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Biomedical subjects

P M Conneally

Publications and source records attributed to P M Conneally.

At least 19 recordsLinked to original sources
PubMed1996

No genetic effect of alpha1-antichymotrypsin in Alzheimer disease.

Alzheimer disease (AD) is the most common neurodegenerative disorder for individuals over the age of 40. AD has a complex etiology, and it is likely that multiple genes, acting independently and/or interacting, affect the risk of developing AD. Several genes involved with AD have been described already, but only the APOE gene on chromosome 19q has been shown to affect the risk of the common late onset form of AD. alpha1-Antichymotrypsin (AACT) is a major component of the amyloid plaques found in the brains of AD patients, and an allele in its gene has been proposed to increase the risk of developing AD when also associated with the APOE-4 allele. We have examined the role of this AACT polymorphism in a large set of families and sporadic cases, and do not see any effect, either alone or in combination with the APOE-4 allele.

Alzheimer Disease↗
PubMed1995

Cognitive scores in carriers of Huntington's disease gene compared to noncarriers.

Huntington's disease (HD) is a progressive neurodegenerative disorder recently shown to be due to an excess number of CAG trinucleotide repeats in the 5' translated region of chromosome 4. One of the cardinal features of HD is cognitive decline. While mental deterioration is obvious later in the disease course, the time of its onset is difficult to determine precisely. A sample of at-risk individuals without signs or symptoms of HD by self-report was studied. The Wechsler Adult Intelligence Test--Revised and a neurological rating scale were administered. The genotypes of 394 individuals were then determined by polymerase chain reaction testing. On all portions of the WAIS-R test, the mean score of the HD gene carriers was lower than that of the noncarriers. Scores on two of the performance subtests, the digit symbol and the picture arrangement, were significantly different in the two groups, even after the scores from all gene carriers who were diagnosed as affected based on their neurological motor examination were removed. The scores for the gene carriers on the various subtests were negatively correlated with the number of CAG repeats in the expanded HD allele. Such a relationship was not seen with the normal alleles of the noncarriers. Taken together, our results suggest that a deficit in cognitive function is an early finding of HD and that in this patient population, the degree of cognitive deficit is proportional to the number of CAG repeats in the HD allele.

Adult↗
PubMed1995

Apolipoprotein E4 allele and Alzheimer disease: examination of allelic association and effect on age at onset in both early- and late-onset cases.

An increased frequency of the apolipoprotein E type 4 allele (APOE-4) has previously been associated with both late-onset sporadic and late-onset familial Alzheimer disease (AD) [Strittmatter et al. (1993) Proc Natl Acad Sci USA 90:1977-1981; Saunders et al. (1993a) Neurology 43:1467-1472]. To further investigate this association we genotyped affected individuals from 92 separate AD pedigrees including both early- and late-onset cases. An increased frequency of the APOE-4 allele was found only among the late-onset cases, both familial and sporadic, confirming the earlier reports. In addition, age at onset was significantly decreased in the APOE-4 homozygotes (in late onset families) compared to either APOE-4 heterozygotes or individuals not carrying an APOE-4 allele. We also observed a significantly decreased frequency of the APOE-2 allele in both the early- and late-onset familial cases. These results strengthen the argument for a direct role of APOE in susceptibility to AD.

Age of Onset↗
PubMed1995

Genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy in a genetic isolate (Amish) and evidence for a new locus.

Limb-girdle muscular dystrophy (LGMD) is a hereditary myopathy presenting clinical and genetic heterogeneity. In 1991, a recessive form (LGMD2A) was linked to chromosome 15q in a genetic isolate from the Isle of La Réunion. Confirmation of this localization was subsequently reported in Brazilian and northern Indiana Amish pedigrees. Here we report the exclusion of the LGMD2A locus in six Amish kindreds from southern Indiana that are related by multiple consanguineous links to the same northern Indiana families in which the involvement of the chromosome 15 locus was previously demonstrated. These findings indicate unexpected genetic heterogeneity of LGMD in an Indiana Amish isolate. Furthermore, genetic analyses also ruled out the possible involvement of the chromosome 2 locus recently described (LGMD2B), thus demonstrating that a mutation within at least one additional locus leads to this condition. Several candidate genes putatively involved in neuromuscular disorders were also excluded.

Chromosomes, Human, Pair 15↗
PubMed1995

Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension.

The genetic basis of familial primary pulmonary hypertension (FPPH) is unknown, but the clinical and pathologic features are the same as in sporadically occurring primary pulmonary hypertension (PPH). Because few families with this disease have been reported, the mode of inheritance and genetic features have not been clearly established. We previously reported a tendency for decreasing age of onset in subsequent generations of affected families. The purpose of this study was to examine the pattern of inheritance in a large number of families in an attempt to find clues to pathogenesis. From 24 families we studied 429 members, 124 of whom were known to carry the gene for disease. We constructed cumulative mortality curves for each gender of the 99 affected individuals. We analyzed gender ratios of progeny of affected members and carriers and compared age at death of affected members by generation. More females (160) than males (122) were born to persons carrying the gene, p < 0.01, suggesting selective wastage of male fetuses or an abnormal primary sex ratio. Genetic anticipation was confirmed; the age at death was 45.6 +/- 14.5 versus 36.3 +/- 12.6 versus 24.2 +/- 11 standard deviation (SD) years in successive generations, p < 0.05. Five cases of male-to-male transmission were observed, excluding X-linkage. Age at death was the same for males and females. More females had the gene (84 females, 40 males) and more females with the gene developed disease (72 of 84 females [86%] versus 27 of 40 males [68%]). The disease has highly variable penetrance among families.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risks of death and Alzheimer's disease.

The apolipoprotein E (APOE) epsilon 4 allele carries an increased risk of a patient developing Alzheimer's disease (AD) while the epsilon 2 allele carries a decreased risk. We compared survival from the onset of AD in subjects with different numbers of epsilon 4 alleles and evaluated changes in genotypic frequencies with age. Two subject groups were investigated: unrelated AD case and control subjects, and affected and unaffected members from 74 multiplex AD families. In both subject groups, survival from onset decreased with increasing onset age, was longer in women, and was unrelated to epsilon 4 gene dose. The epsilon 2/epsilon 3 genotype became more common with age (p = 0.004). The epsilon 4 allele decreased in frequency with age in all patient groups but, unexpectedly, remained unchanged in control subjects. We conclude that the progression of AD is not strongly related to epsilon 4 gene dose, that the higher prevalence of AD in women may involve the longer survival of affected women, and that AD and death are competing risks involving APOE that change over time.

Age of Onset↗
PubMed1994

Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease.

Gene dosage of the apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60). Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families. Our data demonstrate a protective effect of the epsilon 2 allele, in addition to the dose effect of the epsilon 4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of epsilon 4 alleles, risk of AD is lowest in subjects with the epsilon 2/epsilon 3 genotype, with an additional 23% of AD attributable to the absence of an epsilon 2 allele. The opposite actions of the epsilon 2 and epsilon 4 alleles further support the direct involvement of APOE in the pathogenesis of AD.

Age of Onset↗
PubMed1994

Human genetic polymorphisms.

Mutations in the human genome lead to genetic polymorphisms in the population. While many of these are considered to be normal variants, many lead to human disease and are usually maintained in the population by a balance between mutation and selection. The frequency and type of mutations have been determined for a number of loci in man. The frequency of mutation in transgenes is now receiving considerable attention, since proteins synthesized in recombinant DNA biological systems are subject to genetic alteration through mutation and selection. These changes can occur in the transgene, but mutations in the host cell genes can also produce structural modifications for example, by changes in post-translational modification. Mutation rates for human genes may be as high as 10(-5) per locus per generation. Spontaneous mutations that inactivate gene function in bacteria occur at a rate of 10(-5)-10(-6) per locus per generation. On the other hand the frequency of spontaneous mutations per nucleotide is two orders of magnitude less (usually less than 10(-7)).

DNA↗
PubMed1993

A genetic linkage map of the chromosome 4 short arm.

We have generated an 18-interval contiguous genetic linkage map of human chromosome 4 spanning the entire short arm and proximal long arm. Fifty-seven polymorphisms, representing 42 loci, were analyzed in the Venezuelan reference pedigree. The markers included seven genes (ADRA2C, ALB, GABRB1, GC, HOX7, IDUA, QDPR), one pseudogene (RAF1P1), and 34 anonymous DNA loci. Four loci were represented by microsatellite polymorphisms and one (GC) was expressed as a protein polymorphism. The remainder were genotyped based on restriction fragment length polymorphism. The sex-averaged map covered 123 cM. Significant differences in sex-specific rates of recombination were observed only in the pericentromeric and proximal long arm regions, but these contributed to different overall map lengths of 115 cM in males and 138 cM in females. This map provides 19 reference points along chromosome 4 that will be particularly useful in anchoring and seeding physical mapping studies and in aiding in disease studies.

Base Sequence↗
PubMed1993

Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene.

P0, a major structural protein of peripheral myelin, is a homophilic adhesion molecule and maps to chromosome 1q22-q23, in the region of the locus for Charcot-Marie-Tooth neuropathy type 1B (CMT1B). We have investigated P0 as a candidate gene in two pedigrees with CMT1B and found point mutations which are completely linked with the disease (Z = 5.5, theta = 0). The mutations, glutamate substitution for lysine 96 or aspartate 90, are located in the extracellular domain, which plays a significant role in myelin membrane adhesion. Individuals with CMT1B are heterozygous for the normal allele and the mutant allele. Our results indicate that P0 is a gene responsible for CMT1B.

Alleles↗
PubMed1993

Gametic but not somatic instability of CAG repeat length in Huntington's disease.

Instability of a CAG repeat in 4p16.3 has been found in Huntington's disease (HD) chromosomes. Unlike a similar repeat in the fragile X syndrome, the expanded HD repeat showed no evidence of somatic instability in a comparison of blood, lymphoblast, and brain DNA from the same persons. Four pairs of monozygotic HD twins displayed identical CAG repeat lengths suggesting that repeat size is determined in gametogenesis. In contrast with the fragile X syndrome and with HD somatic tissue, mosaicism was readily detected as a diffuse spread of repeat lengths in DNA from HD sperm samples. Typically, the modal repeat size was larger in the sperm DNA than in corresponding lymphoblast DNA, with the greatest degree of gametic mosaicism coinciding with the longest somatic CAG repeats. These data indicate that the developmental timing of repeat instability appears to differ between HD and fragile X syndrome, and that the fundamental mechanisms leading to repeat expansion may therefore be distinct.

Adolescent↗
PubMed1993

Onset symptoms in 510 patients with Huntington's disease.

The onset of Huntington's disease (HD) is preceded or accompanied by events and symptoms which contribute to the natural history of the disease. Data obtained from the first 510 completed 'Questionnaires for Affected Individuals', recorded by the National Huntington's Disease Research Roster (NHDRR) were analysed. The following features were evaluated: (1) neurological and psychiatric onset symptoms; (2) the precipitating effect of stressful events and drugs; (3) the modification after onset of smoking and alcohol consumption. The most frequent psychiatric onset symptom was depression. Stressful events in the year before onset occurred in 43% of patients. However, onset age was the same in patients with and without previous stressful events. Smoking and especially alcohol consumption showed a decreasing trend after onset.

Adolescent↗
PubMed1993

Suicide risk in Huntington's disease.

In order to evaluate the relevance of suicide risk in families affected by Huntington's disease (HD), 2793 subjects registered with the National Huntington's Disease Research Roster were studied. Suicide was the reported cause of death in 205 subjects (7.3%). This group included affected and possibly affected subjects, subjects at 50% and 25% risk, possibly at risk subjects, and normal relatives. In all categories suicide was more frequent than in the general US population. The data suggest that suicide is quite frequent in some families with HD. This increased suicide risk must be carefully considered in planning genetic counselling for predictive testing in HD.

Adult↗
PubMed1993

Limb-girdle muscular dystrophy is closely linked to the fibrillin locus on chromosome 15.

Limb-girdle Muscular Dystrophy (LGMD) is a rare form of muscular dystrophy inherited as an autosomal recessive trait. The LGMD locus was recently mapped to chromosome 15. We tested the hypothesis that fibrillin is a candidate in the etiology of the disorder by genetic linkage analysis. A large Amish kindred segregating the disorder was genotyped for two markers specific for the fibrillin gene on chromosome 15. A total of 105 individuals were genotyped and a maximum LOD score of Z = 9. 135 at theta = 0.04 was obtained. Our results confirmed the mapping of the LGMD on chromosome 15 and excluded fibrillin as a candidate molecule. These data will be useful in the construction of a fine map of the region surrounding the LGMD locus, a prerequisite for the cloning of the LGMD gene.

Base Sequence↗
PubMed1993

The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD.

We evaluated the hypothesis that Huntington disease (HD) is influenced by the normal HD allele by comparing transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring. Analysis of information from 21 sibships in 14 kindreds showed a significant tendency for sibs who have similar onset ages to share the same D4S10 allele from the normal parent. Affected sibs who inherited different D4S10 alleles from the normal parent tended to have more variable ages at onset. These findings suggest that the expression of HD is modulated by the normal HD allele or by a closely linked locus.

Adolescent↗
PubMed1992

Linkage of the Indiana kindred of Gerstmann-Sträussler-Scheinker disease to the prion protein gene.

The Indiana kindred variant of Gerstmann-Sträussler-Scheinker disease has amyloid plaques that contain prion protein (PrP), but is atypical because neurofibrillary tangles like those of Alzheimer disease are present. To map the position of the disease causing gene, we used three markers for linkage analyses. A missense mutation at codon 198 of the PrP gene (PRNP) is found in all definitely affected individuals and yields a maximum lod score of 6.37 (theta = 0). The disease also is concordant with the two other PRNP-region markers. These results demonstrate tight linkage of the disease-causing gene to PRNP and support the hypothesis that the codon 198 mutation is the cause of IK-GSS. Our studies also suggest that methionine/valine heterozygotes at PRNP codon 129 have a later age of onset of the disease than codon 129 valine/valine homozygotes.

Adult↗