Anticipation (genetics)

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

Anticipation of onset age in familial Parkinson's disease.

Abstract: The importance of genetic factors i n the pathogenesis of Parkinson’s disease (PD) has recently been reevaluated.’ Familial cases account for around 15 to 20% of all PD cases and share most of the clinical features of the “sporadic” cases.’ In most families, transmission is compatible with autosomal dominant mechanisms with reduced penetrance, or with multigenic or multifactorial models involving several susceptibility loci that contribute to genetic risk, and environmental factors.’ A large kindred of autosomal dominant, autopsy-proven PD, in which the penetrance approaches loo%, provides strong evidence that the PD clinicopathologic entity can be provoked by a single gene transmitted in mendelian mode.2 However, in the majority of smaller PD kindreds it is not easy to distinguish between an autosomal dominant transmission with reduced penetrance and a multigenic or multifactorial type of inheritance. We observed a clinically typical PD case of very early onset, with affected relatives in both of the parental lines and consanguineous parents (first cousins). Case histories. Index case. We first examined this subiect in October 1993. Born in 1949, he had been healthy until age 28 (1977), when he suffered the onset of rest tremor in his left limbs, which was later accompanied by rigidity and slowness of movements. The course was progressive, with contralateral involvement in subsequent months. The symptoms responded to levodopa. However, tremor worsened markedly in the following years, and the patient underwent stereotactic thalamotomy in 1984, which eliminated the tremor in the left limbs. In more recent years he experienced motor fluctuations and levodopaor dopamine-agonist-induced dyskinesias. At the time of our examination (disease duration 16 years), the patient could be maintained in the “on” phase only by a continuous dopamineagonist subcutaneous infusion plus oral levodopahenserazide (100 mg/25 mg) every 3 hours, and at the cost of having severe and generalized dyskinesias. The UPDRS motor score in the “on” phase was twenty-three. Mental functioning was normal and he was still able to walk unaided and t o perform simple tasks a t home. The father of the index case, born in 1916, came to our center in February 1993 after the onset of bradykinesia and rigidity in 1990, a t age seventy-four. His medical history was unremarkable. Our examination showed parkinsonian posture, generalized bradykinesia, and cogwheel rigidity in the upper extremities; symptoms were levodopa responsive. Because of visual hallucinations, levodopa treatment was limited to daily dosages of 400 mg. He died in August 1993 from cardiac disease. The maternal grandfather, the index case said, suffered from symptoms similar to those of the index case’s fa ther and received a formal diagnosis of PD a t the age of sixty-five. He died 5 years later. Being the paternal grandfather’s brother, he was a common relative of the index case’s parents. This family is of interest because of very early onset PD in a man with affected relatives in both parental lines and because his parents were first cousins. If PD had genetic bases in this family, the parental consanguinity would lead to identical alleles and identical etiology in descendants. The three affected subjects shared neither living environments nor personal habits, pointing against a common, environmental etiology. That PD might have occurred by chance in three consecutive generations of this family is unlikely, but cannot be excluded. We studied nine PD families (unpublished material) with a t least two living, personally examined, affected relatives, but we found no other patients with affected relatives in both parental lines or such a great difference in onset age between pairs of PD relatives. There are very few reported cases of familial PD with affected relatives in both of the parental lines.

Familial cavernous angioma: an unknown, known disease.

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)

Anticipation in lynch syndrome: where we are where we go.

Abstract: Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management of LS patients is complicated by the large variation in age at cancer diagnosis which requires these patients to be enrolled in surveillance protocol starting as early as in their second decade of life. Several environmental and genetic factors have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Although the presence of genetic anticipation in Lynch syndrome has been suspected since 15 years, only recently the phenomenon has been increasingly reported to be present in different cancer genetic syndromes including LS. While the biological basis of earlier cancer onset in successive generations remains poorly known, recent findings point to telomere dynamics as a mechanism significantly contributing to genetic anticipation in Lynch syndrome and in other familial cancers. In this review, we summarize the clinical and molecular features of Lynch syndrome, with a particular focus on the latest studies that have investigated the molecular mechanisms of genetic anticipation.

Genetic Counseling in Huntington's Disease: Potential New Challenges on Horizon?

Abstract: Huntington’s disease (HD) is a rare, hereditary, neurodegenerative and dominantly transmitted disorder affecting about 10 out of 100,000 people in Western Countries. The genetic cause is a CAG repeat expansion in the huntingtin gene (HTT), which is unstable and may further increase its length in subsequent generations, so called anticipation. Mutation repeat length coupled with other gene modifiers and environmental factors contribute to the age at onset in the offspring. Considering the unpredictability of age at onset and of clinical prognosis in HD, the accurate interpretation, a proper psychological support and a scientifically sound and compassionate communication of the genetic test result are crucial in the context of Good Clinical Practice and when considering further potential disease-modifying therapies. We discuss various genetic test scenarios that require a particularly careful attention in psychological and genetic counseling and expect that the counseling procedures will require a constant update.

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.