake, but not BMI, was associated with both higher CAG repeat length (adjusted regression coefficient = 0.26, p = 0.032) and 5-year probability of onset of HD (adjusted regression coefficient = 0.024; p = 0.013). Adjusted analyses showed no differences in macronutrient composition between groups.

    CONCLUSIONS: Increased caloric intake may be necessary to maintain body mass index in clinically unaffected individuals with CAG repeat length > or =37. This may be related to increased energy expenditure due to subtle motor impairment or a hypermetabolic state.

  • 32.
    Margolis, Russell L
    et al.
    USA.
    Holmes, Susan E
    Rosenblatt, Adam
    Gourley, Lisa
    O'Hearn, Elizabeth
    Ross, Christopher A
    Seltzer, William K
    Walker, Ruth H
    Ashizawa, Tetsuo
    Rasmussen, Astrid
    Hayden, Michael
    Almqvist, Elisabeth W
    Harris, Juliette
    Fahn, Stanley
    MacDonald, Marcy E
    Mysore, Jayalakshmi
    Shimohata, Takayoshi
    Tsuji, Shoji
    Potter, Nicholas
    Nakaso, Kazuhiro
    Adachi, Yoshiki
    Nakashima, Kenji
    Bird, Thomas
    Krause, Amanda
    Greenstein, Penny
    Huntington's Disease-like 2 (HDL2) in North America and Japan.2004In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 56, no 5, p. 670-4Article in journal (Refereed)
    Abstract [en]

    Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.

  • 33.
    Mattsson, B
    et al.
    Umeå universitet.
    Almqvist, E W
    Attitudes towards predictive testing in Huntington's disease--a deep interview study in Sweden.1991In: Family Practice, ISSN 0263-2136, E-ISSN 1460-2229, Vol. 8, no 1, p. 23-7Article in journal (Refereed)
    Abstract [en]

    Ten persons with a 50% risk of inheriting Huntington's disease were interviewed in depth about experiences of the disease with special regard to their attitude to a predictive test. The persons showed great interest, concern and worry about a test: six were generally positive while four were negative or uncertain. Every interview had a very personal character and early life experiences seemed to have a determinative influence on the attitude to the test. Persons who were without symptoms of the disease and had passed the mean age of onset within the family (usually older individuals) were largely enthusiastic about a test, as were those with slight and undetermined symptoms. Younger persons, especially those with a qualitatively good contact with the affected parent, seemed to be less interested. Contradictions during the interview were more common among those positive to testing and an ambivalence among many was reflected in a tendency towards changing opinions over time.

  • 34. Orth, Michael
    et al.
    Handley, O J
    Schwenke, C
    Dunnett, S
    Wild, E J
    Tabrizi, S J
    Landwehrmeyer, G B
    Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY.2011In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 82, no 12, p. 1409-12Article in journal (Refereed)
  • 35.
    Otto, C J
    et al.
    Kanada.
    Almqvist, E
    Hayden, M R
    Andrew, S E
    The "flap" endonuclease gene FEN1 is excluded as a candidate gene implicated in the CAG repeat expansion underlying Huntington disease.2001In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 59, no 2, p. 122-7Article in journal (Refereed)
    Abstract [en]

    At least 12 disorders including Huntington disease (HD) are associated with expansion of a trinucleotide repeat (TNR). Factors contributing to the risk of expansion of TNRs and the mechanism of expansion have not been elucidated. Data from Saccharomyces cerevisiae suggest that the flap endonuclease FEN1 plays a role in expansion of repetitive DNA tracts. It has been hypothesized that insufficiency of FEN1 or a mutant FEN1 might contribute to the occurrence of expansion events of long repetitive DNA tracts after polymerase slippage events during lagging strand synthesis. The expression pattern of FEN1 was determined, and ubiquitous tissue expression, including germ cells, suggested that FEN1 has the potential to be involved in HD. Fifteen HD parent/child pairs that demonstrated intergenerational increases in CAG length of greater than 10 repeats were examined for possible mutations or polymorphisms within the FEN1 gene that could underlie the saltatory repeat expansions seen in these individuals. No alterations were observed compared to 50 controls, excluding FEN1 as a trans-acting factor underlying TNR expansion. The identification of a candidate gene(s) in HD or other CAG-expansion disorders implicated in TNR instability will elucidate the mechanism of expansion for this growing family of neurological disorders.

  • 36.
    Paucar, Martin
    et al.
    Karolinska institutet.
    Xiang, Fengqing
    Moore, Richard
    Walker, Ruth
    Winnberg, Elisabeth
    Svenningsson, Per
    Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation.2013In: Prion, ISSN 1933-6896, E-ISSN 1933-690X, Vol. 7, no 6, p. 501-10, article id 27260Article in journal (Refereed)
    Abstract [en]

    A minority of inherited prion diseases (IPD) are caused by four to 12 extra octapeptide repeat insertions (OPRI) in the prion protein gene (PRNP). Only four families affected by IPD with 8-OPRI have been reported, one of them was a three-generation Swedish kindred in which four of seven affected subjects had chorea which was initially attributed to Huntington's disease (HD). Following the exclusion of HD, this phenotype was labeled Huntington disease-like 1 (HDL1). Here, we provide an update on the Swedish 8-OPRI family, describe the clinical features of one of its affected members with video-recordings, compare the four 8-OPRI families and study the effect of PRNP polymorphic codon 129 and gender on phenotype. Surprisingly, the Swedish kindred displayed the longest survival of all of the 8-OPRI families with a mean of 15.1 years from onset of symptoms. Subjects with PRNP polymorphic codon 129M in the mutated allele had significantly earlier age of onset, longer survival and earlier age of death than 129V subjects. Homozygous 129MM had earlier age of onset than 129VV. Females had a significantly earlier age of onset and earlier age of death than males. Up to 50% of variability in age of onset was conferred by the combined effect of PRNP polymorphic codon 129 and gender. An inverse correlation between early age of onset and long survival was found for this mutation.

  • 37. Quarrell, Oliver W
    et al.
    Handley, Olivia
    O'Donovan, Kirsty
    Dumoulin, Christine
    Ramos-Arroyo, Maria
    Biunno, Ida
    Bauer, Peter
    Kline, Margaret
    Landwehrmeyer, G Bernhard
    Discrepancies in reporting the CAG repeat lengths for Huntington's disease.2012In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 1, p. 20-6Article in journal (Refereed)
    Abstract [en]

    Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards.

  • 38.
    Rosenblatt, A
    et al.
    USA.
    Brinkman, R R
    Liang, K Y
    Almqvist, E W
    Margolis, R L
    Huang, C Y
    Sherr, M
    Franz, M L
    Abbott, M H
    Hayden, M R
    Ross, C A
    Familial influence on age of onset among siblings with Huntington disease.2001In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 105, no 5, p. 399-403Article in journal (Refereed)
    Abstract [en]

    In order to provide data relevant to a search for modifying genes for age of onset in Huntington disease, we examined the relationship between CAG number and age of onset in a total of 370 individuals from 165 siblingships, in two cohorts of siblings with Huntington disease: an American group of 144 individuals from 64 siblingships, and a Canadian population of 255 individuals from 113 siblingships. Using a logarithmic model to regress the age of onset on the number of CAG triplets, we found that CAG number alone accounted for 65%-71% of the variance in age of onset. The siblingship an individual belonged to accounted for 11%-19% of additional variance. This adds to the previous evidence that there are familial modifiers of the age of onset, independent of the CAG number. Such modifiers may consist of additional genes, which could be the target of a linkage study. A linkage study is feasible with the cooperation of a number of major centers and may be made more efficient by concentrating on sibling pairs that are highly discordant for age of onset.

  • 39.
    Rubinsztein, D C
    et al.
    Storbritannien .
    Leggo, J
    Coles, R
    Almqvist, E
    Biancalana, V
    Cassiman, J J
    Chotai, K
    Connarty, M
    Crauford, D
    Curtis, A
    Curtis, D
    Davidson, M J
    Differ, A M
    Dode, C
    Dodge, A
    Frontali, M
    Ranen, N G
    Stine, O C
    Sherr, M
    Abbott, M H
    Franz, M L
    Graham, C A
    Harper, P S
    Hedreen, J C
    Hayden, M R
    Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats.1996In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 59, no 1, p. 16-22Article in journal (Refereed)
    Abstract [en]

    Abnormal CAG expansions in the IT-15 gene are associated with Huntington disease (HD). In the diagnostic setting it is necessary to define the limits of the CAG size ranges on normal and HD-associated chromosomes. Most large analyses that defined the limits of the normal and pathological size ranges employed PCR assays, which included the CAG repeats and a CCG repeat tract that was thought to be invariant. Many of these experiments found an overlap between the normal and disease size ranges. Subsequent findings that the CCG repeats vary by 8 trinucleotide lengths suggested that the limits of the normal and disease size ranges should be reevaluated with assays that exclude the CCG polymorphism. Since patients with between 30 and 40 repeats are rare, a consortium was assembled to collect such individuals. All 178 samples were reanalyzed in Cambridge by using assays specific for the CAG repeats. We have optimized methods for reliable sizing of CAG repeats and show cases that demonstrate the dangers of using PCR assays that include both the CAG and CCG polymorphisms. Seven HD patients had 36 repeats, which confirms that this allele is associated with disease. Individuals without apparent symptoms or signs of HD were found at 36 repeats (aged 74, 78, 79, and 87 years), 37 repeats (aged 69 years), 38 repeats (aged 69 and 90 years), and 39 repeats (aged 67, 90, and 95 years). The detailed case histories of an exceptional case from this series will be presented: a 95-year-old man with 39 repeats who did not have classical features of HD. The apparently healthy survival into old age of some individuals with 36-39 repeats suggests that the HD mutation may not always be fully penetrant.

  • 40. Squitieri, F
    et al.
    Almqvist, E W
    Cannella, M
    Cislaghi, G
    Hayden, M R
    Predictive testing for persons at risk for homozygosity for CAG expansion in the Huntington disease gene.2003In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 64, no 6, p. 524-5Article in journal (Refereed)
  • 41.
    Squitieri, F
    et al.
    Kanada.
    Andrew, S E
    Goldberg, Y P
    Kremer, B
    Spence, N
    Zeisler, J
    Nichol, K
    Theilmann, J
    Greenberg, J
    Goto, J
    Almqvist, Elisabeth
    DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence.1994In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 3, no 12, p. 2103-14Article in journal (Refereed)
    Abstract [en]

    This study of allelic association using three intra- and two extragenic markers within 150 kb of the Huntington disease (HD) mutation has provided evidence for linkage disequilibrium for four of five markers. Haplotype analysis of 67 HD families using markers in strong linkage disequilibrium with HD identified two haplotypes underlying 77.6% of HD chromosomes. Normal chromosomes with these two haplotypes had a mean number of CAG repeats significantly larger than and an altered distribution of CAG repeats compared with other normal chromosomes. Furthermore, haplotype analysis of five new mutation families reveals that HD has arisen on these same two chromosomal haplotypes. These findings suggest that HD arises more frequently on chromosomes with specific DNA haplotypes and higher CAG repeat lengths. We then studied CAG and CCG repeat lengths in the HD gene on 896 control chromosomes from different ancestries to determine whether the markedly reduced frequency of HD in Finland, Japan, China and African Blacks is associated with an altered frequency of DNA haplotypes and subsequently lower CAG lengths on control chromosomes compared to populations of Western European descent. The results show a highly significant inverse relationship between CAG and CCG repeat lengths. In populations with lowered prevalence rates of HD, CAG repeat lengths are smaller and the distribution of CCG alleles is markedly different from Western European populations. These findings suggest that, in addition to European emigration, new mutations make a contribution to geographical variation of prevalence rates and is consistent with a multistep model of HD developing from normal chromosomes with higher CAG repeat lengths.

  • 42.
    Squitieri, Ferdinando
    et al.
    Italien.
    Gellera, Cinzia
    Cannella, Milena
    Mariotti, Caterina
    Cislaghi, Giuliana
    Rubinsztein, David C
    Almqvist, Elisabeth W
    Turner, David
    Bachoud-Lévi, Anne-Catherine
    Simpson, Sheila A
    Delatycki, Martin
    Maglione, Vittorio
    Hayden, Michael R
    Donato, Stefano Di
    Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course.2003In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 126, no Pt 4, p. 946-55Article in journal (Refereed)
    Abstract [en]

    Huntington disease is caused by a dominantly transmitted CAG repeat expansion mutation that is believed to confer a toxic gain of function on the mutant protein. Huntington disease patients with two mutant alleles are very rare. In other poly(CAG) diseases such as the dominant ataxias, inheritance of two mutant alleles causes a phenotype more severe than in heterozygotes. In this multicentre study, we sought differences in the disease features between eight homozygotes and 75 heterozygotes for the Huntington disease mutation. We identified subjects homozygous for the Huntington disease mutation by DNA testing and compared their clinical features (age at onset, symptom presentation, disease severity and disease progression) with those of a group of heterozygotes, who were assessed longitudinally. The age at onset of symptoms in the homozygote cases was within the range expected for heterozygotes with the same CAG repeat lengths, whereas homozygotes had a more severe clinical course. The observation of a more rapid decline in motor, cognitive and behavioural symptoms in homozygotes was consistent with the extent of neurodegeneration as available at imaging in three patients, and at the post-mortem neuropathological report in one case. Our analysis suggests that although homozygosity for the Huntington disease mutation does not lower the age at onset of symptoms, it affects the phenotype and the rate of disease progression. These data, once confirmed in a larger series of patients, point to the possibility that the mechanisms underlying age at onset and disease progression in Huntington disease may differ.

  • 43.
    Telenius, H
    et al.
    Kanada.
    Almqvist, E
    Kremer, B
    Spence, N
    Squitieri, F
    Nichol, K
    Grandell, U
    Starr, E
    Benjamin, C
    Castaldo, I
    Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease.1995In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 4, no 2, p. 189-95Article in journal (Refereed)
    Abstract [en]

    We have analysed the CAG repeat in the Huntington disease (HD) gene in sperm and blood from 20 unrelated HD patients. Although the CAG repeat displayed significant mosaicism in sperm from all individuals, there were marked differences in the degree of repeat instability. Individuals who had either inherited or transmitted an expanded CAG repeat displayed the highest levels of repeat mosaicism, whereas individuals who had inherited or transmitted a contracted repeat had very limited CAG mosaicism in sperm. A strong association between intergenerational change in CAG allele size and the level of sperm repeat mosaicism was determined (P = 0.019). In contrast, neither blood CAG size nor repeat mosaicism in blood, were significantly associated with intergenerational CAG changes. These data suggest the presence of a cis-acting factor, separate from CAG size, that strongly influences the intergenerational behaviour of the CAG repeat. Additional studies are needed to determine whether analysis of CAG mosaicism in sperm is useful for assessing an individual's risk for transmitting large expansions or contractions to his offspring.

  • 44.
    Telenius, H
    et al.
    Kanada.
    Kremer, H P
    Theilmann, J
    Andrew, S E
    Almqvist, E
    Anvret, M
    Greenberg, C
    Greenberg, J
    Lucotte, G
    Squitieri, F
    Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent.1993In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 2, no 10, p. 1535-40Article in journal (Refereed)
    Abstract [en]

    Juvenile Huntington disease (HD), characterised by onset of symptoms before the age of 20 with rigidity and intellectual decline, is associated with a predominance of affected fathers. In order to investigate the molecular basis for the observed parental effect, we have analysed the CAG trinucleotide repeat within the HD gene in 42 juvenile onset cases from 34 families. A highly significant correlation was found between the repeat length and age of onset (r = -0.86, p < 10(-7) and it was determined that the sex of transmitting parent was the major influence on CAG expansion leading to earlier onset. Neither the size of the parental upper allele, the age of parent at conception of juvenile onset child, nor the grandparental sex conferred a significant effect upon expansion. Affected sib pair analysis of CAG repeat length, however, revealed a high correlation (r = 0.91, p < 10(-7). Furthermore, analysis of nuclear and extended families showed a familial predisposition to juvenile onset disease. This study demonstrates that the sex of transmitting parent is the major influence on trinucleotide expansion and clinical features in juvenile Huntington disease.

  • 45.
    Tsuang, D
    et al.
    USA.
    Almqvist, E W
    Lipe, H
    Strgar, F
    DiGiacomo, L
    Hoff, D
    Eugenio, C
    Hayden, M R
    Bird, T D
    Familial aggregation of psychotic symptoms in Huntington's disease.2000In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 157, no 12, p. 1955-9Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The mutation responsible for Huntington's disease is an elongated and unstable trinucleotide (CAG) repeat on the short arm of chromosome 4. Psychotic symptoms are more common in patients with Huntington's disease than in the general population. This study explored the relationship of psychosis in Huntington's disease patients with the number of CAG repeats and family history of psychosis.

    METHOD: Forty-four patients with Huntington's disease, 22 with and 22 without psychotic symptoms, were recruited from two university-affiliated medical genetics clinics in Seattle and Vancouver, B.C. Psychiatric assessments of the subjects were made through chart review, and diagnoses were validated by structured interviews in a subset of patients. The demographic and clinical characteristics of the psychotic and nonpsychotic patients were compared.

    RESULTS: The two groups did not differ in demographic and clinical characteristics, except that subjects with psychosis were significantly more likely than nonpsychotic subjects to have a first-degree relative with psychosis. In eight of nine families in which Huntington's disease probands with psychosis had a first-degree relative with psychosis, the relative's psychosis co-occurred with Huntington's disease. In the Huntington's disease probands with psychosis, the onset of psychosis correlated with the onset of the neurological symptoms of Huntington's disease, and the age at onset of psychosis was lower in probands with a higher number of CAG repeats.

    CONCLUSIONS: Patients with Huntington's disease and psychotic symptoms may have a familial predisposition to develop psychosis. This finding suggests that other genetic factors may influence susceptibility to a particular phenotype precipitated by CAG expansion in the Huntington's disease gene.

  • 46.
    Wahlin, T B
    et al.
    Stiftelsen Stockholms läns Äldrecentrum.
    Lundin, A
    Bäckman, L
    Almqvist, E
    Haegermark, A
    Winblad, B
    Anvret, M
    Reactions to predictive testing in Huntington disease: case reports of coping with a new genetic status.1997In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 73, no 3, p. 356-65Article in journal (Refereed)
    Abstract [en]

    A predictive testing program for Huntington disease has been available in Stockholm, Sweden since October 1990. Psychosocial assessments were performed throughout the testing program to evaluate the impact of the risk situation itself and the effect of predictive testing, and to identify those individuals who were most vulnerable to severe stress and anxiety reactions. All subjects underwent neurological, neuropsychological, and psychiatric examinations. Individuals undergoing predictive testing were assessed twice by a genetic counsellor before receiving their results, and at 10 days (gene carriers only) and then 2, 6, 12, and 24 months after receiving the results. The process of coping with the test results and the psychological adjustment to knowledge about new genetic status have been shown to vary considerably. In this report, we describe the results obtained from two gene carriers and two noncarriers. The four persons chosen represent different ways of coping with the outcome of the test and of integrating knowledge about their genetic status into everyday life. These cases illustrate common themes and recurrent problems often surfacing during the counselling and testing process. The longitudinal evaluations provide information about the impact, adaptation, and long-term effects of living with a new genetic status.

  • 47. Winnberg Almqvist, Elisabeth
    et al.
    Huntington Study Group PHAROS Investigators, The
    At risk for Huntington disease: The PHAROS (Prospective Huntington At Risk Observational Study) cohort enrolled.2006In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 63, no 7, p. 991-6Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To identify the emerging clinical precursors that indicate the early onset of Huntington disease (HD) in a reliable and gene-specific manner. This information is critical for the development of therapeutic trials aimed at postponing clinical onset in HD gene carriers. METHODS: Between July 1999 and January 2004, 1001 adults at 50-50 risk for HD agreed to provide longitudinal clinical data and a blood DNA sample under consent provisions that require their individual clinical and genetic information to never be revealed. RESULTS: The Prospective Huntington At Risk Observational Study (PHAROS) cohort is characterized by a 2:1 predominance of women to men, high educational attainment, and gainful employment. Despite the gender disparity, the demographic, hereditary, and clinical characteristics of the female and male participants were similar. Investigators, who are unaware of individual gene status, characterized the baseline cohort to be highly functional with minimal motor or cognitive impairment; 92.3% of participants were judged to have no or nonspecific motor abnormalities; 6.7%, to have possible or probable motor signs; and only 1.0%, to have unequivocal HD. CONCLUSION: The baseline characteristics of the PHAROS cohort make it well suited to generate objective and prospective data about gene-specific clinical precursors that can be used as outcomes in controlled trials aimed at postponing the onset of HD.

  • 48.
    Winnberg, Elisabeth
    et al.
    Ersta Sköndal Bräcke University College, Department of Health Care Sciences.
    Winnberg, Ulrika
    Ersta Sköndal Bräcke University College, Department of Health Care Sciences.
    Pohlkamp, Lilian
    Ersta Sköndal Bräcke University College, Department of Health Care Sciences.
    Hagberg, Anette
    Uppsala universitet.
    What to Do with a Second Chance in Life? Long-Term Experiences of Non-carriers of Huntington's Disease.2018In: Journal of Genetic Counseling, ISSN 1059-7700, E-ISSN 1573-3599, Vol. 27, no 6, p. 1438-1446Article in journal (Refereed)
    Abstract [en]

    Little is known about how people's lives are influenced when going from a 50% risk status of Huntington's disease (HD) to no risk after performing predictive testing. In this study, 20 interviews were conducted to explore the long-term (> 5 years) experiences after receiving predictive test results as a non-carrier of HD. The results showed a broad variety of both positive and negative reactions. The most prominent positive reaction reported was feelings of relief and gratitude, of not carrying the HD mutation for themselves and for their children. Also, the non-carrier status promoted in some individuals' significant life changes such as a wishing to have (more) children, pursuing a career or breaking up from an unhappy relationship. However, negative reactions on their psychological well-being were also described. Some had experienced psychological pressure of needing to do something extraordinary in their lives; others expressed feelings of guilt towards affected or untested siblings, resulting in sadness or clinical depression. The new genetic risk status could generate a need of re-orientation, a process that for some persons took several years to accomplish. The results of the present study show the importance of offering long-term post-result counselling for non-carriers in order to deal with the psychological consequences that may follow predictive testing.

  • 49.
    Xiang, F
    et al.
    Karolinska institutet.
    Almqvist, E W
    Huq, M
    Lundin, A
    Hayden, M R
    Edström, L
    Anvret, M
    Zhang, Z
    A Huntington disease-like neurodegenerative disorder maps to chromosome 20p.1998In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 63, no 5, p. 1431-8Article in journal (Refereed)
    Abstract [en]

    Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor disturbance, cognitive loss, and psychiatric manifestations. The disease is associated with a CAG trinucleotide-repeat expansion in the Huntington gene (IT15) on chromosome 4p16.3. One family with a history of HD was referred to us initially for predictive testing using linkage analysis. However, the chromosome 4p region was completely excluded by polymorphic markers, and later no CAG-repeat expansion in the HD gene was detected. To map the disease trait segregating in this family, whole-genome screening with highly polymorphic dinucleotide-, trinucleotide-, and tetranucleotide-repeat DNA markers was performed. A positive LOD score of 3.01 was obtained for the marker D20S482 on chromosome 20p, by two-point LOD-score analysis with the MLINK program. Haplotype analysis indicated that the gene responsible for the disease is likely located in a 2.7-cM region between the markers D20S193 and D20S895. Candidate genes from the mapping region were screened for mutations.

  • 50. Almqvist, E W (Contributor)
    A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease.2001In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 57, no 3, p. 397-404Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To determine whether chronic treatment with coenzyme Q10 or remacemide hydrochloride slows the functional decline of early Huntington's disease (HD).

    METHODS: The authors conducted a multicenter, parallel group, double-blind, 2 x 2 factorial, randomized clinical trial. Research participants with early HD (n = 347) were randomized to receive coenzyme Q10 300 mg twice daily, remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were evaluated every 4 to 5 months for a total of 30 months on assigned treatment. The prespecified primary measure of efficacy was the change in total functional capacity (TFC) between baseline and 30 months. Safety measures included the frequency of clinical adverse events.

    RESULTS: Neither intervention significantly altered the decline in TFC. Patients treated with coenzyme Q10 showed a trend toward slowing in TFC decline (13%) over 30 months (2.40- versus 2.74-point decline, p = 0.15), as well as beneficial trends in some secondary measures. There was increased frequency of nausea, vomiting, and dizziness with remacemide and increased frequency of stomach upset with coenzyme Q10.

    CONCLUSIONS: Neither remacemide nor coenzyme Q10, at the dosages studied, produced significant slowing in functional decline in early HD.

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