Showing papers on "Anticipation (genetics) published in 2006"

Anticipation in familial pancreatic cancer

Abstract: Background: Previous studies of anticipation in familial pancreatic cancer have been small and subject to ascertainment bias. Our aim was to determine evidence for anticipation in a large number of European families. Patients and methods: A total of 1223 individuals at risk from 106 families (264 affected individuals) were investigated. Generation G3 was defined as the latest generation that included any individual aged over 39 years; preceding generations were then defined as G2 and G1. Results: With 80 affected child-parent pairs, the children died a median (interquartile range) of 10 (7, 14) years earlier. The median (interquartile range) age of death from pancreatic cancer was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively. These indications of anticipation could be the result of bias. Truncation of Kaplan-Meier analysis to a 60 year period to correct for follow up time bias and a matched test statistic indicated significant anticipation (p = 0.002 and p Conclusion: This study provides the first strong evidence for anticipation in familial pancreatic cancer and must be considered in genetic counselling and the commencement of secondary screening for pancreatic cancer.

Interruptions in the expanded ATTCT repeat of spinocerebellar ataxia type 10: repeat purity as a disease modifier?

Abstract: Spinocerebellar ataxia type 10 (SCA10) is one of numerous genetic disorders that result from simple repeat expansions. SCA10 is caused by expansion of an intronic ATTCT pentanucleotide repeat tract. It is clinically characterized by progressive ataxia, seizures, and anticipation, which can vary within and between families. We report two SCA10 families showing distinct frequencies of seizures and correlations of repeat length with age at onset. One family displayed uninterrupted ATTCT expansions, whereas the other showed multiple interruptions of the repeat by nonconsensus repeat units, which differed both in the length and/or sequence of the repeat unit. Disease-causing microsatellite expansions have been assumed to be composed of uninterrupted pure repeats. Our findings for SCA10 challenge this convention and suggest that the purity of the expanded repeat element may be a disease modifier.

Chemical modifiers of unstable expanded simple sequence repeats: what goes up, could come down.

Abstract: A mounting number of inherited human disorders, including Huntington disease, myotonic dystrophy, fragile X syndrome, Friedreich ataxia and several spinocerebellar ataxias, have been associated with the expansion of unstable simple sequence DNA repeats. Despite a similar genetic basis, pathogenesis in these disorders is mediated by a variety of both loss and gain of function pathways. Thus, therapies targeted at downstream pathology are likely to be disease specific. Characteristically, disease-associated expanded alleles in these disorders are highly unstable in the germline and somatic cells, with a tendency towards further expansion. Whereas germline expansion accounts for the phenomenon of anticipation, tissue-specific, age-dependent somatic expansion may contribute towards the tissue-specificity and progressive nature of the symptoms. Thus, somatic expansion presents as a novel therapeutic target in these disorders. Suppression of somatic expansion should be therapeutically beneficial, whilst reductions in repeat length could be curative. It is well established that both cis- and trans-acting genetic modifiers play key roles in the control of repeat dynamics. Importantly, recent data have revealed that expanded CAG·CTG repeats are also sensitive to a variety of trans-acting chemical modifiers. These data provide an exciting proof of principle that drug induced suppression of somatic expansion might indeed be feasible. Moreover, as our understanding of the mechanism of expansion is refined more rational approaches to chemical intervention in the expansion pathway can be envisioned. For instance, the demonstration that expansion of CAG·CTG repeats is dependent on the Msh2, Msh3 and Pms2 genes, highlights components of the DNA mismatch repair pathway as therapeutic targets. In addition to potential therapeutic applications, the response of expanded simple repeats to genotoxic assault suggests such sequences could also have utility as bio-monitors of environmentally induced genetic damage in the soma.

Juvenile Huntington disease.

Abstract: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder related to expansion of a triplet repeat sequence in the huntington gene on chromosome 4. Adult HD usually presents with chorea and personality changes. Juvenile HD is far less common and presents with parkinsonism, dystonia and seizures. We report a case of juvenile HD, showing extreme anticipation, in which diagnosis was delayed because of failure to recognise the significance of the family history and the characteristic clinical and radiologic features of this condition.

Huntington disease in a 9-year-old boy: clinical course and neuropathologic examination.

Abstract: Huntington disease is a dominantly inherited, neurodegenerative disorder, usually with onset in the fourth to fifth decade of life but in a small proportion of patients before the age of 20 years. The early-onset form, juvenile Huntington disease, is clinically different from that of more common adult-onset forms and includes cognitive decline, parkinsonism, myoclonus, and seizures. We report a case of a boy with juvenile Huntington disease with a very early age at disease onset (3 years). The suspected clinical diagnosis was confirmed by DNA analysis, which revealed (CAG)(n) expansion into the range characteristic of juvenile Huntington disease (95 repeats). The clinical course of the disease was typical for the juvenile form of Huntington disease, but the diagnosis was not so obvious because there was no history of any neurodegenerative disorder in the family. The child died at the age of 11 years. The detailed neuropathologic investigations performed postmortem showed the characteristic features of Huntington disease. As the patient's de novo mutation was very unlikely to occur, genetic counseling and the possibility of predictive testing were proposed to the family. Indirect molecular data indicate the familial character of the disease, with strong anticipation of transmission.

Triplet Repeat Diseases

Abstract: The repeat expansion disorders are a group of human diseases that are caused by the elongation of a DNA repeat sequence In this chapter, we provide an overview of the discovery of repeat expansion as an important cause of human disease, and we summarize the molecular genetics and mechanistic basis of 27 microsatellite repeat disorders Comparison of the many repeat expansion disorders reveals distinct categories of repeat diseases, allowing us to propose a classification of the repeat expansion disorders based upon mutation sequence and pathogenic mechanism The four types of repeat expansion disorders defined by this approach are the CAG/polyglutamine repeat diseases; the loss-of-function repeat diseases; the RNA gain-of-function repeat diseases; and the polyalanine diseases Although the genetic basis for most of these diseases was determined less than a decade or so ago, considerable advances have been made in our understanding of how “dynamic mutations” produce molecular pathology and human disease Keywords: Aggregate; Anticipation; Gain of function; Loss of function; Repeat Expansion; Trinucleotide

Anticipating disaster: the genetics of familial pancreatic cancer

Abstract: To be born into a family with familial pancreatic cancer, an inheritable, autosomal dominant disorder, has various implications for an individual's life—and none is fortunate. The prospects just turned even darker because of “anticipation”, the phenomenon that successive generations are affected by an inheritable disorder at a progressively earlier age. An up to date study shows that “anticipation” is also operative in familial pancreatic cancer, meaning that affected children die approximately 10 years earlier than their affected parents

Anticipation in lymphoproliferative disorders.

Abstract: Anticipation denotes younger age at debut of a disease and/or increased severity in successive generations within a family. Anticipation cannot be explained from Mendelian mechanisms and, most likely, anticipation depends on epigenetic DNAmolecular mechanisms, e.g. trinuleotide repeats and partial DNA-methylation, FAS-mutations, influence of micro-RNA, parental imprinting or maternal affection from microchimerism during pregnancy. Pleiotrophy and anticipation are sometimes associated, as in families with lymphoprolifertive diseases (LPD), where knowledge on the initial germ-line mutation of the monoclonal expansion of cells for CLL, myeloma, non-Hodgkin’sand Hodgkin’s lymphoma and other diagnoses within LPD is strongly needed for the true understanding of disease, for proper counselling of the family and for the design of technology behind the future curative DNAmanipulation. In LPD, this primary mutation is apparently different from the cytogenetic abnormalities used for diagnostic purposes and caused by subsequent somatic mutations during the development of disease. In this issue of Leukemia & Lymphoma, Alexandrescu et al. [1] report and confirm a significant decline in the age at debut of disease in parent – offspring combinations of LPD with anticipation and pleiotrophy. It is a challenge to interpret such observations because they undoubtedly reflect and expose the mode of non-Mendelian molecular action [2]. The paper by Alexandrescu et al. shows the importance of looking at family histories to extract data for such studies. LPD-pedigree studies are in principle only possible when all patients and all healthy members of the family are known and the pedigree has been completed with extra-matrimonial off-springs, stillborns and when the pedigrees are seen in relation to the frequency of spontaneous, early abortions. Even the best organized registration of LPD cannot disregard minor faults in registration (e.g. from very old patients where LPD is a side diagnose or an unexpected finding at autopsy) and confusion over time about the true diagnosis since terminology and diagnostic criteria of LPD have been changed nearly every decade during the past 50 years (e.g. Rappaport-, Kieler-, Workingand WHO Formulations). This means in principle that each case of LPD must be reviewed, including crosschecks of old records and specimens from blood, bone marrow and tissue in those cases where such specimens are stored and available. In the present paper by Alexandrescu et al. [1] no such histological and diagnostic review was possible and any notion on lowand high-grade lymphomas was thus avoided, which does not exclude analysis of age-at-debut. The registration of data on healthy family members to patients with LPD must be approved by official and ethical authority. The rational for counting normal, healthy persons from National Registries with data on name, place of birth, age and control cross-check with the Cancer Registry and/or the Registry of Medical Diagnoses is:

Anticipation in familial pancreatic cancer

Abstract: Background: Previous studies of anticipation in familial pancreatic cancer have been small and subject to ascertainment bias Our aim was to determine evidence for anticipation in a large number of European families Patients and methods: A total of 1223 individuals at risk from 106 families (264 affected individuals) were investigated Generation G3 was defined as the latest generation that included any individual aged over 39 years; preceding generations were then defined as G2 and G1 Results: With 80 affected child-parent pairs, the children died a median (interquartile range) of 10 (7, 14) years earlier The median (interquartile range) age of death from pancreatic cancer was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively These indications of anticipation could be the result of bias Truncation of Kaplan-Meier analysis to a 60 year period to correct for follow up time bias and a matched test statistic indicated significant anticipation (p = 0002 and p 0001) To minimise bias further, an iterative analysis to predict cancer numbers was developed No single risk category could be applied that accurately predicted cancer cases in every generation Using three risk categories (low with no pancreatic cancer in earlier generations, high with a single earlier generation, and very high where two preceding generations were affected), incidence was estimated without significant error Anticipation was independent of smoking Conclusion: This study provides the first strong evidence for anticipation in familial pancreatic cancer and must be considered in genetic counselling and the commencement of secondary screening for pancreatic cancer

Cysltr2 polymorphisms in aspirin intolerance in asthma

Abstract: CysLTR2(cysteinyl-leukotriene receptor 2) polymorphisms associated with aspirin intolerance in asthma are provided to diagnose and anticipate the aspirin intolerance, and develop drugs for controlling aspirin intolerance The CysLTR2 polymorphisms for diagnosis and anticipation of aspirin intolerance are provided, wherein the CysLTR2 polymorphisms include CysLTR2-819G>T, CysLTR2+2079C>T, CysLTR2+2534A>G and CysLTR2+2842A>G gene polymorphisms

[IT15 gene analysis in two pedigrees of Huntington's disease].

Abstract: To investigate the relationship between the clinical features and (CAG)n trinucleotide repeats in two pedigrees of Chinese Huntington's disease (HD). Clinical and neuroimaging features, the age of disease onset and pattern of transmission of the patients were studied in the two pedigrees of HD. Genomic DNA of 42 family members was used for amplification of the (CAG)n repeats of IT15 gene by PCR. The numbers of (CAG)n were determined by electrophoresis through a 6% polyacrylamide gel and direct sequence analysis. Results showed that patients in pedigree 1 were absent of the typical triad of HD symptoms or caudate atrophy. A total of 9 (5 patients and 4 asymptomatic) out of 18 family members had 40-50 (CAG)n repeats in the IT15 gene. In pedigree 2, all the patients were characterized by a triad of symptoms, including motor disturbance, cognitive impairment and psychiatric features. Three patients and two asymptomatic relatives had more than 50 (CAG)n repeats in the IT15 gene. In conclusion, the clinical symptoms are partly determined by (CAG)n repeats in the IT15 gene. The age of onset was correlated with (CAG)n repeats over 50, and the phenomenon called "anticipation" was found to have played a role.

Influence of parent age and gender on anticipation in familial B-cell malignancies

Abstract: Anticipation occurs when a disease manifests at an earlier age and/or with an increased clinical severity in the next generation. Its relationship with parental age and gender is relevant to the patterns of genetic transmission of familial B-cell neoplasms. One hundred and sixty pairs [44 non-Hodgkin’s lymphoma (NHL), 38 Hodgkin’s disease (HD), 48 HD/NHL, and 30 CLL] were analyzed retrospectively for presence of anticipation in paternal (PT), maternal (MT), and overall transmission. Overall mean anticipation measured −23.0 yr, and varied between −18.93 and −26.46 yr with no significant difference among different diseases, except between CLL and mixed HD/NHL (mean difference −7.68 yr, p=0.03). A significant Pearson correlation (PC) between the parental age at conception and anticipation was found for all malignancies (PC=−0.339, p<0.0001), with the exception of mixed HD/NHL pairs of MT. Higher PCs were observed with PT than MT for all diseases. Anticipation manifests in all familial B-cell malignancies analyzed and it correlates with the parental age at conception. Although less prominent than with neurological disease, this phenomenon indicates a possible germline inheritance of B-cell malignancies and a common genetic basis for HD and NHL.

Short communication Meiotic CAG repeat instability in spinocerebellar ataxia type 6: Maternally transmitted elongation in a presumed sporadic case

Abstract: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominantly inherited disorder characterized by cerebellar ataxia, dysarthria and nystagmus The molecular background for the disorder is a CAG repeat expansion in the CACNA1A gene located on chromosome 19 The size of SCA6 expanded alleles is usually stable, and variation in repeat size over successive generations is rare We report a Danish family with one case of SCA6 resembling a sporadic case of spinocerebellar ataxia Analysis of the CACNA1A gene showed meiotic CAG repeat instability in the transmission from a 70-year-old woman with no subjective symptoms to her symptomatic son The CAG repeat size expanded from 22 repeats in the mother to 23 repeats in the proband This case demonstrates maternal repeat instability and clinical anticipation in a family with SCA6 D 2005 Elsevier BV All rights reserved

Does anticipation exist in familial pancreatic cancer

Abstract: BACKGROUND Pancreatic cancer has been hypothesized to involve both genetic and environmental components. Literature has demonstrated that this cancer might run in certain families and that anticipation—successive generations of a family developing pancreatic cancer at an earlier age than previous generations—might exist. Studies of anticipation in familial pancreatic cancer (FPC) have, however, suffered limitations of poor study design and ascertainment bias.