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M Mullan

Publications and source records attributed to M Mullan.

At least 73 records · Page 4Linked to original sources
PubMed1996

beta-Amyloid-mediated vasoactivity and vascular endothelial damage.

Deposits of beta-amyloid are apparent in ageing and Alzheimer's disease, but the role of this peptide in neurodegeneration is unclear. The free-radical theory of ageing may also account for Alzheimer-type degeneration and consequently links between free-radical generation and beta-amyloid have been sought. We demonstrate here that beta-amyloid interacts with endothelial cells on blood vessels to produce and excess of superoxide radicals, with attendant alterations in endothelial structure and function. The superoxide radical can scavenge endothelium-derived relaxing factor and produce potent oxidizing agents, which can cause lipid peroxidation and other degenerative changes. The alterations in vascular tone and endothelial damage are prevented by the oxygen-radical-scavenging enzyme superoxide dismutase. These observations suggest a normal vasoactive role for beta-amyloid as well as a mechanism by which beta-amyloid may play a role in vascular abnormalities and neurodegeneration mediated by free radicals.

Acetylcholine↗
PubMed1995

Occurrence of the Cys311 DRD2 variant in a pedigree multiply affected with panic disorder.

Following the detection of the rare DRD2 codon 311 variant (Ser-->Cys) in an affected member from a large, multiply affected panic disorder family, we investigated the occurrence of this variant in other family members. The variant occurred in both affected and unaffected individuals. Further screening in panic disorder sib pairs unrelated to this family failed to detect the Cys311 variant. Our data suggests that this variant has no pathogenic role in panic disorder.

Base Sequence↗
PubMed1995

Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer's Disease but is not causative.

An association has been observed in several independent data sets between late onset Alzheimer's Disease (AD) and the APOE locus on chromosome 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the epsilon 4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and non-stringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease free survival suggested that APOE genotype contributes a small fraction of the total variance indicating that the APOE locus is a poor predictor of disease free survival age within late onset families. One explanation for the age dependent association reported by other groups, and our results, is that the APOE locus enhances the rate of progression of the disease process in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause the disease. We suggest this hypothesis is compatible with the current literature regarding APOE and AD.

Age Factors↗
PubMed1995

Clinical features of early onset, familial Alzheimer's disease linked to chromosome 14.

Early onset familial Alzheimer's disease (AD) has an autosomal dominant mode of inheritance. Two genes are responsible for the majority of cases of this subtype of AD. Mutations in the beta-amyloid precursor protein (beta APP) gene on chromosome 21 have been shown to completely cosegregate with the disease. We and others have previously described the clinical features of families with beta APP mutations at the codon 717 locus in an attempt to define the phenotype associated with a valine to isoleucine (Val-->Ile) or a valine to glycine (Val-->Gly) change. More recently, a second locus for very early onset disease has been localized to chromosome 14. The results of linkage studies in some families suggesting linkage to both chromosomes have been explained by the suggestion of a second (centromeric) locus on chromosome 21. Here we report the clinical features and genetic analysis of a British pedigree (F74) with early onset AD in which neither the beta APP locus nor any other chromosome 21 locus segregates with the disease, but in which good evidence is seen for linkage on the long arm of chromosome 14. In particular we report marker data suggesting that the chromosome 14 disease locus is close to D14S43 and D14S77. Given the likelihood that F74 represents a chromosome 14 linked family, we describe the clinical features and make a limited clinical comparison with the beta APP717 Val-->Ile and beta APP717 Val-->Gly encoded families that have been previously described.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Association of apolipoprotein E but not B with Alzheimer's disease.

In our studies apolipoprotein E4 (APOE4) is associated with both early- and late-onset Alzheimer's disease. Alzheimer's patients from West Texas were screened for the APOE4 allele, which was found at frequencies of 0.43 and 0.59 in familial late- and early-onset cases. Sporadic cases had lower frequencies, but they still were 2-4 times higher than control spouses. To determine whether the APOE association may be a risk factor for coronary disease as well, we examined two APOB gene restriction sites that have previously been found to be associated with coronary artery disease, especially myocardial infarctions. The APOB alleles were found at similar frequencies in Alzheimer's patients and control spouses.

Aged↗
PubMed1994

Technical feasibility of genetic testing for Alzheimer's disease.

This article examines the feasibility of using molecular genetic information for diagnostic and predictive testing in Alzheimer's disease (AD). The scope is limited largely to early onset familial cases, but a brief update on genetic research in late onset disease is included. The usefulness and accuracy of such testing is determined by the results and interpretation of current research data which are presented herein. The ethical and legal issues implicated in such procedures are not covered but are examined elsewhere in this issue. During the course of the genetic analysis of AD, it has become clear that it is an etiologically heterogeneous disorder. In understanding the genetic predisposition to AD there should be continual attention to this message. Age of onset and familiality have emerged as the most useful clinical features demarcating subgroups with common origins. At least two genes predispose (independently) to early onset familial AD: the beta-amyloid precursor protein gene (beta APP) and an unidentified gene on chromosome 14. Germ line mutations in these genes act dominantly. The accurate use of genetic data in AD, for diagnostic, screening and predictive purposes relies on the most up-to-date knowledge of the transmission of the disorder in relation to mutations in these genes. The interpretation of genetic data is examined for each of the known early onset genes. In addition, we review the data pertaining to late onset disease and risk conferred by the APOE locus to both familial and nonfamilial cases. The use of these data in genetic risk analysis must be reserved until a full explanation of the association and its meaning is forthcoming. Isolated cases of AD occur at all ages of onset, but no AD mutations in the beta APP gene have yet been identified in isolated cases.

Adult↗
PubMed1994

Physical and genetic map of 5q31: use of fluorescence in situ hybridization data to identify errors in the CEPH database. Centre d'Etude de Polymorphisme Humain.

Chromosome 5, band q31, contains the genes responsible for a number of interesting genetic and malignant diseases, as well as many cloned genes. To prepare a high-resolution map of this region, eight anonymous DNA markers were mapped by combining genetic data derived from linkage analysis, with physical data obtained using two-color fluorescent in situ hybridization (FISH). Probe order was determined by FISH on metaphase cells, supplemented with interphase analysis, while genetic distance and likely order were determined by multipoint linkage analysis using genotype data from Centre d'Etude de Polymorphisme Humain (CEPH) pedigrees. Discrepancies between the genetic and physical maps suggested that there was a high rate of genotyping errors in the CEPH data for these markers, and prompted a statistical analysis to identify these errors. By assuming a known physical order (as determined by FISH) it was possible to identify markers which had the greatest degree of error. The average typing error was estimated at 1.8%, but several markers had much higher error rates; a 14% error rate was predicted for one locus, which was subsequently confirmed by retyping. The analysis led to the preparation of a revised map spanning 24.5 cM of 5q31. This study illustrates the power of FISH to determine physical order over a wide genomic distance, and demonstrates how order can be used as an adjunct to linkage analysis, particularly in the identification of genotyping errors.

Chromosome Mapping↗
PubMed1993

Age of onset in familial early onset Alzheimer's disease correlates with genetic aetiology.

Age of onset is the most robust clinical feature demarcating aetiologic subtypes of familial Alzheimer's disease. It has previously been noted that early onset disease (arbitrarily below the age of 65 years) conforms to an autosomal dominant pattern of transmission. Late onset disease is generally thought to have a more complex aetiology. We present data here suggesting that early onset disease can be subdivided by genetic aetiology with which age of onset correlates. In general, those pedigrees showing linkage to the chromosome 14 locus have a mean age of onset in the forties whereas those pedigrees with an APP mutation have an age of onset in the fifties.

Adult↗
PubMed1993

Screening for the APP codon 670/671 mutations in Alzheimer's disease.

A mutation at codons 670 and 671 of exon 16 of the amyloid precursor protein has recently been identified as a cause of early onset familial Alzheimer's disease. Using restriction enzyme digestion, screening failed to reveal the occurrence of this mutation in 43 families with early onset, 31 families with late onset, 30 cases of sporadic Alzheimer's disease or 30 clinically normal individuals.

Adult↗
PubMed1993

Genetic characterization of a familial non-specific dementia originating in Jutland, Denmark.

Dementias with non-specific pathological changes are a relatively common but under diagnosed form of presenile dementia. A high proportion of reported cases are familial. We report on molecular genetic findings in the largest known pedigree with this syndrome. We have excluded the mutations known to cause familial prion disease, APP-linked familial Alzheimer's disease and candidate regions for Huntington's disease, other forms of Alzheimer's disease and motor neuron disease. We have demonstrated that familial non-specific dementia is a novel genetic dementia.

Aged↗
PubMed1993

Genetic and molecular advances in Alzheimer's disease.

The abnormal deposition of amyloid beta protein (A beta) in the brain is the major neuropathological characteristic of Alzheimer's disease (AD). The disease in some early-onset familial cases develops as a result of mutations in the gene coding for the beta-amyloid precursor protein (beta APP) and in the majority of the rest appears to be caused by an unidentified gene on chromosome 14. Only one of the beta APP gene mutations has been associated with aberrant beta APP processing, resulting in an excess production of A beta in vitro, a result suggesting that there might be excessive A beta cleavage from beta APP in AD in vivo. By contrast with the beta APP mutants, no particular allele of the apolipoprotein E (APOE) gene predicts the disease completely but one allele is associated with the disease suggesting APOE is a risk locus for AD. This discovery has been linked to increased deposition of A beta in those cases carrying the risk allele. However, the genetic evidence is currently not sufficient to indicate whether beta APP mismetabolism, direct or indirect A beta neurotoxicity or dysfunction of beta APP (or its derivatives) are central to the AD process.

Age of Onset↗
PubMed1993

Familial Alzheimer's disease. A pedigree with a mis-sense mutation in the amyloid precursor protein gene (amyloid precursor protein 717 valine-->glycine).

Ten affected individuals are described from a kindred with autosomal dominant familial Alzheimer's disease in which a mutation in the amyloid precursor protein gene results in a valine to glycine substitution at amyloid precursor protein 717 which co-segregates with the disease. The mean age at onset of symptoms was 52 years with a range from 40 years to 67 years. The median duration of the disease was 11 years, with a range of 7-16 years. All individuals fulfilled the National Institute for Neurological and Communicative Disorders and Stroke criteria for probable Alzheimer's disease. A homogeneous clinical and neuropsychological pattern was evident within the family. Myoclonic jerks, seizures, depression and a lack of insight were common features. Positron emission tomography demonstrated biparietal bitemporal hypometabolism in the one affected individual who was studied. The diagnosis was confirmed histopathologically in one individual.

Adult↗
PubMed1992

Familial Alzheimer's disease with the amyloid precursor protein position 717 mutation and sporadic Alzheimer's disease have the same cytoskeletal pathology.

The cytoskeletal pathology of a patient with familial Alzheimer's disease (AD) associated with the probably causal amyloid precursor protein (APP) codon 717 Val----Ile mutation is described. In addition to moderately extensive beta A4 protein deposition within the substance of the brain and in blood vessel walls (congophilic angiopathy), there was abundant cytoskeletal pathology in the form of neurofibrillary tangles, plaque neurites and neuropil threads. Interestingly, plentiful cortical and subcortical Lewy bodies were also seen. In order to compare the cytoskeletal pathology in this case with that seen in sporadic cases of AD we (1) studied the immunohistochemical profile of the amyloid and cytoskeletal pathology with antibodies to beta A4 protein, tau, phosphorylated neurofilament epitopes and ubiquitin and (2) performed a biochemical fractionation and Western blot analysis for the abnormally phosphorylated form of tau (A68) characteristically seen in AD. No substantial difference between the familial case and sporadic cases could be found. We conclude that it is now reasonable to hypothesise that an abnormality in APP metabolism is responsible not only for the deposition of beta A4 protein, but also for the range of cytoskeletal pathology, typical of AD.

Alzheimer Disease↗
PubMed1992

A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.

Mutations at codon 717 in exon 17 of the beta-amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co-segregates with the disease in two large (probably related) early-onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of beta-amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the beta-amyloid sequence.

Alzheimer Disease↗
PubMed1992

A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene.

Although mutations in the beta-amyloid precursor protein gene (APP) on chromosome 21 cause some cases of early-onset Alzheimer's disease (AD), most cases evidently do not have mutations in APP. We analysed ten early-onset families for linkage to APP and markers elsewhere in the genome. One family (F172) was consistent with linkage to chromosome 21 and was subsequently found to have an APP Val to Ile mutation. Of the others, all but one were consistent with linkage to markers in the middle long arm of chromosome 14. However, no family showed independent evidence of linkage with two point analysis and only one showed independent evidence of linkage on multipoint analysis. Therefore, we cannot rule out heterogeneity at these loci although tests for heterogeneity were not significant.

Adult↗