Showing papers on "Anticipation (genetics) published in 2010"

Peer Contagion and Adolescent Depression: The Role of Failure Anticipation

Abstract: The current study investigated the mechanisms underlying peer contagion of depressive symptoms in adolescence. Five annual measurements of data were gathered from a large (N = 842) community-based network of adolescents (M = 14.3 years at first measurement). Results showed that, after controlling for selection and deselection of friends on the basis of depressive symptoms, peers' depressive symptoms predicted increases in adolescents' depressive symptoms over time. Failure anticipation mediated effects of peers' depressive symptoms on adolescents' depressive symptoms, particularly for girls. Thus, results suggest that peers' depressive symptoms place adolescents at risk of developing depressive symptoms through increasing in failure anticipation.

A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome

Abstract: Anticipation, manifested through decreasing age of onset or increased severity in successive generations, has been noted in several genetic diseases. Statistical methods for genetic anticipation range from a simple use of the paired t-test for age of onset restricted to affected parent-child pairs to a recently proposed random effects model which includes extended pedigree data and unaffected family members [Larsen et al., 2009]. A naive use of the paired t-test is biased for the simple reason that age of onset has to be less than the age at ascertainment (interview) for both affected parent and child, and this right truncation effect is more pronounced in children than in parents. In this study, we first review different statistical methods for testing genetic anticipation in affected parent-child pairs that address the issue of bias due to right truncation. Using affected parent-child pair data, we compare the paired t-test with the parametric conditional maximum likelihood approach of Huang and Vieland [1997] and the nonparametric approach of Rabinowitz and Yang [1999] in terms of Type I error and power under various simulation settings and departures from the modeling assumptions. We especially investigate the issue of multiplex ascertainment and its effect on the different methods. We then focus on exploring genetic anticipation in Lynch syndrome and analyze new data on the age of onset in affected parent-child pairs from families seen at the University of Michigan Cancer Genetics clinic with a mutation in one of the three main mismatch repair (MMR) genes. In contrast to the clinic-based population, we re-analyze data on a population-based Lynch syndrome cohort, derived from the Danish HNPCC-register. Both datasets indicate evidence of genetic anticipation in Lynch syndrome. We then expand our review to incorporate recently proposed statistical methods that consider family instead of affected pairs as the sampling unit. These prospective censored regression models offer additional flexibility to incorporate unaffected family members, familial correlation and other covariates into the analysis. An expanded dataset from the Danish HNPCC-register is analyzed by this alternative set of methods.

Anticipation of age at onset in multiple sclerosis: methodologic pitfalls.

Abstract: Background/aim - There are several reports that claim anticipation in complex or polygenic diseases such as multiple sclerosis (MS), Crohn disease or schizophrenia. The aim of the present study was to assess age at onset of MS during the last 60 years in the region of Costa de Ponent (Barcelona, Spain) showing how apparent changes in age at onset between generations can be an artefact of analysis based on cohorts that have not been followed enough time. Methods - The study comprised 1100 patients diagnosed of MS. The method used to correct for follow-up time bias involves constructing comparison cohorts that had been observed for the same amount of time. To ensure equal follow-up times, we restricted our analysis to patients whose onset was by 37 years of age (percentile 75) and were at least 37 years old. We analysed differences in age at onset using log-rank test to compare survival curves estimated by Kaplan-Meier method. Results - Age at onset decreases progressively from older to younger generations. However, when adjustment to equal follow-up time was done, anticipation in age at onset was not found. Conclusion - Anticipation of age at onset is undetectable when adjusted for follow-up time.

Fahr’s disease – a model of neuropsychiatric illness with cognitive and psychotic symptoms

Abstract: In this issue of Acta Psychiatrica Scandanivica, Shirahama et al. report on a remarkable pedigree with a probable three generation expression of Fahr s Disease. This illness is characterized by basal ganglia calcifications, psychotic symptoms and cognitive impairment. The calcified hyperintensities in the basal ganglia of these patients on CT scan are the characteristic neuroimaging finding in Fahr s disease; indeed, the diagnosis is unlikely in the absence of this finding. As the cognitive symptoms are quite classic in this pedigree as well, the interest in relating the psychiatric symptoms to the basal ganglia calcifications is obvious and appealing. As is seen in other illnesses affecting the basal ganglia (e.g. Parkinson s disease, Huntington s disease), the symptomatic expression in cases of Fahr s disease may overlap between cognitive and psychotic symptoms. It is sometimes the case in clinical psychiatry to focus one s clinical attention primarily on psychotic, mood, and anxiety symptoms and disorders, while not devoting the full measure of one s clinical attention to cognitive disorders. It is not unusual in the literature to see this exclusionary approach to cognitive disorders even encouraged by the use of language such as cognitive disorders and psychiatric illness , as if cognitive disorders were somehow not psychiatric illness. Psychiatrists should fully embrace cognitive disorders and their evaluation and management as essential to their clinical practice. The advances in psychopharmacology for dementing disorders (primarily studied for Alzheimer s disease but logically extended to other dementias) put the psychiatrist in the position to offer helpful clinical intervention. In addition, cognitive disorders are often accompanied by additional psychotic, mood, and ⁄or anxiety symptoms conceptualized as psychiatric co-morbidity . As such, the psychiatrist is the physician of choice to manage the common psychiatric co-morbidities in dementia patients. In addition, it is not yet necessarily routine clinical practice in all venues to routinely obtain screening neuroimaging for all cases of dementia or psychotic disorders. While not likely to change clinical management in the majority of cases, perhaps, neuroimaging in cases of such neuropsychiatric illnesses is an important component in the process of identification, clinical classification, and, ultimately, in the understanding of the pathophysiology of these fascinating cases. Finally, this case series illustrates a genetically determined neuropsychiatric illness. As progress in genetic analysis proceeds rapidly, the likelihood is that, in the future, more illnesses with various psychiatric symptoms will be appreciated as having a genetic origin. As such, the clinician needs to consider the possibility of genetically-determined neuropsychiatric illness, especially when confronting a three-generation pedigree of affected patients.

Interaction gènes-environnement dans les troubles affectifs

Abstract: Kindling and behavioural sensitization were probably the first among the animal models of affective disorders, to suggest that genes-environment interactions were likely to be involved in the pathophysiology of these disorders. Cross-sensitization among stressors, drugs of abuse and illness episodes was deemed to be supported by the induction of a series of transcription factors, such as the proto-oncogene c-fos that subsequently alter gene expression by binding at DNA sites and inducing mRNAs for substances that may exert effects over long time periods. This was an anticipation of epigenetics which is currently defined as a functional modification to the DNA that does not involve an alteration of sequence. Epigenetic modifications are most commonly regulated by DNA methylation and histone acetylation which are usually associated with the silencing and activation of gene transcription, respectively. In animal models, it was shown that parents can actively remodel epigenetic marks, and thus affect patterns of gene expression in the offspring, whereas environmental adversity decreases parental investment in the offspring and thus alters phenotypic development. In line with this, some laboratories have sought to identify changes in gene expression in post mortem brain samples of humans with affective disorders. Finally, gene-environment interactions have been directly studied, both in animals and humans, by testing how a functional polymorphism in candidate genes would moderate the influence of stressful life events on behavioural expression. Interesting results have been found and replicated for unipolar depression, however date are scarce for bipolar disorder. Findings from these studies allow the building of more sophisticated models for unipolar and bipolar genetics.

Huntington’s Disease: Genetics

Abstract: Huntington's disease (HD) results from a CAG repeat expansion mutation in IT15 leading to an expanded polyglutamine sequence in the huntingtin protein. Disease severity correlates with CAG/polyglutamine repeat length, and there is expansion bias with male transmission. The mutant polyglutamine tract accumulates as neurotoxic aggregates, which disrupt multiple cellular processes.

Ataxia and progressive encephalopathy in a 4-year-old girl

Abstract: The spinocerebellar ataxias (SCAs) are a rare group of neurodegenerative disorders with progressive cerebellar ataxia as the primary feature. These disorders are phenotypically and genetically variable, both between and within subtypes. Seven of the SCA subtypes are caused by CAG trinucleotide repeats within the respective genes, and clinically most of these diseases demonstrate anticipation. Testing for these disorders typically relies upon conventional polymerase chain reaction (PCR) and fragment analysis. However, conventional PCR may give false-negative results in cases in which the CAG expansion is unusually long. We report a case of spinocerebellar ataxia type 2 (SCA2) in a 4-year-old girl with false-negative conventional PCR results. Specifically, the SCA2 disorder is caused by a CAG repeat within the ATXN2 gene on chromosome 12. Subsequent confirmatory testing using modified PCR and primers specific for the CAG repeat were performed and revealed an expanded allele with 109 repeats in our patient.

Distrofi a miotónica tipo I (Enfermedad de Steinert) y embarazo. Descripción de un caso clínico Myotonic distrophy type I (Steinert Disease) and pregnancy.

Abstract: Type I myotonic dystrophy or Steinert’s disease (DM1, OMIM 160900), is an autosomal dominant mulsystem disease of variable expresion caused by a (CTG) n , expansion mutation in the gene encoding for the myotonic dystrophy protein kinase (DMPK) in 19q13. The disease is characterized by a phenomenon of anticipation, resulting in a more severe expression of the disease in successive generations, in correlation with the size of the triplet expansion. The congenital form of the disease, ussually of maternal transmision, may cause polyhidramnios, foetal or neonatal death, or a sever neonatal fl oppy infant syndrome charaterized by facial diplegia, dysphagia, respiratory distress syndrome and a variable degree of mental retardation in 60% of the cases. The aim of this report is to describe a DM1 affecting a 35 years old woman and her fetus of 28 weeks of gestation at the moment of diagnosis. We describe the evolution of the pregnancy and her neonate, we discuss the reciprocal infl uence between pregnancy and the disease , enhacing the antenatal and neonatal complications.