Showing papers on "Anticipation (genetics) published in 2009"

Familial Ménière's disease: clinical and genetic aspects.

Abstract: Background and purpose Meniere's disease is not uncommon, with an incidence in Caucasians of about one in 2000. The incidence peaks in the fifth decade. Cases are usually isolated or sporadic, but in perhaps five per cent other family members are affected. We report here the clinical and genetic characteristics of a comprehensive set of familial Meniere's disease cases from the UK. Methods Forty-six affected families were studied. All cases were diagnosed using the American Academy of Otolaryngology-Head and Neck Surgery committee on hearing and equilibrium 1995, or more stringent, criteria. Outcomes and results Autosomal dominant inheritance with reduced penetrance was the most likely mode of inheritance overall. Apparent genetic anticipation was observed, but may also be a result of ascertainment bias given the collection strategy. There was also a slight tendency for cases to result from maternal transmission within the families in this set. The family pedigrees are presented, and the authors have also set up a website at which all the pedigrees may be viewed in greater detail.

Role for Genetic Anticipation in Lynch Syndrome

Abstract: Purpose Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum. Patients and Methods In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290 parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation. Results Both methods revealed anticipation with children developing cancer mean 9.8 years (P < .001) earlier than parents using the paired t-test and 5.5 years (P < .001) earlier using the bivariate model. Birth cohort effect...

Clinical and genetic characteristics of non-Asian dentatorubral-pallidoluysian atrophy: A systematic review.

Abstract: Dentatorubral-pallidoluysian atrophy (DRPLA) is an inherited neurodegenerative disorder regarded as found almost exclusively among the Japanese. We have performed as systematic review of published literature to investigate the clinical and genetic characteristics of non-Asian DRPLA. We identified 183 non-Asian patients in 27 families reported with DRPLA with a variable level of clinical information. Mean age at onset was 31 (range 1–67) with epilepsy, ataxia, and chorea common presenting features. A highly significant relationship was identified between repeat length and age at onset with repeat length accounting for 62% of the observed variation in age at onset (P < 0.0001). In addition, a highly significant relationship between repeat length and main presenting complaint was identified (P < 0.001). There was evidence of marked anticipation with a median intergenerational reduction in age at onset of 19 years with a corresponding increase of five repeats per generation. DRPLA is not exclusively found among the Japanese but has been reported worldwide. As such, DRPLA should be considered in the differential diagnosis of a wide spectrum of neurological disease, particularly if there is a dominant family history. Non-Asian DRPLA clinico-genetic phenomenology are similar to Asian series and our study confirms marked genetic anticipation together with a clear association between repeat length and clinical phenotype and disease severity.

A parametric model for analyzing anticipation in genetically predisposed families.

Abstract: Anticipation, i.e. a decreasing age-at-onset in subsequent generations has been observed in a number of genetically triggered diseases. The impact of anticipation is generally studied in affected parent-child pairs. These analyses are restricted to pairs in which both individuals have been affected and are sensitive to right truncation of the data. We propose a normal random effects model that allows for right-censored observations and includes covariates, and draw statistical inference based on the likelihood function. We applied the model to the hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome family cohort from the national Danish HNPCC register. Age-at-onset was analyzed in 824 individuals from 2-4 generations in 125 families with proved disease-predisposing mutations. A significant effect from anticipation was identified with a mean of 3 years earlier age-at-onset per generation. The suggested model corrects for incomplete observations and considers families rather than affected pairs and thereby allows for studies of large sample sets, facilitates subgroup analyses and provides generation effect estimates.

Anticipation in Lynch Syndrome: Still Waiting for the Answer

Abstract: Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. For some diseases, genetic anticipation is a well-recognized clinical feature with an elegantly and completely characterized molecular mechanism. Lynch syndrome is not one of these diseases. Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer, was originally described by Aldred Warthin in 1913 as a cancer family syndrome characterized by the early onset of gastrointestinal, uterine, and other cancers. Ninety-five years later, we are still gathering data to understand whether successive generations are truly affected at earlier ages than their ancestors and whether the severity of the disease is more or less pronounced. In this issue of Journal of Clinical Oncology, Nilbert et al revisit the hypothesis of genetic anticipation in Lynch syndrome using the population-based Danish Hereditary Nonpolyposis Colorectal Cancer Registry. Examining data from 290 parent-child pairs from families with Lynch syndrome who are known to carry a mutation in one of three causal genes, they show that the mean age of onset of cancer is lower in children than in their parents. The authors used a statistical method that accounts for the fact that children are always younger than their parents. The younger age of cancer among children also persisted even in analyses that excluded those cancers diagnosed during surveillance. However, their conclusion that this statistically significant difference in age at diagnosis represents biologically meaningful genetic anticipation is not entirely convincing. It is worthwhile to review the molecular genetic basis of syndromes where the evidence for genetic anticipation is crystal clear, to understand just how far we have to go to complete the story of Lynch syndrome. Genetic anticipation is a cardinal feature of more than a dozen neurodegenerative disorders such as Huntington disease, fragile X, myotonic dystrophy, and Friedreich ataxia, among others. The molecular mechanism of each these examples is explained by understanding trinucleotide expansion repeat disorders, where a generational expansion of a repetitive trinucleotide sequence during meiosis leads to disease. For example, the normal number of copies of the DNA sequence CAG that encodes a polyglutamine tract within the HD gene ranges between 9 and 35. More than 40 copies of this CAG repeat, (CAG)40, causes Huntington disease; both the severity and age of onset depend on the number of repeats. Individuals with 40 to 50 repeats are often asymptomatic until late in life, whereas children with 70 to 121 repeats develop severe disease in the juvenile form of the disease. The juvenile form is always paternally inherited, as a consequence of the fact that trinucleotide expansion occurs most frequently during male gametogenesis. This phenomenon also explains the sexspecific inheritance patterns that are frequently observed with genetic anticipation. One might hypothesize that a gene involved in mismatch repair (such as one of the genes that cause Lynch syndrome) might lead to a similar type of generational instability in repetitive sequences of DNA, and that this could serve as a biologic basis of genetic anticipation. The only problem with this hypothesis is that there is little evidence to support it. No studies to date have evaluated generational differences in microsatellite instability in the typical targets of defective mismatch repair. The studies that have examined clinical populations for genetic anticipation have generally led to conflicting conclusions, and none have been accompanied by mechanistic data supporting these diverse interpretations. One might also hypothesize that defective mismatch repair might enhance the generational expansion of trinucleotide repeats in models of Huntington disease. The only problem with this hypothesis is that the opposite appears to be true, at least in animal models. Msh2 is required for (CAG) expansion in a mouse model of Huntington disease, and transgenic mice with a complete absence of Msh2 have perfectly stable polyglutamine tracts. Several studies show that Msh2 deficiency actually inhibits intergenerational trinucleotide expansion. Therefore, if genetic anticipation is shown to be clinically relevant in Lynch syndrome, it is unlikely to occur due to the same type of trinucleotide expansion responsible for anticipation in neurodegenerative disorders. Anticipation has been difficult to study in cancer genetic syndromes. However, intriguing new evidence from studies of LiFraumeni syndrome (LFS) and Dyskeratosis Congenita (DC) suggest that there may be at least one other mechanism that plays a role in modifying the age of onset of some types of cancer susceptibility. Accelerated telomere attrition has been reported in affected carriers with LFS compared with unaffected carriers as well as compared with normal wild-type controls, leading investigators to speculate that defects in TP53 allow cells with shorter telomeres to escape senescence and proliferate. If this type of selection for shorter telomeres applies to both somatic and germline tissues, then one would expect that shorter telomeres would be identified at birth in each successive generation. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 3 JANUARY 2

Novel KRIT1 mutation and no molecular evidence of anticipation in a family with cerebral and spinal cavernous malformations.

Abstract: Background: Cerebral cavernous malformations (CCM) are vascular brain anomalies which can result in a variety of neurological symptoms. Familial CCM is inherited as an autosomal-dom

Variation in phenotypic appearance of Graves' disease: effect of genetic anticipation and duration of complaints.

Abstract: Objective: Both genetic and environmental factors contribute to susceptibility of Graves’ disease. In this study, we evaluated whether the duration of symptoms or a positive family history of autoimmune thyroid disease (AITD) are related to specific phenotypes in patients with a first episode of Graves’ hyperthyroidism (GH). Design: Cross-sectional multicentre observational study. Patients: Two hundred and sixty-three consecutive untreated patients (mean age (GS.D.) 42.6G12.4 years; range 16–79 years) with a first episode of GH were included. Biochemical and clinical severity of GH was evaluated. Participants were asked to complete questionnaires about environmental factors (smoking behavior, use of estrogens, stress etc.), the duration of symptoms (interval between start of symptoms and date of referral) and family history for AITD. We ascertained the autoimmune nature of thyroid disease in affected relatives. Family history scores (FHS; high score indicating a close genetic relationship and/or a large number of affected relatives) were calculated for patients with a positive family history for AITD. Results: The peak incidence for the diagnosis of GH was 2–3 months after onset of symptoms (32% of patients). Duration of symptoms was negatively associated with age (P for trendZ0.04). A positive family history for AITD was present in 42.6% of patients. Patients with the highest FHS were more often male (PZ0.01) while age at onset was lower (PZ0.02) compared to patients with a lower FHS. Among patient groups with different FHS, no differences were found in exposure to environmental factors, nor in clinical or biochemical severity of hyperthyroidism. Conclusion: Our study does not support the hypothesis that a short duration of thyrotoxic symptoms until diagnosis is related to more severe hyperthyroidism in Graves’ disease. We have found supporting evidence for the existence of genetic anticipation in Graves’ disease by means of a lower age of onset in the group with the highest FHS.

[Anticipation in patients with iridescent multicoloured posterior capsular lens opacities ("Christmas tree cataract") : The Role in the diagnosis of myotonic dystrophy].

Abstract: Background Myotonic dystrophy (DM type 1) is the most common type of muscular dystrophy in adults, accompanied by myotonia, iridescent multicoloured posterior capsular lens opacities ("Christmas tree cataract", CTC), and, for example, cardiac arrhythmias and respiratory failure. A further feature is anticipation, which is the occurrence of increasing disease severity and decreasing age of onset in successive generations, depending on inherited unstable DNA sequences that become larger with each generation. Aim To evaluate the frequency of clinically manifest DM in patients with CTC and the age at diagnosis of CTC. Methods Retrospective analysis of ophthalmologic, neurologic, and internal findings in 18 consecutively diagnosed patients with CTC. Results Three of 18 CTC patients showed clinical signs of DM. The mean age at diagnosis was 72,8+/-16,5 years (range 36-94 years). Discussion A relationship existed between CTC and manifest DM in 16.7% of the patients with CTC. A hypothesis states that the other 83.3% might have premutations in the DMPK gene, which might lead to a complete mutation after transmission through subsequent generations. In the meantime, molecular genetic DM tests are available. Because of clinical heterogeneity and the anticipation phenomenon in DM, confirmation with such molecular genetic DM tests should be obtained.

How much expansion to be diseased?: toward repeat size and myotonic dystrophy type 2.

Abstract: Myotonic dystrophies (DMs) encompass at least two genetically distinct disorders: the classic type 1 (DM1), also known as Steiner disease, and type 2 (DM2), also referred to as proximal myotonic myopathy or Moxley-Ricker disease. Both disorders are characterized by variably expressed multisystem phenotypes with core features of progressive skeletal muscle weakness and degeneration with myotonia. DMs are caused by unstable repeat expansions: in DM1, a CTG repeat expansion in the 3′ untranslated region of DMPK in chromosome 19q13.3, and in DM2, a CCTG repeat expansion in intron 1 of ZNF9 in 3q21.3.1,2 In DM1, a reservoir of premutation alleles in the population provides the source of de novo DM1 alleles. The expanded progenitor allele has a propensity to increase the CTG repeat size in successive generations, causing anticipation. The congenital form of DM1, with a large allele and the inability to reproduce offspring, represents the endpoint of anticipation. The stoichiometric balance between de novo mutations and losses of the mutant allele may explain the relatively stable prevalence of DM1. The gender of the transmitting parent is …

Antizipation bei Patienten mit Christbaumschmuckkatarakt : Ihre Bedeutung für die Diagnose der myotonen Dystrophie (Originalien)

Abstract: BackgroundMyotonic dystrophy (DM type 1) is the most common type of muscular dystrophy in adults, accompanied by myotonia, iridescent multicoloured posterior capsular lens opacities (“Christmas tree cataract”, CTC), and, for example, cardiac arrhythmias and respiratory failure. A further feature is anticipation, which is the occurrence of increasing disease severity and decreasing age of onset in successive generations, depending on inherited unstable DNA sequences that become larger with each generation.AimTo evaluate the frequency of clinically manifest DM in patients with CTC and the age at diagnosis of CTC.MethodsRetrospective analysis of ophthalmologic, neurologic, and internal findings in 18 consecutively diagnosed patients with CTC.ResultsThree of 18 CTC patients showed clinical signs of DM. The mean age at diagnosis was 72,8±16,5 years (range 36-94 years).DiscussionA relationship existed between CTC and manifest DM in 16.7% of the patients with CTC. A hypothesis states that the other 83.3% might have premutations in the DMPK gene, which might lead to a complete mutation after transmission through subsequent generations. In the meantime, molecular genetic DM tests are available. Because of clinical heterogeneity and the anticipation phenomenon in DM, confirmation with such molecular genetic DM tests should be obtained.

Antepartum Risk Factors

Abstract: Identification of risk factors allows anticipation of shoulder dystocia and prevention of brachial plexus palsy. Obesity, diabetes, and increased fundal height are the most important risk factors.

Preconceptual Risk Factors

Abstract: Identification of risk factors and anticipation of shoulder dystocia will help prevent fetal injury.

Challenges and pitfalls in HNPCC: a pedigree of an Austrian HNPCC family beyond four generations!

Abstract: In this study we present an Austrian family with HNPCC, which was diagnosed by clinical criteria (Amsterdam I). Subsequent to the diagnosis, genetic counselling and testing was offered to all family members. A causal mutation was detected in exon 12 of the MLH1 gene by determining the genomic sequence. The mutation had resulted in the deletion of an adenine nucleotide at position 1343 (c.1343delA; respective cDNA NCBI accession number: NM_000249), creating a new reading frame (p.E448fs). Within this pedigree it was possible, with frequent colonoscopy screening, to detect an early-stage tumour localised in the coecum. Furthermore, there is evidence for genetic anticipation. The median ages at diagnosis of colorectal cancer decreased from 51.5 in the second generation to 33.5 in the third generation.