scispace - formally typeset
Search or ask a question

Showing papers on "Anticipation (genetics) published in 1998"


Journal ArticleDOI
TL;DR: The mutation was highly unstable during transmission, with a mean increase of 10 +/- 16 CAG repeats, which was significantly greater in paternal than in maternal transmissions, and correlated well with the marked anticipation observed in the families.
Abstract: Spinocerebellar ataxia 7 (SCA7) is caused by the expansion of an unstable CAG repeat in the first exon of the SCA7 gene. We have analyzed the SCA7 mutation in 19 families and one isolated case of various geographical origins, presenting with autosomal dominant cerebellar ataxia with progressive macular dystrophy. The SCA7 CAG repeat was expanded in 77 patients and in 11 at-risk individuals, with alleles containing from 37 to 130 repeats, demonstrating that SCA7 is genetically homogeneous. Repeats on normal alleles contained from 7 to 35 CAGs. There was a strong negative correlation (r = -0.84) between the age at onset and the size of the CAG repeat expansion in SCA7 patients. Larger expansions were associated with earlier onset, a more severe and rapid clinical course, and a higher frequency of decreased vision, ophthalmoplegia, extensor plantar response and scoliosis. The frequency of other clinical signs such as dysphagia and sphincter disturbances increased with disease duration. The mutation was highly unstable during transmission, with a mean increase of 10 +/- 16 CAG repeats, which was significantly greater in paternal (15 +/- 20) than in maternal (5 +/- 5) transmissions. This correlated well with the marked anticipation (19 +/- 13 years) observed in the families. Gonadal mosaicism, observed in the sperm of a patient, was particularly important, with expanded alleles ranging from 42 to >155 CAG repeats. The degree of instability during transmission, resulting mostly in expansions, is greater than in the seven other neurodegenerative disorders caused by polyglutamine expansions.

263 citations


Journal ArticleDOI
TL;DR: Genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations.
Abstract: Although mosaicism can have important implications for genetic counseling of families with hereditary disorders, information regarding the incidence of mosaicism is available for only a few genetic diseases. Here we describe an evaluation of 156 families with retinoblastoma; the initial oncogenic mutation in the retinoblastoma gene had been identified in these families. In 15 ( approximately 10%) families, we were able to document mosaicism for the initial mutation in the retinoblastoma gene, either in the proband or in one of the proband's parents. The true incidence of mosaicism in this group of 156 families is probably higher than our findings indicate; in some additional families beyond the 15 we identified, mosaicism was likely but could not be proven, because somatic or germ-line DNA from key family members was unavailable. Germ-line DNA from two mosaic fathers was analyzed: in one of these, the mutation was detected in both sperm and leukocyte DNA; in the other, the mutation was detected only in sperm DNA. Our data suggest that mosaicism is more common than is generally appreciated, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations. The possibility of mosaicism should always be considered during the genetic counseling of newly identified families with retinoblastoma. As demonstrated here, genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA.

168 citations


Journal ArticleDOI
TL;DR: These results provide the first evidence of de novo SCA7 expansions from IAs that are not associated with the phenotype but can expand to the pathological range during some paternal transmissions, and constitute a reservoir for future de noovo mutations that occur in a recurrent but random manner.
Abstract: Spinocerebellar ataxia 7 (SCA7) is the eighth neurodegenerative disorder caused by a translated CAG repeat expansion. Normal SCA7 alleles carry from four to 35 CAG repeats, whereas pathological alleles carry from 37 to approximately 200. Intermediate alleles (IAs), with 28-35 repeats in the SCA7 gene are exceedingly rare in the general population and are not associated with the SCA7 phenotype, although they have been found among relatives of four SCA7 families. In two of these families, IAs bearing 35 and 28 CAG repeats gave rise, during paternal transmission, to SCA7 expansions of 57 and 47 repeats, respectively, that were confirmed by haplotype reconstructions in one case and by inference in the other. Furthermore, the four haplotypes segregating with IAs were identical to the expanded alleles in each kindred, but differed among the families, indicating multiple origins of the SCA7 mutation in these families with different geographical origins. Our results provide the first evidence of de novo SCA7 expansions from IAs that are not associated with the phenotype but can expand to the pathological range during some paternal transmissions. IAs that segregate in unaffected branches of the pedigrees might, therefore, constitute a reservoir for future de novo mutations that occur in a recurrent but random manner. This would explain the persistence of the disease in spite of the great anticipation (approximately 20 years/generation) characteristic of SCA7. So far, de novo expansions among the disorders caused by polyglutamine repeats have only been demonstrated in Huntington's disease.

105 citations


Journal ArticleDOI
TL;DR: A novel procedure for quick isolation of expanded trinucleotide repeats and the corresponding flanking nucleotide sequence directly from small amounts of genomic DNA is described, used to clone the pathogenic SCA7 CAG expansion from an archived DNA sample of an individual affected with ataxia and retinal degeneration.
Abstract: Trinucleotide repeat expansions have been shown to cause a number of neurodegenerative diseases. A hallmark of most of these diseases is the presence of anticipation, a decrease in the age at onset in consecutive generations due to the tendency of the unstable trinucleotide repeat to lengthen when passed from one generation to the next. The involvement of trinucleotide repeat expansions in a number of other diseases--including familial spastic paraplegia, schizophrenia, bipolar affective disorder and spinocerebellar ataxia type 7 (SCA7; ref. 10)--is suggested both by the presence of anticipation and by repeat expansion detection (RED) analysis of genomic DNA samples. The involvement of trinucleotide expansions in these diseases, however, can be conclusively confirmed only by the isolation of the expansions present in these populations and detailed analysis to assess each expansion as a possible pathogenic mutation. We describe a novel procedure for quick isolation of expanded trinucleotide repeats and the corresponding flanking nucleotide sequence directly from small amounts of genomic DNA by a process of Repeat Analysis, Pooled Isolation and Detection of individual clones containing expanded trinucleotide repeats (RAPID cloning). We have used this technique to clone the pathogenic SCA7 CAG expansion from an archived DNA sample of an individual affected with ataxia and retinal degeneration.

104 citations


Journal ArticleDOI
TL;DR: The editors have set out to create a comprehensive, up-to-date review of what is an increasingly broad field of triplet-repeat diseases, and succeed admirably in their task.
Abstract: Only 7 years have passed since the discovery of trinucleotide-repeat expansions, yet, somehow, it seems that we have waited a long time for a comprehensive text on the subject. This delay is understandable. The triplet-repeat field moves so rapidly that reviews written just a few years ago are laughably out of date. Given that it takes ∼2 years to get a book to publication, a text devoted to trinucleotide repeats runs the risk of being behind the times, even before its time. Now, at last, we have the first major text devoted to repeat-expansion diseases, Genetic Instabilities and Hereditary Neurological Diseases. The editors have set out to create a comprehensive, up-to-date review of what is an increasingly broad field. They succeed admirably in their task. R. D. Wells and S. T. Warren have enlisted recognized experts in the field, to contribute discussions about the various diseases and their underlying mechanisms, with the end result being chapters that are usually highly informative and that nearly always present the latest findings. This text, like most, is not meant to be read from cover to cover; the amount of detail is exhaustive, and nearly every one of its >800 pages is packed with facts. Instead, Genetic Instabilities is an extremely useful reference book that geneticists, researchers, and clinicians will want on their shelves.Although the book touches briefly on other genetic instabilities, it focuses on trinucleotide repeats. The first half of the book is dedicated to the individual triplet-repeat diseases, beginning with an excellent overview chapter by G. R. Wilmot and S. T. Warren. The diseases are presented in their order of discovery, more or less, beginning with the two diseases discovered virtually simultaneously in 1991, fragile X and spinal and bulbar muscular atrophy (SBMA), and ending with Friedreich ataxia. For many of the diseases, separate chapters describe the clinical features, molecular mechanisms, and animal models. Chapters on the molecular basis of fragile X, SBMA, and spinocerebellar ataxia type 1 (SCA1); P. Harper's review of the clinical and genetic features of myotonic dystrophy, which includes a nice description of the history of anticipation; and all three chapters on Huntington disease are outstanding. This section is followed by a brief discussion about neuropsychiatric disorders that may show anticipation and, thus, may be candidate triplet-repeat diseases, followed by several chapters that describe commonly used techniques of identification of expanded triplet–repeat disease genes and proteins. Some of these technique chapters read like lab protocols, but researchers just entering the field may find them useful. The next 13 chapters—very nearly the last half of the book—represent a remarkably detailed discussion of the molecular basis of genetic instabilities. Included here are numerous chapters on the biophysical properties of DNA-repeat sequences, the basic mechanics of DNA replication and repair, and model systems for the analysis of repeat instability. For many clinicians and some geneticists, these chapters will be difficult reading. Several chapters, however, are quite enjoyable and at the same time are detailed (e.g., the chapters on genetic instabilities in yeast and on duplex triplet-repeat structures). The book's final section contains two superb reviews of the general mechanism of polyglutamine toxicity and single chapters on the dodecanucleotide repeat disease, progressive myoclonic epilepsy, and microsatellite instabilities in cancer. The book concludes with a (too brief) chapter that highlights the things we don't know about triplet repeats, the areas that still demand research.Genetic Instabilities is not without its faults. Many chapters repeat the same points about general mechanisms; a few strategically placed overview chapters would be better. For the second edition (and surely there will be one), the editors should strive to eliminate this redundancy. Some diseases also receive a disproportionate amount of attention, whereas others are neglected. For example, if an extremely rare dentatorubral pallidoluysian atrophy variant, Haw River syndrome, deserves its own chapter, then surely so does SCA6, a relatively common form of hereditary ataxia. Likewise, there is little discussion about the clinical and pathological features of Machado-Joseph disease, also known as SCA3, which may be the most common dominant ataxia worldwide. Harper's otherwise excellent description of myotonic dystrophy is missing its last nine references. Last, it would have made more sense to group the diseases by category. For example, chapters on the eight glutamine-repeat diseases and polyglutamine toxicity would make a logical subgrouping. These are minor flaws, however, that do not mar an otherwise excellent text. There is no doubt that Genetic Instabilities will be a much-sought-after reference text in many laboratories—it certainly already is in ours.

100 citations


Journal ArticleDOI
TL;DR: Although dynamic repeat expansions from paternal transmissions are greater than those from maternal transmissions, maternal transmission of disease is more common, suggesting germline or embryonic effects of the repeat expansion.
Abstract: The gene for spinocerebellar ataxia 7 (SCA7) includes a transcribed, translated CAG tract that is expanded in SCA7 patients We have determined expansions in 73 individuals from 17 SCA7 kindreds and compared them with repeat lengths of 180 unaffected individuals Subjects with abnormal expansions comprise 59 clinically affected individuals and 14 at-risk currently unaffected individuals predicted to carry the mutation by haplotype analysis For expanded alleles, CAG repeat length correlates with disease progression and severity and correlates inversely with age of onset Increased repeat lengths are seen in generational transmission of the disease allele, consistent with the pattern of clinical anticipation seen in these kindreds Repeat lengths in expanded alleles show somatic mosaicism in leukocyte DNA, suggesting that these alleles are unstable within individuals as well as between generations Although dynamic repeat expansions from paternal transmissions are greater than those from maternal transmissions, maternal transmission of disease is more common, suggesting germline or embryonic effects of the repeat expansion

100 citations


Journal ArticleDOI
TL;DR: In this paper, the presence of genetic anticipation in families with Behcet's syndrome (BS) was examined by interviewing a total of 18 families with 40 affected members in two successive generations and concluding that genetic anticipation was present in 15 of 18 of the families with BS in the form of earlier disease onset in the children compared with their parents.
Abstract: OBJECTIVE—To examine the presence of genetic anticipation in families with Behcet's syndrome (BS). METHODS—A total of 18 families with 40 affected members in two successive generations were evaluated by interviewing them for their ages at the onset of the first symptom of BS and for their ages at the time they fulfilled the diagnostic criteria. RESULTS—It was noted that the age of onset of the first symptom was lower in the second generation in 14 families (p=0.01) with a mean (SD) age of 20.57 (7.47) years in the children compared with 33.29 (9.92) years in the parents (t=7.79, p<0.0001), whereas the diagnostic criteria were fulfilled at an earlier age in the children in 15 families (p=0.01) with a mean age of 21.2 (6.74) years in the children compared with 36.4 (9.55) years in the parents (t=7.41, p<0.0001). CONCLUSION—Genetic anticipation was present in 15 of 18 (84%) of the families with BS in the form of earlier disease onset in the children compared with their parents. Keywords: Behcet's syndrome; familial; genetic anticipation

90 citations


Journal ArticleDOI
TL;DR: The symptomatic treatment of chorea is unsatisfactory and, at least in HD, neuropsychiatric disturbance may be much more important for the family, and potential disease-modifying treatments are now being explored in this condition.
Abstract: Chorea can have many causes, some hereditary and many sporadic in nature. The archetypal hereditary cause of chorea is Huntington's disease (HD). However, this condition often manifests as a mixed movement disorder, and some individuals with the Westphal variant may not display chorea at all. Moreover, since gene-specific testing has become available, we now know that in many cases of HD, particularly those with late onset, a positive family history may be lacking. In addition, dentatorubro-pallidoluysian atrophy (DRPLA), another dominantly inherited CAG repeat disease, can produce a similar clinical picture. In both conditions, the phenotype may vary according to repeat length, and anticipation and excess of paternal inheritance in younger-onset cases with longer repeat lengths are seen. Neuroacanthocytosis is probably genetically heterogenous, and many instances of "benign hereditary chorea" have been caused by other conditions. If it exists at all, this disorder is exceedingly rare. The principal causes of sporadic chorea include drugs, pregnancy, vascular disease, thyrotoxicosis, systemic lupus erythematosus (SLE) and the lupus anticoagulant syndrome, polycythaemia rubra vera, AIDS and both initial and recurrent Sydenham's chorea. The symptomatic treatment of chorea is unsatisfactory and, at least in HD, neuropsychiatric disturbance may be much more important for the family. Potential disease-modifying treatments such as anti-excitotoxins, antioxidants, free radical scavengers and neuronal grafting are now being explored in this condition.

88 citations


Journal ArticleDOI
TL;DR: 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.
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.

82 citations


Journal ArticleDOI
01 Feb 1998-Gut
TL;DR: Patients in the second affected generation acquire their disease at an earlier time in life in some but not all familial cases of Crohn’s disease.
Abstract: Background—OVspring with a family history of Crohn’s disease have an earlier age of onset than their parents. This might be due to genetic anticipation, characterised by earlier and/or more severe disease in subsequent generations. Aims—To investigate the possibility of genetic anticipation in aVected parentchild pairs with Crohn’s disease from France and Belgium. Patients and methods—In a cohort of 160 multiply aVected families with Crohn’s disease,57 parent-first aVected child pairs were detected. Clinical characteristics (age at diagnosis,disease extent,and type) of both parents and children were registered and compared. Results—Children were younger than their parents at diagnosis in 48/57 (84%) pairs. The median age at diagnosis was 16 years younger in children than in parents (p<0.0001). However, the diVerence was related to the age at diagnosis in the parents and was not present in 12 parentchild pairs with an early age at diagnosis for the parents. In most cases, disease extent and type were not considered more severe in children than in parents. Parental sex aVected neither age at diagnosis nor extent and type of disease in children. Conclusion—Patients in the second affected generation acquire their disease at an earlier time in life in some but not all familial cases of Crohn’s disease. Several explanations including genetic anticipation and environmental factors might explain this phenomenon. (Gut 1998;42:170‐174)

67 citations


Journal ArticleDOI
Kanji Yamamoto1, S.-I. Ikeda, N. Hanyu, S. Takeda, N. Yanagisawa 
TL;DR: Strong evidence is shown that anticipation in the transmission of Met30-TTR FAP is a true biological phenomenon and not all ascertainment biases could be eliminated.
Abstract: In type I familial amyloid polyneuropathy (FAP) caused by a variant Met30-transthyretin (TTR), genetic anticipation has been reported. To determine whether anticipation of the disease is a true biological phenomenon or the result of ascertainment bias, we compared age at onset of the affected child with that of the affected parent in 68 parent-child pairs (including data on assumed age at onset and on asymptomatic obligate heterozygotes and parents at obligate 50% risk) in 15 families. Excluding the parent-child pairs involving the proband and "bilineal pairs", onset occurred earlier in the child than in the transmitting parent in 60 out of 68 "unilineal pairs". After correction for ascertainment bias resulting from incomplete penetrance and reduced biological fitness in early onset patients, the number of anticipation pairs (60 pairs) was still significantly larger than that of non-anticipation pairs (29.7 pairs) (p < 0.05). When the children were sons, the difference in age at onset was significantly greater in the mother-son pairs than in the father-son pairs (p = 0.023). Although not all ascertainment biases could be eliminated, these data show strong evidence that anticipation in the transmission of Met30-TTR FAP is a true biological phenomenon.

Journal ArticleDOI
TL;DR: Molecular testing revealed that in these patients the SCA6/CACNL1A4 gene carries the smallest known expanded CAG repeat (21 repeat units), which describes a Japanese family which includes 13 patients in five generations who have dominantly inherited ataxia.

Journal ArticleDOI
TL;DR: A genetic cause for anticipation in familial cavernous angiomas is supported by the findings of a study of 52 families from the International Familial Cavernous Angioma Study.

Journal ArticleDOI
TL;DR: An association between a long CAG/CTG repeat and BPAD in the French population sample studied was not found, but a short repeat (<40 repeats) might still be implicated, and this possibility warrants further study.
Abstract: Anticipation has been described in bipolar affective disorder (BPAD). However, there are conflicting results from association studies screening for a link between BPAD and CAG/CTG repeat expansions, the molecular basis of anticipation in several hereditary neurodegenerative disorders. Here, the repeat expansion detection (RED) method was used to screen for CAG repeat expansion in 119 French BPAD patients. Western blotting was also used to search for polyglutamine stretches, encoded by CAG expansion, among proteins, extracted from lymphoblastoid cell lines, from six selected familial cases. Maximum CAG/CTG repeat length did not differ significantly (P = 0.38) between the 119 BPAD patients and the 88 controls included in the study. Several categories of subgroups were used, none of which showed significant association with a long repeat. Nor was a specific protein with an unusually long polyglutamine stretch (lower detection limit, ∼33 polyglutamines) detected in cell lysates from the familial cases studied. In conclusion, an association between a long CAG/CTG repeat and BPAD in the French population sample studied was not found. Nonetheless, a short repeat (<40 repeats) might still be implicated, and this possibility warrants further study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:338–341, 1998. © 1998 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: Anticipation in Crohn's disease may be influenced by gender and ethnicity of the transmitting parent as well as by the patient's age and gender identity.

Journal ArticleDOI
TL;DR: It is found that CAG/CTG repeat expansion is not likely to be a major etiological factor for psychosis in Chinese populations and no detectable association with age at onset and repeat length in either bipolar affective disorder or schizophrenia is found.

Journal ArticleDOI
TL;DR: Results suggest that trinucleotide repeats found in 12 families from the United Kingdom and Iceland are not involved in the etiology of schizophrenia, and the techniques used for detecting repeat expansions have limits to their sensitivity.
Abstract: Many diseases caused by trinucleotide expansion exhibit increased severity and decreased age of onset (genetic anticipation) in successive generations. Apparent evidence of genetic anticipation in schizophrenia has led to a search for trinucleotide repeat expansions. We have used several techniques, including Southern blot hybridization, repeat expansion detection (RED) and locus-specific PCR to search for expanded CAG/CTG repeats in 12 families from the United Kingdom and 11 from Iceland that are multiplex for schizophrenia and demonstrate anticipation. The unstable DNA theory could also explain discordance of phenotype for schizophrenia in pairs of monozygotic twins, where the affected twin has a greater number of repeats than the unaffected twin. We used these techniques to look for evidence of different CAG/CTG repeat size in 27 pairs of monozygotic twins who are either concordant or discordant for schizophrenia. We have found no evidence of an increase in CAG/CTG repeat size for affected members in the families, or for the affected twins in the MZ twin sample. Southern hybridization and RED analysis were also performed for the twin and family samples to look for evidence of expansion of GAA/TTC repeats. However, no evidence of expansion was found in either sample. Whilst these results suggest that these repeats are not involved in the etiology of schizophrenia, the techniques used for detecting repeat expansions have limits to their sensitivity. The involvement of other trinucleotide repeats or other expandable repeat sequences cannot be ruled out.

Journal ArticleDOI
TL;DR: Anticipation is supported in this specific set of families and, if it is confirmed by other studies, a role for trinucleotide repeat sequences may be considered to account for the familial aggregation of panic disorder.
Abstract: OBJECTIVE: Anticipation (i.e., the decrease in age at onset or the increase in severity of a disorder in successive generations) has recently been reappraised as a key to understanding the genetics of some familial illnesses. The purpose of this study was to search for possible anticipation in panic disorder. METHOD: Thirty-eight unilineal, multigenerational families with multiple directly interviewed members who had panic disorder were compared across two successive generations for 1) age at the first panic attack, 2) age at the onset of panic disorder, and 3) the highest degree of agoraphobia ever experienced, as a tentative index of severity of illness. Intergenerational pairwise comparisons were implemented according to four different sampling schemes: random pairs, random transmitting pairs, all possible pairs, and all possible transmitting pairs. RESULTS: Life table analyses showed a significant decrease in the time before the first episode of panic and onset of panic disorder from the older to the ...

Journal ArticleDOI
TL;DR: Although the majority of individuals harbored multiple CA, a single lesion does not exclude the inherited form of this vascular malformation, and an interesting observation is presented which could facilitate the search for the candidate genes.
Abstract: Familial aggregation of cavernous angiomas (CA) of the central nervous system (CNS) has been well described in the literature. In 1928, Hugo Friedrich Kufs (1) first assumed a common pathological basis in two members of the same family. He reported on an 81-year-old male patient whose autopsy showed multiple cerebral and hepatic CA. At the age of 17, his daughter presented with an “apoplexia pontis”, consisting of a right-sided hemiparesis and hemihypesthesia. Although no pathological confirmation was available in the daughter, Kufs has to be given the credit for the first description of this entity. Subsequently, only 2 additional families with this syndrome were described until the era of computer tomography and magnetic resonance imaging. Since then, however, the number of reported families has enormously increased. A literature review (see Table 1) yielded a total of 109 families with at least two members harboring either pathologically or radiologically confirmed CA. In these families, with up to four affected generations, a total of 431 affected individuals have been reported. Among the 379 individuals in whom data were available, 91 (24%) were asymptomatic at the time of presentation. In symptomatic individuals, the most common symptoms encountered were epileptic seizures (in 162 individuals or 43%0), followed by gross hemorrhages (108 or 28%), chronic headache (88 or 23%0), or focal neurological deficits (56 or 15%). Although the majority of individuals (69%) harbored multiple CA, a single lesion does not exclude the inherited form of this vascular malformation. In 30 families at least one member harbored only one CA. In 6 additional families, the reported individuals had exclusively single lesions. Coexistence of CA of the CNS and other organs (e.g. skin or retina) has been described in several families. The question is still open whether each type among the various location patterns represents an own entity or whether there is only one entity with ubiquitous CA. Analysis of large kindreds with familial CA of the CNS showed an autosomal dominant inheritance with a high penetrance. At present, the identification of the candidate genes responsible for the inherited form of CA is the focus of considerable research. In 1995, Dubovsky et al. (2) mapped a gene for familial CA in a 33 cM (33 million base pairs) interval on the long arm of chromosome 7q (7q11-22) bracketed by markers D7S502 and D7S821 or D7S479. Subsequently, this finding was confirmed by several groups studying familial CA (e.g. the Yale study group and the study group at the Duke University). However, the candidate gene on chromosome 7q has yet been identified. Moreover, Giinel et al. (3) excluded linkage to chromosome 7q in 2 families indicating genetic heterogeneity. Recently, a French national multi-center study found linkage to chromosome 7q only in 50% of the studied 35 families (4). In this issue of Acta Neurologica Scandinavica the “Znternational Familial Cavernous Angioma Study” (IFCAS) group presents an interesting observation which could facilitate the search for the candidate genes. The authors report on anticipation in 55 families with inherited CA. Anticipation describes the progressively earlier age of onset andlor increase in severity of an inherited disease in successive generations. This phenomenon has already been described by the French Benedict Auguste Morel in the last century (‘‘Trait6 des DCgCnCrescences”, 1857) but the term “anticipation” was coined b y the English Mott (5)

Journal ArticleDOI
TL;DR: Results suggest genetic anticipation occurs in nodal osteoarthritis and if confirmed a search for trinucleotide repeats is warranted.
Abstract: OBJECTIVE—Evidence was sought for genetic anticipation (disease occurring at an earlier age in subsequent generations, with increasing severity) in nodal osteoarthritis (NOA). METHODS—Age at symptom onset and disease severity was compared within 30 parent/offspring pairs with NOA. Correlation between the offspring age of disease onset and the parental age at conception was also assessed. RESULTS—The age at onset of nodal symptoms was earlier in the offspring (43 years (95% confidence intervals (CI) 38 to 47) v 61 (CI 58 to 65); mean difference 18 years (CI 13 to 22): p< 0.001) as was large joint symptom onset (48 years (CI 41 to 55) v 67 (CI 61 to 73); mean difference 20 years (CI 13 to 27): p< 0.01). A negative correlation existed between age of offspring symptom onset and parental age at conception. Fifteen (50%) offspring had similar or more extensive disease than their parents. CONCLUSIONS—These results suggest genetic anticipation occurs in NOA and if confirmed a search for trinucleotide repeats is warranted. Keywords: nodal osteoarthritis; genetic anticipation; trinucleotide repeats

Journal ArticleDOI
TL;DR: Assessment of understanding and experience of the clinical and genetic aspects of myotonic dystrophy and attitudes to prenatal diagnosis for affected women found that the lack of information concerning clinical severity made PND for MD difficult to consider.
Abstract: Twenty-five affected women of reproductive age known to the North West Regional Genetics Family Register (NWRGFR) were interviewed. A semistructured questionnaire, completed by the interviewer, was used to assess understanding and experience of the clinical and genetic aspects of myotonic dystrophy (MD) and attitudes to prenatal diagnosis (PND). Characteristic features of MD (muscle weakness and wasting and myotonia) were well known. Knowledge of other features and complications reflected experience. All subjects were aware that MD is inherited, but only 56% (14/25) knew the risk to their own children and subjects tended to overestimate this risk. Anticipation and maternal transmission of congenital myotonic dystrophy (CMD) were often misunderstood. Almost half of the subjects (12/25) perceived themselves to be moderately or severely affected and 40% (10/25) felt that their symptoms restricted daily life. Feelings of devastation, depression, worry about the future, and guilt at the risk of transmission to their children were described. Many subjects (10/25) said that the worst aspect of MD is the risk of transmission to their children. Over half (14/25) said that the risk of transmitting MD had influenced or would influence their own reproduction. Three-quarters of subjects who felt that MD had influenced their reproductive decisions (9/12) chose to limit their family or have no children; only 25% (3/12) requested PND. Subjects felt that the lack of information concerning clinical severity made PND for MD difficult to consider.

Book ChapterDOI
TL;DR: Dynamic mutations are caused by amplification of a trinucleotide or other simple sequence repeat, which leads to disease and/or expression of a fragile site, and show non-mendelian inheritance, as the amplified repeat expands or contracts when transmitted from one generation to the next.
Abstract: Dynamic mutations are caused by amplification of a trinucleotide or other simple sequence repeat, which leads to disease and/or expression of a fragile site (Richards and Sutherland 1992). In contrast to the mendelian inheritance observed in most hereditary disorders caused by point mutations, deletions, insertions, or duplications, dynamic mutations show non-mendelian inheritance, as the amplified repeat expands or, more rarely, contracts when transmitted from one generation to the next. In the normal population, these simple sequence repeats are small, but polymorphic, having a different length. Repeats in the normal size range are stably transmitted from one generation to the next. However, a minority of individuals have larger repeats that are meiotically unstable and generally expand upon transmission from one generation to the next. If the dynamic mutation causes disease, this progressive amplification is reflected in increasing frequency and severity of the disease in successive generations. When the repeat is below a specific threshold size in an individual of the older generations of the family, the disease may not manifest itself at all. However, when the repeat exceeds a threshold size in the progeny, the disease symptoms become clear. This phenomenon of increased disease severity with successive generations, characteristic of dynamic mutations, is called anticipation.

Journal ArticleDOI
TL;DR: Evidence of anticipation among 44 Japanese two-generation pairs with schizophrenia found by reviewing nine years of admission records is explored, suggesting biological anticipation such as the involvement of trinucleotide repeats expansion in G2.
Abstract: The identification of anticipation in schizophrenia is a recent focus in the genetic epidemiology of schizophrenia, although it involves some controversial methodological issues. We explored the evidence of anticipation among 44 Japanese two-generation pairs with schizophrenia found by reviewing nine years of admission records (1986–1994) at the Department of Neuropsychiatry, Nagasaki University Hospital and Michino-o Hospital, Nagasaki. The 44 pairs consisted of 27 two-generation pairs of first-degree relatives group (FDRG) and 17 pairs of second-degree relatives group (SDRG). On pairwise comparison and a life table analysis, the age at onset (AO) was significantly earlier in the lower generation (G2) than in the upper generation (G1) in all of the pairs and in the two subgroups, FDRG and SDRG. Earlier AO was shown in G2 even after minimizing some statistical biases for the study of anticipation in schizophrenia. A significant earlier mean AO was found in G2 even when a cohort effect was controlled for. There was no marked difference in AO between paternal and maternal transmission. These results provide further evidence for epidemiological anticipation, suggesting biological anticipation such as the involvement of trinucleotide repeats expansion in G2. The limitations of the study are also discussed.

Journal ArticleDOI
TL;DR: The human brain is a “spatially aggregating organ” and the role of language and language impairment in the development of Alzheimer’s disease is “an important role”, according to Munksgaard.
Abstract: OBJECTIVES: Anticipation has been linked to unstable trinucleotide repeats in many neurological disorders. We examined the hypothesis of genetic anticipation in familial cavernous angioma (FCA) of the central nervous system. MATERIAL AND METHODS: The mean ASO of affected individuals was compared between successive generations in 55 families. Intergenerational pair-wise comparisons were employed to avoid several ascertainment biases. Regarding severity of disease both type of manifestation and number of cavernous angiomas were compared between generations. RESULTS: The mean ASO decreased significantly both from the first to the second generation (31.6 vs 17.8 years; P = 0.000) and from the second to the third generation (17.8 vs 6.7 years; P = 0.002). The pair-wise comparisons also showed significantly earlier ASO. No clear evidence for anticipation with regard to severity of disease was found. CONCLUSIONS: Molecular genetic studies will determine whether trinucleotide repeats are the underlying mechanism for our observation of anticipation in FCA.

Journal ArticleDOI
TL;DR: A significant inverse correlation between age of onset and the length of the CAG repeat expansion is found, and anticipation is described through four succeeding generations.

Journal ArticleDOI
TL;DR: The results do not support the association between long CAG repeats and schizophrenia, however, the possibility that expansions with fewer than 40 repeats are involved in schizophrenia cannot be excluded.
Abstract: A decrease in age of onset of schizophrenia through consecutive family generations (anticipation) has been found in several studies. Anticipation is known to result from expansion of CAG repeats in genes that determine several neurodegenerative disorders. In a previous study we analysed 26 unilineal two-generation French pedigrees and found clinical evidence of anticipation. A 10-year mean reduction in age of onset of schizophrenia was found in the second generation compared with the parental generation. The repeat expansion detection method was used to screen for CAG expansion in 21 of the 26 families with evidence of anticipation for the disease and in 59 sporadic schizophrenics and 59 controls. Comparison of the frequency distributions of CAG/CTG repeat size observed in schizophrenics and controls showed no significant difference, even when we considered familial (P = 0.23) and sporadic (P = 0.25) affected individuals separately. These results do not support the association between long CAG repeats and schizophrenia. However, the possibility that expansions with fewer than 40 repeats are involved in schizophrenia cannot be excluded.

Journal ArticleDOI
TL;DR: A large DM family is identified in which multiple members had minimal CTG repeat expansions, and in which the number of CTG repeats remained in the minimally expanded range through at least three, and possibly four, generations.
Abstract: The genetic basis for myotonic dystrophy (DM) is a CTG trinucleotide repeat expansion. The number of CTG repeats commonly increases in affected individuals of successive generations, in association with anticipation. We identified a large DM family in which multiple members had minimal CTG repeat expansions, and in which the number of CTG repeats remained in the minimally expanded range through at least three, and possibly four, generations. This relative stability of minimal CTG repeat expansions may help to maintain the DM mutation in the population.

Journal ArticleDOI
TL;DR: The author wishes to thank two anonymous reviewers, for helpful discussions and insightful suggestions, and Drs.
Abstract: The author wishes to thank two anonymous reviewers, for helpful discussions and insightful suggestions, and Drs. Seymour Grufferman, Andrew Collins, and Jeff O'Connell, for critical comments. Support from National Cancer Institute research grant R01CA47473-08 is gratefully acknowledged.

Journal ArticleDOI
TL;DR: The finding of anticipation in this pedigree suggests that the mutation in LGMD1A may be the result of the expansion of an unstable trinucleotide repeat, and this implies that autosomal dominant limb-girdle muscular dystrophy is segregating.
Abstract: Anticipation, an increase in severity or decrease in age of onset (AO) inherent in the transmission of the disease gene from affected parent to affected child, has been increasingly described in human disease. To assess anticipation in a large kindred in which autosomal dominant limb-girdle muscular dystrophy (LGMD1A) is segregating, age of disease onset was collected from patient interviews of affected family members. A total of 25 parent-offspring pairs, in which the parents are three (3R), four (4R), or five (5R) generations removed from a common founding ancestor, were available for analysis. Life table analyses showed significant decreases in age at first reported symptoms in the offspring of the 3R (chi2=5.55, p=0.02) and 4R (chi2=7.81, p=0.005) parents. Pairwise analyses confirmed this decrease with a median decrease of 13 years in transmission to offspring from 3R parents and 18 years in transmission to offspring from 4R parents. The finding of anticipation in this pedigree suggests that the mutation in LGMD1A may be the result of the expansion of an unstable trinucleotide repeat.

Journal ArticleDOI
TL;DR: Two cases of familial HCL syndromes are described: a mother and son with HCL, and a HCL patient whose aunt developed Hodgkin's Disease, the first reported familial association of HCL with HD.
Abstract: Familial hairy cell leukemia (HCL) occurs rarely, and HCL occurring in association with other hematologic malignancies is even rarer We describe two cases of familial HCL syndromes: a mother and son with HCL, and a HCL patient whose aunt developed Hodgkin's Disease (HD) This is the first reported familial association of HCL with HD