Anticipation (genetics)

About: Anticipation (genetics) is a research topic. Over the lifetime, 669 publications have been published within this topic receiving 21784 citations. The topic is also known as: Genetic Anticipation & Anticipation, Genetic.

Anticipation in Swedish families with bipolar affective disorder.

Abstract: Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity or decrease in age at onset or both in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in different disorders. We have studied differences of age at onset and disease severity between two generations in 14 families with unilinear inheritance of bipolar affective disorder (BPAD). There was a significant difference in age at onset (p < 0.008), in episodes per year with (p < 0.006) and without (p < 0.03) lithium treatment, and in total episodes per year (p < 0.002) between generations I and II. Furthermore, there was a highly significant correlation (p < 0.001) in age at onset between generations I and II. No evidence for specific paternal or maternal inheritance was found. We found evidence of anticipation and could rule out ascertainment bias or some other artefact. Anticipation is thus an inheritance pattern in BPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in BPAD.

The Hereditary Ataxias

Abstract: Efforts to classify the hereditary ataxias by their clinical and neuropathological phenotypes are troubled by excessive heterogeneity. Linkage analysis opened the door to a new approach with the methods of molecular biology. The classic form of autosomal recessive ataxia, Friedreich's ataxia (FA), is now known to be due to an intronic expansion of a guanine-adenine-adenine (GAA)-trinucleotide repeat. The autosomal dominant ataxias such as olivopontocerebellar atrophy (OPCA), familial cortical cerebellar atrophy (FCCA), and Machado-Joseph disease (MJD) have been renamed the spinocerebellar ataxias (SCA). Specific gene loci are indicated as SCA-1, SCA-2, SCA-3, SCA-4, SCA-5, SCA-6, and SCA-7. In 5 of them (SCA-1, SCA-2, SCA-3, SCA-6, and SCA-7), expanded cytosine-adenine-guanine (CAG)-trinucleotide repeats and their abnormal gene products cause the ataxic condition. The most common underlying loci for olivopontocerebellar atrophy (OPCA) are SCA-1 and SCA-2, although other genotypes may be added in the future. A major recent advance was the identification of the gene for SCA-3 and MJD, and the high prevalence of this form of autosomal dominant ataxia. In FA and the SCA with expanded CAG-trinucleotide repeats, clinical and neuropathological severity are inversely correlated with the lengths of the repeats. Anticipation in the dominant ataxias can now be explained by lengthening of the repeats in successive generations. Progress is being made in the understanding of the pathogenesis of FA and SCA as the absent or mutated gene products are studied by immunocytochemistry in human and transgenic murine brain tissue. In FA, frataxin is diminished or absent, and an excess of mitochondrial iron may cause the illness of the nervous system and the heart. In SCA-3, abnormal ataxin-3 is aggregated in neuronal nuclei, and in SCA-6, a mutated alpha1A-calcium channel protein is the likely cause of abnormal calcium channel function in Purkinje cells and in the death of these neurons.

Dentatorubral and pallidoluysian atrophy (DRPLA) Clinical and neuropathological findings in genetically confirmed north american and european pedigrees

Abstract: Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder that clinically overlaps with Huntington's disease (HD) and manifests combinations of chorea, myoclonus, seizures, ataxia, and dementia. DRPLA is caused by a CAG triplet repeat (CTG-B37) expansion coding for polyglutamine on chromosome 12 and exhibits the genetic phenomenon of anticipation. This neurodegenerative disease has only rarely been reported in non-Japanese pedigrees, and there are only a few neuropathological studies in genetically confirmed patients. We report 10 cases of DRPLA from two North American and two British pedigrees in which CTG-B37 expansions have been demonstrated within each kindred (54-83 repeats), individually in 8 of the 10 cases, and describe the neuropathological findings in 4 cases. Members of DRPLA kindreds have a wide range of clinical phenotypes and markedly variable ages at onset. The neuropathological spectrum is centered around the cerebellifugal and pallidofugal systems, but neurodegenerative changes can be found in many nuclei, tracts, and systems. Evidence of CTG-B37 triplet repeat expansion should be sought in HD-like cases that are negative for expanded triplet repeats within the HD IT15 gene or in autopsy cases with degeneration of the dentatorubral or pallidoluysian systems.

Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias

Abstract: Autosomal dominant cerebellar ataxia type 1 (ADCA1) is a clinical and genetic heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia. One defective gene responsible for the disease was first localised to 6p (SCA1, spinocerebellar ataxia type 1) and the mutation has been more recently characterised. We have analysed the CAG-repeat mutation responsible for the SCA1 phenotype in a large Spanish kindred with 41 affected members, in which positive linkage with D6S89 was previously shown. All (10) clinically affected members analysed were heterozygous with one disease allele being between 41 to 57 CAG repeats, and the other in the normal range, from 6 to 39 repeats. Nine clinically unaffected individuals who were between the ages of 18 and 40, were found to have expansions of the CAG repeat (41 to 59), and 22 other 'at risk' individuals were found to have inherited the SCA1 gene with copies of the CAG repeat in the normal range. We have also observed that affected fathers passed on the mutated SCA1 gene with larger increases in the number of CAG repeats than affected mothers did. In one case a decrease in the number of CAG repeats (51 to 50) was detected in the transmission from the affected mother, and in two cases no change was observed in the transmission of a 41 allele repeat by a mother. As in the other disorders in which knowledge of the mutation has been obtained, analysis of the repeat expansion dramatically changes diagnosis of SCA1.

Frequency and stability of the myotonic dystrophy type 1 premutation

Abstract: Background: Myotonic dystrophy type 1 (DM1) is associated with the expansion of an unstable CTG repeat. Larger alleles are associated with a more severe form of the disease and almost always increase in length from one generation to the next, accounting for the clinical anticipation characteristic of DM1. As such, expanded alleles are rapidly lost from the population. However, the incidence of the disease appears to remain constant. It was the authors’ our aim to determine the frequency and germline stability of the DM1 premutation alleles that give rise to new DM1 families. Methods: The authors measured the size of the DM1 CTG repeat in blood DNA derived from a large number of individuals in DM1 families, including distant and unaffected relatives. Results: It was determined that DM1 premutation alleles can be identified both in distant relatives of DM1 probands and more rarely in unaffected spouses. These premutation alleles are not directly associated with a clinical phenotype in the carrier but are highly unstable and liable to expand in succeeding generations, particularly when transmitted by a man. In addition, the authors observed occasional expansion-biased instability of alleles within the high end of the normal size range. Conclusions: Individuals carrying premutation alleles are at high risk of having affected offspring within a limited number of generations. Such data indicate that premutation alleles cannot be the long-term source of new DM1 families, which must ultimately arise from mutations of alleles within the upper normal size range.