Showing papers on "Anticipation (genetics) published in 1999"

Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice.

Abstract: Huntington disease (HD), an autosomal dominant, progressive neurodegenerative disorder, is caused by an expanded CAG repeat sequence leading to an increase in the number of glutamine residues in the encoded protein. The normal CAG repeat range is 5-36, whereas 38 or more repeats are found in the diseased state; the severity of disease is roughly proportional to the number of CAG repeats. HD shows anticipation, in which subsequent generations display earlier disease onsets due to intergenerational repeat expansion. For longer repeat lengths, somatic instability of the repeat size has been observed both in human cases at autopsy and in transgenic mouse models containing either a genomic fragment of human HD exon 1 (ref. 9) or an expanded repeat inserted into the endogenous mouse gene Hdh (ref. 10). With increasing repeat number, the protein changes conformation and becomes increasingly prone to aggregation, suggesting important functional correlations between repeat length and pathology. Because dinucleotide repeat instability is known to increase when the mismatch repair enzyme MSH2 is missing, we examined instability of the HD CAG repeat by crossing transgenic mice carrying exon 1 of human HD (ref. 16) with Msh2-/- mice. Our results show that Msh2 is required for somatic instability of the CAG repeat.

DNA secondary structure: A common and causative factor for expansion in human disease

Abstract: The discovery of unstable transmission has changed the face of genetics because it provides an alternative to the single-gene/single-trait pattern of Mendelian inheritance More than 10 hereditary diseases are caused by instability at simple trinucleotides Expansion causes disease when a particular base sequence is repeated beyond the normal range, interfering with the expression or properties of a gene product (1–2) As the length of the repeat grows, so also do the size of the successive expansions and the likelihood of another unstable event This accounts for clinical anticipation in which the severity increases and the age of onset decreases in successive generations In Huntington’s disease, for example, instability and pathogenesis are not observed at 28 repeats, occur frequently at 38 repeats, and are almost certain above 60 repeats Although different genes are affected and different features of pathogenesis are evident, there is a common pattern of unstable transmission among the trinucleotide repeat diseases, suggesting common elements to the mechanism

Mapping of a New Autosomal Dominant Spinocerebellar Ataxia to Chromosome 22

Abstract: The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. The clinical symptoms include cerebellar dysfunction and associated signs from dysfunction in other parts of the nervous system. So far, five spinocerebellar ataxia (SCA) genes have been identified: SCA1, SCA2, SCA3, SCA6, and SCA7. Loci for SCA4 and SCA5 have been mapped. However, approximately one-third of SCAs have remained unassigned. We have identified a Mexican American pedigree that segregates a new form of ataxia clinically characterized by gait and limb ataxia, dysarthria, and nystagmus. Two individuals have seizures. After excluding all known genetic loci for linkage, we performed a genomewide search and identified linkage to a 15-cM region on chromosome 22q13. A maximum LOD score of 4.3 (recombination fraction 0) was obtained for D22S928 and D22S1161. This distinct form of ataxia has been designated "SCA10." Anticipation was observed in the available parent-child pairs, suggesting that trinucleotide-repeat expansion may be the mutagenic mechanism.

Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees.

Abstract: Restless legs syndrome (RLS) can occur with an autosomal-dominant mode of inheritance. To determine if there are distinguishing features of RLS pedigrees which might clarify molecular mechanisms of pathogenesis, five pedigrees with 81 affected members were analyzed for age of onset, sex ratio, and transmission pattern. One-factor analysis of variance of ages of onset between generations was carried out, and segregation ratios were calculated for each generation. These kindreds showed an autosomal-dominant mode of inheritance and a male:female ratio of 1:1.4 (p = 0.15). One of the five analyzed pedigrees shows some evidence of reduced penetrance. In two of the five analyzed pedigrees, there is statistical support for anticipation (p<0.05). These variations in penetrance and anticipation suggest possible genetic heterogeneity.

Genetic mapping to 10q23.3-q24.2, in a large italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy

Abstract: We have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition.

Very Large (CAG)n DNA Repeat Expansions in the Sperm of Two Spinocerebellar Ataxia Type 7 Males

Abstract: Genetic anticipation, i.e. increasing disease severity and decreasing age of onset from one generation to the next, is observed in a number of diseases, including myotonic dystrophy type 1, Huntington's disease and several of the spinocerebellar ataxias. All of these disorders are associated with the expansion of a trinucleotide repeat and array length is positively correlated with disease severity and inversely correlated with the age of onset. The expanded repeat is highly unstable and continues to expand from one generation to the next, providing a molecular explanation for anticipation. Spinocerebellar ataxia type 7 (SCA7) is one of the latest additions to the list of triplet repeat diseases and is distinct from the other SCAs in that it is accompanied by retinal degeneration. Pedigree analyses have previously revealed that the SCA7 repeat is highly unstable and liable to expand, in particular when transmitted by a male. Surprisingly, though, an under-representation of male transmission has also been reported. We now demonstrate directly by single molecule analyses that the expanded repeat is extraordinarily unstable in the male germline and biased toward massive increases. Nearly all of the mutant sperm of two SCA7 males contain alleles that are so large that most of the affected offspring would at best have a severe infantile form of the disease. Indeed, the gross under-representation of such very large expanded alleles in patients suggests that a significant proportion of such alleles might be associated with embryonic lethality or dysfunctional sperm.

Myotonic dystrophy: the correlation of (CTG) repeat length in leucocytes with age at onset is significant only for patients with small expansions

Abstract: Myotonic dystrophy (DM) was the first of a group of diseases to be identified for which the genetic basis is the expansion of a triplet repeat. Myotonic dystrophy also exhibits anticipation, in which the disease worsens through successive generations. These two features have led many groups to analyse whether a significant negative correlation between triplet repeat length and severity of disease exists. However, the recent molecular finding that two distinct subsets of classically affected DM patients exist, those who export expansion derived DMPK RNA and those who do not, led us to question whether combining data from these two sets of patients is statistically valid. We found that although patients with small expansions showed a significant correlation between age at onset and triplet repeat length, those with larger expansions did not. The theoretical triplet repeat size, which separated the two groups, was also deduced.

Myotonic dystrophy and proximal myotonic myophathy.

Abstract: Myotonic dystrophy (DM) is a well-known multisystem disorder with dominant inheritance. Proximal myotonic myopathy (PROMM) has been defined only recently, it is rather similar to but distinct from DM. Molecular genetic testing of the CTG trinucleotide repeat expansion is a reliable diagnostic method in DM. In PROMM these CTG repeats are normal, and no genetic test is so far available. Comparing the phenotypes of DM and PROMM, an important point seems to be that PROMM is a more benign disorder. There are almost no obvious mental changes in PROMM patients; premature death is extremely rare; anticipation appears to be present but to a milder degree; a severe congenital type of PROMM apparently is very rare if it occurs at all. On the other hand, at least in the German population, the frequency of PROMM may be almost equal to that of DM.

Why children with inflammatory bowel disease are diagnosed at a younger age than their affected parent

Abstract: BACKGROUND Genetic anticipation has been proposed to explain observed age differences at diagnosis of Crohn’s disease in affected parents and offspring. AIMS To compare affected parent-child pairs with Crohn’s disease and ulcerative colitis with a control group of non-familial patients with inflammatory bowel disease (IBD) in order to quantify whether ascertainment bias could account for this effect. METHODS 137 affected parent-child pairs from 96 families and 214 patients with sporadic IBD were studied. Age at onset of symptoms and diagnosis were ascertained by interview and disease confirmed from clinical records. RESULTS Of the 137 affected parent-child pairs, 50 had Crohn’s disease only, 51 had ulcerative colitis only, and in 36, one had Crohn’s disease and the other ulcerative colitis. The median age of parents at diagnosis was 17.5 years older, 16 years older, and 18 years older in the Crohn’s disease, ulcerative colitis, and mixed disease families respectively (p CONCLUSIONS There was no evidence of genetic anticipation or genomic imprinting of age at diagnosis in this sample of IBD families. Ascertainment bias is responsible for the age differences at diagnosis between affected parents and children.

The myotonic dystrophies.

Abstract: Myotonic dystrophy, or dystrophia myotonica (DM), is the most common inherited muscle disorder in adults. DM is a multisystem disease in which the most disabling feature is muscle wasting that begins in the distal limb and cranial muscles. The genetic basis for DM is an expanded CTG repeat in the DMPK gene on chromosome 19. The size of the expanded repeat, and the severity of the disease, tend to increase in successive generations. The mechanism by which this unusual mutation leads to muscle wasting, myotonia, cataracts, heart block, and neurobehavioral abnormalities has not been clearly defined. Identification of the DM gene has made it easier to delineate other DM-like disorders that are clinically and genetically distinct. The most common of these is proximal myotonic myopathy (PROMM), which is characterized by early involvement of proximal limb muscles. The genetic locus for another DM-like disorder, called DM type 2, was recently mapped to chromosome 3.

Clustering of ALS patients in central Italy due to the occurrence of the L84F SOD1 gene mutation.

Abstract: Objective: To study three new apparently unrelated Italian families with ALS and several sporadic ALS patients living in the same rural area. Background: One Italian family with ALS carrying a superoxide dismutase 1 (SOD1) gene mutation (G41S) and no regional ALS clustering has been reported in Italy. Methods: Genetic analysis was performed by automated and manual sequencing of the SOD1 gene in 13 family members and in 6 of 10 unrelated patients with sporadic cases of ALS living in the same area. The authors also determined SOD1 activity in erythrocytes and lymphocytes. Results: The three families included a total of 28 affected members distributed over six generations. Despite a wide variability in age at onset and disease duration, the clinical pattern is uniform, with onset in the lower limbs, ascending progression, and predominant lower motor neuron involvement in all subjects. Generational anticipation is evident in the last two generations. All familial ALS patients and one of the six sporadic patients carry the same L84F missense point mutation in exon 4 of the SOD1 gene. SOD1 enzyme activity and SOD1 protein levels were not decreased significantly in the L84F patients. Conclusion: The ALS patients carrying the L84F mutation derive from a common ancestor. This mutation is responsible for ALS clustering in the area. The L84F mutation does not modify SOD1-specific activity.

No evidence for involvement of KCNN3 (hSKCa3) potassium channel gene in familial and isolated cases of schizophrenia.

Abstract: Several studies have reported in schizophrenia a decrease of age of onset in successive family generations, and this observation is consistent with anticipation. Anticipation is known to result from expansion of CAG repeats in several neurodegenerative disorders. Longer alleles of the KCNN3 gene, which contains a highly polymorphic CAG repeat, and encodes a neuronal small conductance calcium-activated potassium channel, have recently been shown to be over-represented in sporadic cases of schizophrenia. In this report, we tested the hypothesis of an association between longer alleles of CAG repeat in the KCNN3 gene and schizophrenia in 20 families with clinical evidence for anticipation and in 151 unrelated schizophrenic cases. No significant difference in the distributions of allele frequencies was observed between familial cases of schizophrenia and controls, and between unrelated cases and controls. Furthermore, no intergenerational CAG repeat instability was detected in the 20 families. Our results do not support the involvement of the KCNN3 (hSKCa3) gene in the etiology of schizophrenia.

Single Sperm Analysis of the CAG Repeats in the Gene for Dentatorubral-Pallidoluysian Atrophy (DRPLA): The Instability of the CAG Repeats in the DRPLA Gene is Prominent Among the CAG Repeat Diseases

Abstract: Dentatorubral-pallidoluysian atrophy (DRPLA) is known to show the most prominent genetic anticipation among CAG repeat diseases. To investigate the mechanism underlying the meiotic instability of expanded CAG repeats in the gene for DRPLA, we determined the CAG repeat sizes of 427 single sperm from two individuals with DRPLA. The mean variance of the change in the CAG repeat size in sperm from the DRPLA patients (288.0) was larger than any variances of the CAG repeat size in sperm from patients with Machado-Joseph disease (38. 5), Huntington's disease (69.0) and spinal and bulbar muscular atrophy (16.3), which is consistent with the clinical observation that the genetic anticipation on the paternal transmission of DRPLA is the most prominent among CAG repeat diseases. The variance of the change in CAG repeat size was significantly different between the two DRPLA patients (F-test, P < 0.0001). However, the segregation ratio of single sperm with an expanded allele to ones with a normal allele is not statistically different ( P = 0.161) from the expected 1:1 segregation ratio, and thus segregation distortion of expanded alleles in meiosis in male patients with DRPLA was not demonstrated.

Polyglutamine-containing proteins in schizophrenia.

Abstract: Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamine-expanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab 1C2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia.

Genetic anticipation in Portuguese kindreds with familial amyloidotic polyneuropathy is unlikely to be caused by triplet repeat expansions.

Abstract: Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant type of amyloidosis resulting from the deposition of transthyretin (ATTR) variants in the peripheral and autonomic nervous systems. ATTR V30M-associated FAP exhibits marked genetic anticipation in some families, with clinical symptoms developing at an earlier age in successive generations. The genetic basis of this phenomenon in FAP is unknown. Anticipation has been associated with the dynamic expansion of trinucleotide repeats in several neurodegenerative disorders, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. We have used the repeat expansion detection (RED) assay to screen affected members of Portuguese FAP kindreds for expansion of any of the ten possible trinucleotide repeats. Nine generational pairs with differences in their age of onset greater than 12 years and a control pair with identical ages of onset were tested. No major differences were found in the lengths of the ten trinucleotide repeats analyzed. The distribution of the maximal repeat sizes was consistent with reported studies in unrelated individuals with no known genetic disease. The present data do not support a role for trinucleotide repeat expansions as the molecular mechanism underlying anticipation in Portuguese FAP.

No evidence to support the association of the potassium channel gene hSKCa3 CAG repeat with schizophrenia or bipolar disorder in the Irish population.

Abstract: Anticipation has attracted much interest and has been demonstrated in several neuropsychiatric disorders. For some disorders, this phenomenon has been found to correlate with the repeat number in large and unstable repeats (CAG/CTG). In addition, case control studies have suggested an increase in triplet repeat size in the psychoses. Recently, it was reported that the larger alleles (longer than 19 repeats) of the second potassium channel gene hSKCa3 are associated with schizophrenia in European and American samples. A similar trend, though not statistically significant, was also seen in bipolar disorder samples. This was further supported by an independent UK study.1 In this investigation, we have examined Irish familial schizophrenic patients, bipolar affective disorder patients and ethnically matched controls in an effort to replicate these findings. No significant differences between the patients and the control groups were observed. In addition, linkage analyses in the multiplex schizophrenic families showed no evidence for linkage or linkage disequilibrium. We concluded that the polymorphism of the second CAG repeat of the hSKCa3 gene is not a risk factor in schizophrenia or bipolar disorder, at least in the Irish population.

Anticipation in schizophrenia: a review and reconsideration.

Abstract: There have been several reports on anticipation and schizophrenia, and the purpose of the present article is to review the literature and present data from an ongoing family study of schizophrenia. The published data find on average a 10-year difference in the age of onset between the parental and offspring generation in family sets that have been ascertained for a genetic linkage study. The biases inherent in such studies include the biases of ascertainment that were described by Penrose [1948]. Several investigators have searched for evidence of enlarged triplet repeats, and some find evidence consistent with expanded triplet repeats, whereas others do not. In any event the phenomenon of anticipation in schizophrenia appears to be consistently found and an explanation is needed. Data are presented from pairwise analyses using intergenerational pairs from 61 pedigrees with schizophrenia showing evidence of anticipation as well as the fertility bias. Anticipation was found in aunt:niece/nephew pairs (14.5 years) but not in uncle:niece/nephew pairs (0.5 years). The sex difference in age of onset was accentuated in uncles versus aunts (8.5 years), present in parents (4.5 years), but absent in the proband generation. Therefore, there appears to be an interaction within families between age of onset and sex that deserves further investigation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:686-693, 1999.

Testing for age-at-onset anticipation with affected parent-child pairs.

Abstract: The tendency for the onset of a genetic disease to occur at progressively earlier ages or with progressively greater severity in successive generations is known as anticipation. Following the discovery of trinucleotide repeat expansion as a plausible genetic mechanism for anticipation, interest in testing for anticipation has increased. Studies of anticipation can be biased when parents with late onset or children with early onset are preferentially ascertained. This paper presents a nonparametric approach to testing for age-at-onset anticipation that adjusts for such preferential ascertainment. The approach is illustrated through application to data on panic disorder.

Genetic anticipation and breast cancer: a prospective follow-up study.

Abstract: Genetic anticipation is characterized by an earlier age of disease onset, increased severity, and a greater proportion of affected individuals in succeeding generations. The discovery of trinucleotide repeat expansion (TRE) mutations as the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders has led to a resurgence of interest in this phenomenon. Because of the difficulties presented to traditional genetics by complex diseases, the testing for genetic anticipation coupled with TRE detection has been proposed as a strategy for expediting the identification of susceptibility genes for complex disorders. In the case of breast cancer, a number of previous studies found evidence consistent with genetic anticipation. It is known that a proportion of such families are linked to either BRCA1 or BRCA2, but no TRE mutations have been identified. It has been shown that the typical ascertainment employed in studies purporting to demonstrate genetic anticipation combined with unadjusted statistical analysis can dramatically elevate the type I error. We re‐examine the evidence for anticipation in breast cancer by applying a new statistical approach that appears to have validity in the analysis of anticipation to data ascertained from a recent follow‐up of a large prospective cohort family study of breast cancer. Using this approach, we find no statistically significant evidence for genetic anticipation in familial breast cancer. We discuss the limitations of our analysis, including the problem of adequate sample size for this new statistical test.

Preliminary evidence for anticipation in genetic E200K Creutzfeldt-Jakob disease.

Abstract: Article abstract Creutzfeldt-Jakob disease (CJD) linked to the E200K mutation of the prion protein (PrP) gene presents within a wide range of phenotypic heterogeneity, including the age at disease onset. We report an earlier disease onset for mutation carriers of the offspring generation when compared with that of their parents, suggesting the possibility of anticipation. A still unidentified environmental or genetic element may affect the age at onset in mutation carriers of different generations.

Clinical and molecular analysis of 11 Sicilian SCA2 families: influence of gender on age at onset.

Abstract: Autosomal dominant cerebellar ataxias (ADCAs) are a complex group of slowly progressive neurodegenerative disorders characterized by gait and stance ataxia, dysarthria and other symptoms of nervous system involvement. ADCA type I is the commonest form and is genetically heterogeneous; several loci have been identified. Spinocerebellar ataxia type 2 (SCA2) has been mapped to chromosome 12, with expanded cytosine-adenine-guanine (CAG) repeats being identified as the mutational cause of the disease. We investigated 15 families, all originating from mid-eastern Sicily, with ADCA type I; molecular studies performed in 12 families showed the SCA2 mutation to be present in 11 of them (91.6%) - the highest occurrence so far reported in the literature. The CAG repeat of the affected alleles varied between 34 and 44 repeats. Age at onset and repeat length revealed an inverse correlation. Mean age at onset was 37.32 ± 16.74 years, and occurred earlier in males than in females. There were no differences in mean CAG repeat units between the sexes. However, a higher instability of CAG repeats was observed for paternal transmission than for maternal transmission. Age at onset and anticipation were not related to parental transmission. Our data suggest that in SCA2 an unknown sexlinked factor may play a role in the modulation of toxic effects of the polyglutamine tract.

Repeats may not be everything in anticipation

Abstract: Anticipation is the clinical phenomenon in which disease onset becomes progressively earlier with increasing severity in successive generations.1 Because this phenomenon seemed counter to simple genetic principles, geneticists long dismissed anticipation as an artifact of ascertainment biases. The universal acceptance of anticipation as a genuine biological process did not come until 1992 when the discovery of an unstable CGG repeat expansion gave a molecular explanation for anticipation in fragile X syndrome.2 Subsequent identification of expansion mutations involving unstable CTG/CAG repeats solved the controversies of anticipation in diseases such as myotonic dystrophy; Huntington’s disease (HD); spinocerebellar ataxia (SCA) types 1, 2, 3, and 7; and dentatorubral pallidoluysian atrophy (DRPLA).3,4 Two key observations provided the molecular explanation: 1) intergenerational increases of the size of the expanded repeat allele and 2) an inverse correlation between the size of the expanded allele and the age at onset. Two articles in this issue of Neurology revisit anticipation from unique angles. First, MacDonald et al. show data suggesting the presence of a genetic factor other than the HD gene …

Anticipation is not associated with CAG repeat expansion in parent-offspring pairs of patients affected with schizophrenia.

Abstract: With the rationale that a disease that presents with anticipation could be associated with expansion of trinucleotide repeats, we selected parent-offspring pairs of schizophrenia patients with earlier age at onset in the filial generation to measure the expansion of CAG repeats using the repeat expansion detection (RED) method. Intergenerational comparisons were made for age at onset, length of CAG repeats, and clinical variables. Although the patients from the filial generation became affected 13 years earlier than the parents (P < 0.0005), we did not find larger CAG repeats in the offspring. No association was found between size of CAG repeat and age at onset or with any other clinical variable. Overall, the frequency of patients with CAG repeats longer than 40 was 32%, which was similar to that observed in control subjects (27%). It is particularly noteworthy that in 86% of the pairs, the mother was the affected parent. In this Spanish sample with parent-offspring pairs presenting schizophrenia with clinical anticipation and apparent female bias of transmission, neither the phenomenon of anticipation nor disease status was associated with the expansion of CAG repeats.

Paragenetic suppressors of suppressor genes--a new class of oncodeterminants.

Abstract: Impairment or loss of suppressor genes is a common event permitting the oncogene/suppressor gene machinery to develop neoplasia. Following prenatal treatment with X-rays and UV-B, we detected a new class of oncodeterminants that could not be specified as genes. This points to paragenetic elements that suppress suppressorgenes and thus provoke melanoma at earlier ages of onset as expected, with increased severity and increased number of incidences in successive generations, in the absence of further treatment. These elements were isolated from a xiphophorine DNA library by endogenously labeled long terminal repeats (LTR) of a xiphophorine retrovirus, and were characterized as retrotransposons by Southern and Northern blotting and reverse transcription/polymerase chain reaction and transient transfection studies, in situ hybridization, and sequencing. They appear in multiple copies in the telomeric chromosome regions, where they can extend. Three open reading frames (ORF) are flanked by LTR that contain genetically active regulatory elements, and are inducible by UV-B. ORF 3 shows nests of CG dinucleotides and CGG trinucleotides, which are reminiscent of CGG nests predisposing subjects to anticipation of certain human diseases involving tumor generation. Genetic anticipation as defined by Nettleship (1909) or Warren (1996) including an increase of neoplasia might represent an acquired genetic load in preceding generations, which might provide a lead to a molecular understanding of the worldwide increase of incidences of human tumor.

Anticipating the onset of inflammatory bowel disease

Abstract: See article on page 812 The great interest in identifying susceptibility genes in inflammatory bowel diseases (IBD) has recently triggered the aggregation of family trees throughout Europe and the United States. This has led to a better knowledge of empirical risk and clinical characteristics of familial IBD. One of the most consistent findings in families with Crohn’s disease was early onset in most affected children of an affected parent, with an average difference of 15 years. This may be a more general feature of familial IBD, as shown in this issue by Lee et al (see page 808) who observed a similar time span (16–18 years) between generations in 50 pure Crohn’s disease, 51 pure ulcerative colitis and 36 mixed disease families. Genetic anticipation has been suggested as a possible explanation for this finding.1 This term denotes a decrease in the age of onset and an increase in severity as a disease is passed through generations.2 Genetic anticipation has been described in monogenic neurological illnesses such as Huntington’s disease, myotonic dystrophy and more recently Friedreich’s ataxia. In these diseases, there …

Genetic anticipation in a large family with pure autosomal dominant hereditary spastic paraplegia.

Abstract: We have reinvestigated a large kindred identified over 25 years ago segregating for a form of pure autosomal dominant hereditary spastic paraplegia (HSP). We have examined additional relatives in order to refine the clinical and genetic characteristics of this disorder, and performed an analysis to determine if anticipation is present in this family. Analysis of onset ages in parent-to-child transmissions of HSP is consistent with anticipation. These results provide support for dynamic mutation as the underlying mechanism of this form of HSP, and suggest a trinucleotide repeat instability occurring primarily in the female germ line.

Genetic Analysis of a Dentatorubral-Pallidoluysian Atrophy Family: Relevance to Apparent Sporadic Cases

Abstract: Dentatorubral-pallidoluysian atrophy (DRPLA) is associated with an unstable CAG trinucleotide sequence. We describe a DRPLA family whose members have an allele containing an expanded CAG repeat, even in an elderly neurologically normal individual. The proband developed DRPLA at age 14. She was initially considered a sporadic case, but later her sister became symptomatic. Investigation of the number of CAG repeat units in her family revealed the 81-year-old father to have an expanded CAG repeat of 51 units. To our knowledge, such an advanced aged unaffected patient has not been previously documented. The present example may explain apparent sporadic cases.