Showing papers on "Anticipation (genetics) published in 1994"

Instability of CAG repeats in Huntington's disease: relation to parental transmission and age of onset.

Abstract: Huntington's disease (HD) has recently been found to be caused by expansion of a trinucleotide (CAG) repeat within the putative coding region of a gene with an unknown function. We report here an analysis of HD mutation and the characteristics of its transmission in 36 HD families. CAG repeats on HD chromosomes were unstable when transmitted from parent to offspring. Instability appeared more frequent and stronger upon transmission from a male than from a female, with a clear tendency towards increased size. We have also found a significant inverse correlation (p = 0.0001) between the age of onset and the CAG repeat length. The observed scatter would, however, not allow an accurate individual prediction of age of onset. Three juvenile onset cases analysed had an HD mutation of paternal origin. In at least two of these cases a large expansion of the HD allele upon paternal transmission may explain the major anticipation observed. Our results suggest that several features of the expansion mutation in HD are similar to those previously observed for mutations of similar size in spinobulbar muscular atrophy and in myotonic dystrophy, and to those observed more recently in spinocerebellar ataxia type 1 and in dentatorubropallidoluysian atrophy, four diseases also caused by expansion of CAG repeats.

Trinucleotide repeat expansion in neurological disease.

Abstract: Expansion of trinucleotide repeats is now recognized as a major cause of neurological disease. At least seven disorders result from trinucleotide repeat expansion: X-linked spinal and bulbar muscular atrophy (SBMA), two fragile X syndromes of mental retardation (FRAXA and FRAXE), myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). The expanded trinucleotide repeats are unstable, and the phenomenon of anticipation, i.e., worsening of disease phenotype over successive generations, correlates with increasing expansion size. In this review, we compare the clinical and molecular features of the trinucleotide repeat diseases, which may be classified into two types. Fragile X and myotonic dystrophy are multisystem disorders usually associated with large expansions of untranslated repeats, while the four neurodegenerative disorders, SBMA, Huntington's disease, SCA1, and DRPLA, are caused by smaller expansions of CAG repeats within the protein coding portion of the gene. CAG repeats encode polyglutamine tracts. Polyglutamine tract expansion thus appears to be a common mechanism of inherited neurodegenerative disease. Although polyglutamine tract lengthening presumably has a toxic gain of function effect in the CAG trinucleotide repeat disorders, the basis of this neuronal toxicity remains unknown.

Evidence for anticipation in schizophrenia

Abstract: Anticipation, or increasing severity of a disorder across successive generations, is a genetic phenomenon with an identified molecular mechanism: expansion of unstable trinucleotide repeat sequences. This study examined anticipation in familial schizophrenia. Three generations of siblines from the affected side of families selected for unilineal, autosomal dominant-like inheritance of schizophrenia were studied (n = 186). Across generations more subjects were hospitalized with psychotic illness (P<.0001), at progressively earlier ages (P<.0001), and with increasing severity of illness (P<.0003). The results indicate that anticipation is present in familial schizophrenia. These findings support both an active search for unstable trinucleotide repeat sequences in schizophrenia and reconsideration of the genetic model used for linkage studies in this disorder. 32 refs., 2 figs., 1 tab.

Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight families.

Abstract: We describe 54 members of eight families with a distinct autosomal dominant cerebellar ataxia associated with visual failure secondary to a pigmentary macular dystrophy. The presenting symptom was ataxia in two-thirds of patients and visual failure or both in the remainder. The macular abnormalities were often subtle in early cases, even in some with moderately reduced visual acuity. Other neurological features included pyramidal tract signs and a supranuclear ophthalmoplegia with progressive saccadic palsy. Ages of onset and clinical course were very variable, even within families, and included a rapidly progressive, infantile-onset phenotype. Pedigree analysis showed the existence of non-manifesting obligate carriers and anticipation in the offspring of affected fathers; transmission of the disease to severe, infantile-onset cases was always from an affected father. Similar genetic phenomena have been reported in myotonic dystrophy and Huntington's disease and it is likely that the gene mutation in this condition will similarly consist of an unstable trinucleotide repeat expansion.

Anticipation in Swedish families with bipolar affective disorder.

Abstract: Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity or decrease in age at onset or both in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in different disorders. We have studied differences of age at onset and disease severity between two generations in 14 families with unilinear inheritance of bipolar affective disorder (BPAD). There was a significant difference in age at onset (p < 0.008), in episodes per year with (p < 0.006) and without (p < 0.03) lithium treatment, and in total episodes per year (p < 0.002) between generations I and II. Furthermore, there was a highly significant correlation (p < 0.001) in age at onset between generations I and II. No evidence for specific paternal or maternal inheritance was found. We found evidence of anticipation and could rule out ascertainment bias or some other artefact. Anticipation is thus an inheritance pattern in BPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in BPAD.

Apparent regression of the CGG repeat in FMR1 to an allele of normal size.

Abstract: The fragile X syndrome is the result of amplification of a CGG trinucleotide repeat in the FMR1 gene and anticipation in this disease is caused by an intergenerational expansion of this repeat. Although regression of a CGG repeat in the premutation range is not uncommon, regression from a full premutation (>200 repeats) or premutation range (50–200 repeats) to a repeat of normal size (<50 repeats) has not yet been documented. We present here a family in which the number of repeats apparently regressed from approximately 110 in the mother to 44 in her daughter. Although the CGG repeat of the daughter is in the normal range, she is a carrier of the fragile X mutation based upon the segregation pattern of Xq27 markers flanking FMR1. It is unclear, however, whether this allele of 44 repeats will be stably transmitted, as the daughter has as yet no progeny. Nevertheless, the size range between normal alleles and premutation alleles overlap, a factor that complicates genetic counseling.

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.

Anticipation in hereditary dentatorubral-pallidoluysian atrophy

Abstract: Anticipation refers to the progressively earlier onset and increase in disease severity in successive generations. We studied four families with hereditary dentatorubral-pallidoluysian atrophy (DRPLA), a neurodegenerative disease, and anticipation was present in the mode of inheritance. In subsequent generations DRPLA shows an earlier onset and more severe as well as additional symptoms. Older onset patients suffer from cerebellar ataxia with or without dementia, whereas younger onset patients present as progressive myoclonus epilepsy syndrome, which consists of mental retardation, dementia, and cerebellar ataxia as well as epilepsy and myoclonus. Anticipation with paternal transmission was significantly greater than with maternal transmission.

Anticipation resulting in elimination of the myotonic dystrophy gene: a follow up study of one extended family.

Abstract: We have re-examined an extended myotonic dystrophy (DM) family, previously described in 1955, in order to study the long term effects of anticipation in DM and in particular the implications for families affected by this disease. This follow up study provides data on 35 gene carriers and 46 asymptomatic at risk family members in five generations. Clinical anticipation, defined as the cascade of mild, adult, childhood, or congenital disease in subsequent generations, appeared to be a relentless process, occurring in all affected branches of the family. The cascade was found to proceed asynchronously in the different branches, mainly because of an unequal number of generations with mild disease. The transition from the mild to the adult type was associated with transmission through a male parent. Stable transmission of the asymptomatic/mild phenotype showed a female transmission bias. We further examined the extent and causes of gene loss in this pedigree. Gene loss in the patient group was complete, owing to infertility of the male patients with adult onset disease and the fact that mentally retarded patients did not procreate. Out of the 46 at risk subjects in the two youngest generations, only one was found to have a full mutation. This is the only subject who may transmit the gene to the sixth generation. No protomutation carriers were found in the fourth and fifth generations. Therefore it is highly probable that the DM gene will be eliminated from this pedigree within one generation. The high population frequency of DM can at present not be explained by the contribution of asymptomatic cases in the younger generations of known families, but is probably caused by the events in the ancestral generations.

Molecular genetics of hereditary ataxias.

Abstract: The hereditary ataxias are a very heterogeneous group of disorders characterized by cerebellar dysfunction that can be either isolated or accompanied by other neurological manifestations. The classification of the hereditary ataxias based on clinical or histopathological findings has been difficult because of the significant overlap of phenotypes among the various genotypes. The patterns of inheritance observed in ataxias include autosomal dominant, autosomal recessive and X-linked. Friedreich's ataxia, the most frequent form among the recessive ataxias, has been mapped to the long arm of chromosome 9 based on close linkage to the markers D9S5 and D9S15. This close linkage allows the use of these two DNA markers for prenatal diagnosis in families with one affected offspring. In the past year, significant research progress has been accomplished by applying molecular genetic studies to the dominantly inherited spinocerebellar ataxias. Spinocerebellar ataxia type 1 (SCA1), which maps to the short arm of chromosome 6, has been found to be caused by expansion of an unstable trinucleotide (CAG) repeat. This mutational mechanism explains the presence of the clinical phenomenon of anticipation in some families with SCA1. The finding of an unstable repeat in SCA1 will facilitate the diagnosis of SCA1 in familial and isolated cases and will allow preclinical and prenatal diagnosis in families with this disease. In addition to the cloning of the SCA1 gene, two dominantly inherited ataxias have been genetically mapped: SCA2, to the long arm of chromosome 12, and Machado-Joseph disease (MJD), to the long arm of chromosome 14. Given that anticipation has been observed in patients with SCA2 and MJD, it is likely that trinucleotide repeat expansion could be a common mechanism involved in all the spinocerebellar ataxias. Last, significant research progress has been accomplished in the field of hereditary ataxias associated with DNA repair defects which should facilitate our understanding of mechanisms involved in cerebellar degeneration.

Anticipation in Myotonic Dystrophy: A Parental-Sex-Related Phenomenon

Abstract: We report anticipation in an extensive sample of myotonic dystrophy (MyD) kindreds taken from an epidemiological survey recently conducted in Guipuzcoa, Spain. Analysis of the parent-child pairs ascertained showed a mean anticipation of 2.86 decades (range 0-6). Greater anticipation occurred when the transmissor parent was the mother. These results suggest a possible sex-related effect in the transmission of the MyD gene, and are in agreement with recent discoveries at the molecular level.

A dominant spinocerebellar ataxia gene (SCA5) in a family descendent from the paternal grandparents of President Lincoln maps to chromosome 11

Abstract: Four different genes that cause spinocerebellar ataxia (SCA1, SCA2, Machado Joseph`s Disease (MJD)/SCA3 and SCA4) have been mapped to chromosomes 6p, 12q, 14q, and 16q, respectively. We have examined and collected 170 individuals (56 affected) from a previously unreported 10 generation kindred (the Lincoln Family) with a dominant ataxia that is clinically and genetically distinct from those previously mapped. The family has two major branches from Indiana and Kentucky. Of historical interest is that both branches descend from the paternal grandparents of President Abraham Lincoln. While the ataxia in this kindred is disabling, the most striking clinical distinction from SCA1, SCA2 and MJD/SCA3 is that it is generally not life threatening. This clinical difference is explained by the absence of bulbar paralysis and lower motor neuron degeneration that causes respiratory muscle weakness. We have mapped the gene, SCA5, using microsatellite markers spaced at 20-40 cM intervals throughout the genome. After 75 markers, the first to demonstrate a lod score greater than 3.0 was D11S871 (Zmax=5.05). Four additional markers from the centromeric region of chromosome 11 also gave lod scores greater than 3. The highest lod scores were 12.3 for both D11S905 ({theta}=0.056) and D11S913 ({theta}=0.030). Multipoint linkage and haplotype analysesmore » indicate the most likely location for SCA5 is within the 7 cM interval between GATA2A01 and D11S913. A statistical analysis of the age of onset of parent-offspring pairs within the family supports (p<0.0002) the presence of anticipation. Several dramatic examples of anticipation have been observed in which grandmothers have onsets 10-20 years later in life than their daughters who have onsets 10-20 years later than their children. Interestingly, all four of the juvenile onset cases are maternally inherited, suggesting a maternal bias in anticipation for SCA5 rather than a paternal bias as seen with SCA1.« less

Correlation between degrees of the CTG repeat expansion and clinical features of myotonic dystrophy

Abstract: The mutation in myotonic dystrophy gene has recently been identified as an unstable expansion of trinucleotide CTG repeat located at the 3'-untranslated region of myotonin protein kinase gene. In this paper we report the correlation between the degree of CTG amplification and clinical features in 35 individuals with myotonic dystrophy. The analysis of CTG repeat expansion was performed with Southern blot hybridization. Genomic DNA from peripheral blood leukocytes was digested with a restriction endonuclease, Pst I, instead of commonly used EcoRI. Since small expansion (about 100 bp) could be detected with PstI digestion and furthermore, the DNA fragment did not contain insertion/deletion polymorphism, we were able to accurately determine the exact sizes of CTG repeat expansion. We have observed a tendency of earlier ages of onset with larger allele sizes. The good correlation between the size of the expansion and the severity in muscle weakness was clearly demonstrated especially if the analysis was focused on the patients at same age group at 40-45 years. The severity of motor disability was classified into three stages. The mean size of expansion was 0.33 +/- 0.17 (M +/- SD) kbp in stage I, 2.58 +/- 1.42 kbp in stage II, and 4.75 +/- 0.93 kbp in stage III. The tendency was also observed when patients were categorized according to the intellectual grade. The anticipation was observed in all the parent-child pairs. When the increases of the repeat expansions were compared between father-child and mother-child transmissions, broader variation of the increases was observed in father-child transmissions.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence suggesting possible SCA1 gene involvement in schizophrenia

Abstract: Several findings suggest a possible role for the SCA1 gene on chromosome 6p in some cases of schizophrenia. First, linkage analyses in Irish pedigrees provided LOD scores up to 3.0 for one model tested using microsatellites closely linked to SCA1. Reanalysis of these data using affected sibpair methods yielded a significant result (p = 0.01) for one marker. An attempt to replicate this linkage finding was made using 44 NIMH families (206 individuals, 80 affected) and 12 Utah families (120 individuals, 49 affected). LOD scores were negative in these new families, even allowing for heterogeneity, as were results using affected sibpair methods. However, one Utah family provided a LOD score of 1.3. We also screened the SCA1 trinucleotide repeat to search for expansions characteristic of this disorder in these families and in 38 additional unrelated schizophrenics. We found 1 schizophrenic with 41 repeats, which is substantially larger than the maximum size of 36 repeats observed in previous studies of several hundred controls. We are now assessing whether the distribution of SCA1 repeats differs significantly in schizophrenia versus controls. Recent reports suggest possible anticipation in schizophrenia (also characteristic of SCA1) and a few cases of psychiatric symptoms suggesting schizophrenia have beenmore » observed in the highly related disorder DRPLA (SCA2), which is also based on trinucleotide repeat expansion. These findings suggest that further investigations of this gene and chromosome region may be a priority.« less

Heritable trinucleotide repeats and neurological disorders

Abstract: In the past 3 years, seven human neurological disorders have been found to be associated with an abnormal number of unstable trinucleotide repeats within exons or non-expressed regions of a gene. These forms of mutations are called dynamic mutations. The expansion in copy number of trinucleotide repeats may represent a large number of hereditary disorders. The correlation between the length of the repeated size and the disease severity and variable onset has provided some genetic explanation for a phenomenon called anticipation. However, there are numerous questions which cannot be explained by anticipation. Many other factors such as genomic imprinting and variable DNA methylation may also contribute to the puzzling features of these phenotypes.

Trinucleotide repeat expansion and DRPLA (Smith`s disease): Molecular characterization of atrophin-1

Abstract: Smith`s disease (also known as dentatorubral pallidoluysian atrophy or DRPLA) is a rare, progressive, fatal neuropsychiatric disorder similar to Huntington`s disease (HD). Smith`s disease is characterized by ataxia, choreoathetosis, myoclonic epilepsy, dementia, and genetic anticipation. Neuropathological findings include prominent cell loss in the dentate nucleus of the cerebellum, the globus pallidus, the red nucleus, and the subthalamic nucleus. An expansion of a CAG trinucleotide repeat encoding polyglutamine in a gene originally identified in our laboratory as part of a program to clone candidate genes for disorders with anticipation has recently been found to cause this disorder. We have identified two families that demonstrate the pathological and genetic features (expanded CAG repeat and anticipation) of this disease. Northern analysis indicates that the gene, which we have termed atrophin-1, is widely expressed as a 5 kb mRNA in normal human brain and peripheral tissues. Brain expression is highest in the cerebellum. The developmental expression of the rat homologues of IT-15 (the gene in which a CAG expansion causes HD) and atrophin-1 were compared. Atrophin-1 was most highly expressed in early rat embryo brain (E16), whereas the greatest expression of IT-15 was in the adult rat brain. Cloning and sequencing of the openmore » reading frame from inserts contained in brain cDNA libraries is in progress. In addition to the CAG repeat, the ORF contains an unusual region of alternating acidic and basic amino acids. Further characterization of atrophin-1, and comparison of it to other genes in which trinucleotide repeat expansion leads to neuropsychiatric disorders, should lead to a better understanding of the pathophysiology by which CAG repeat expansion causes human disease.« less

Molecular Mechanisms of Non-Mendelian Inheritance in Genetic Diseases

Abstract: Recently identified molecular mechanisms (mitochondrial DNA mutations, genomic imprinting, uniparental disomy, unstable trinucleotide repeats) responsible for the non-Mendelian patterns of some genetic diseases are reviewed. Among the diseases considered are LHON (Leber’s hereditary optic neuropathy), MERRF (myoclonic epilepsy with ragged-red fibers), MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), Prader-Willi syndrome, Angelman syndrome, fragile-X syndrome, myotonic dystrophy, as well as others.

Anticipation inSwedish families withbipolar affective disorder

Abstract: Anticipation describes aninheritance patternwithin apedigree withanincrease in disease severity ordecrease inageatonset orbothinsuccessive generations. The phenomenonofanticipation hasrecently beenshowntobecorrelated withtheexpansion oftrinucleotide repeat sequences indifferent disorders. We havestudied differences ofageatonsetanddisease severity betweentwogenerations in14 families withunilinear inheritance ofbipolaraffective disorder (BPAD). Therewasasignificant difference inage atonset(p<0008), inepisodes peryear with(p<0006) andwithout (p<003)lithiumtreatment, andintotal episodes per year(p<0002) betweengenerations Iand II.Furthermore, therewasa highlysignificant correlation (p<0001)inageat onsetbetweengenerations IandII.No evidence forspecific paternal ormaternal inheritance wasfound. We foundevidence ofanticipation and couldruleoutascertainment biasorsome otherartefact. Anticipation isthusaninheritance pattern inBPAD whichsuggests thattheexpansion oftrinucleotide repeat sequencesisa possible mode of inheritance inBPAD.

Myotonic dystrophy: analysis of clinical-genetic correlation in a parent-child pair

Abstract: We report the case of a child with myotonic dystrophy (DM) with symptoms begining at the age of seven, whose genetic study showed an additional DNA fragment, greater than of his father, an asymptomatic carrier. The clinical and molecular analysis of this parent-child pair are probably the first described in Brazil, since the recent discovery of genetic abnormality in DM by American and European researchers, that explained the long-debated phenomenon of "anticipation" in this disease. The main advances in molecular genetics in DM and its correlation with increasing severity and earlier onset of the symptoms in sucessive generations of a family are commented briefly.