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Biomedical subjects

M Mullan

Publications and source records attributed to M Mullan.

At least 91 records · Page 5Linked to original sources
PubMed1992

Inherited prion disease with 144 base pair gene insertion. 2. Clinical and pathological features.

A large family with autosomal dominant segregation of presenile dementia, and other neurological and behavioural features is described. At various times, family members have carried diagnoses of Alzheimer's disease, Huntington's disease, Parkinson's disease, myoclonic epilepsy, atypical dementia, Pick's disease, Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome. Molecular genetic studies have enabled classification of this disease at the molecular level as one of the group of inherited prion diseases. Here we describe the phenotype of inherited prion disease (PrP 144 bp insertion).

Adult↗
PubMed1992

Screening for mutations in the open reading frame and promoter of the beta-amyloid precursor protein gene in familial Alzheimer's disease: identification of a further family with APP717 Val-->Ile.

Following the identification of mutations in the beta-amyloid precursor protein (APP) gene in familial, early onset Alzheimer's disease (AD), we have developed a screening protocol using single strand conformation analysis (SSCA) to screen exon 17 for the known mutations within APP. In addition, we used this protocol to screen the other seventeen exons of APP and a three hundred and thirty base pair regulatory region of the promoter for new mutations in 9 families with early onset AD. Exons 16 and 17, which encode the deposited beta-amyloid peptide, were screened in a further 10 families. Our screening procedure identifies all the reported mutations within APP. While we have identified a further family with APP717 Val-->Ile, we did not find any previously undescribed mutations. Screening of other exons of APP in 2 families in which we have previously reported mutations at APP717, failed to reveal other sequence abnormalities supporting the hypothesis that the mutations at APP717 cause the disease in these families. These data suggest that mutations in APP are a rare cause of familial early onset AD (3/21 families tested) and that within APP most, possibly all, mutations which cause AD are in exon 17.

Adult↗
PubMed1992

Engaging patients with alcohol problems in treatment: the first consultation.

This paper considers the impact of the first consultation at a specialist alcohol clinic on patients' perceptions of their drink problem and on their expectations of help from three sources: an alcohol clinic, general practitioners and Alcoholics Anonymous. At intake, males had higher expectations than females of help from the alcohol clinic while people in manual occupations and those in the 'less heavy' drinking category had higher expectations of general practitioner help than other patients. Change was found to occur during the first clinic consultation so that by the end of the session patients had raised their rating of problem severity and their expectations of help from the three sources examined. Overall, patient perceptions of the clinic assessment session were positive. The study highlights the importance of obtaining a full understanding of the process of engagement in treatment and indicates the potential of a clinical assessment to effect change in patient attitudes.

Adult↗
PubMed1992

The use of services for alcohol problems: general practitioner and specialist alcohol clinic.

A sample of 40 patients referred to a specialist alcohol clinic were given a full assessment by a clinician and then randomly allocated to one of two groups. The first group received continuing care from the clinic. The second group were returned to the management of their general practitioners who were offered specialist support in caring for their patients. Patients and general practitioners were followed-up 6 months after the clinic assessment. This paper reports on the uptake of clinic and general practice services by patients and examines the possible factors associated with continuing attendance, including patient attributes, service activity, patients' self-assessments of their drink problem and their expectations of help from services. Qualitative data is used to examine patients' perceptions and experiences of clinic and general practice-based care for drinking problems. The findings highlight some of the difficulties reported by patients in receiving help for their problems particularly from general practitioners.

Adult↗
PubMed1991

Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene in 14 families with early onset Alzheimer's disease fails to reveal mutations in the beta-amyloid sequence.

A mutation within exon 17 at codon 717 of the beta-amyloid protein precursor (APP) gene is one cause of early onset familial Alzheimer's disease. Direct sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene in 14 families with familial early onset Alzheimer's disease without the known pathogenic mutation (APP717) failed to reveal other mutations within the beta-amyloid sequence in this form of the disorder.

Adult↗
PubMed1991

Screening for the beta-amyloid precursor protein mutation (APP717: Val----Ile) in extended pedigrees with early onset Alzheimer's disease.

Screening for the APP717 mutation in 5 further families with early onset Alzheimer's disease failed to reveal further cases with this variant. Screening a further 100 normal individuals for this mutation also failed to reveal further occurrences of this variant in the general population. Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene (the exons which encode the beta-amyloid fragment) in pedigree FAD4 revealed them to be of normal sequence. The significance of these observations to the genetics of Alzheimer's disease is discussed.

Alzheimer Disease↗
PubMed1991

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.

A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.

Alzheimer Disease↗
PubMed1991

Genetic characterization of a novel familial dementia.

Clinical and neuropathologic findings from a Danish family in which a dementing illness is segregating as an apparent autosomal dominant disorder were previously described (Gydesen et al. 1987). We present here genetic findings from this family in which linkage analysis has excluded Huntington's disease and chromosome 21-encoded Alzheimer's disease. None of the known prion mutations has been detected in affected individuals from this family. However, linkage analysis with the prion gene has been uninformative. This family probably represents a novel genetic dementia.

DNA Probes↗
PubMed1990

Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder.

Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.

Alzheimer Disease↗
PubMed1989

Alcoholism and the 'new genetics'.

Molecular biology is transforming our view of psychiatry. For the first time methods are becoming available to detect directly the genetic abnormalities leading to psychiatric illness. This article examines the ways in which the new marker technology might bridge the gap between classical genetic knowledge of alcoholism and the precise identification and localization of specific genes implicated in its aetiology.

Alcoholism↗
PubMedDate not supplied

The molecular genetics of Alzheimer's disease.

The major pathological characteristic of Alzheimer's disease (AD) is the abnormal deposition of beta-amyloid peptide (A beta) in the brain. In some early onset cases, the disease develops because of mutations in the gene coding for beta-amyloid precursor protein (beta APP). However, the majority of AD families in the early onset subgroup are linked to a locus on chromosome 14. The genetic analysis and age of onset correlates of both the beta APP gene and the chromosome 14 locus are discussed. We speculate on the mechanisms by which the beta APP mutations cause the disease and discuss recent advances in beta APP processing that may be relevant to the pathogenesis of the late-onset (common) form of the disease. In addition, we review the association of the APOE locus with late-onset familial and nonfamilial disease. Further work is required to establish the effects of this locus on disease occurrence, age of onset, and progression. The molecular pathology of ApoE in relation to AD development and the identification of the chromosome 14 gene will greatly contribute to a general pathogenic model of AD, and will clarify the role of beta APP and its derivatives.

Age of Onset↗
PubMedDate not supplied

Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val-->Ile mutation in the amyloid precursor protein gene.

Alzheimer's disease (AD) is the most common cause of dementia (32). Although the majority of cases of AD are sporadic, the most consistent risk factor detected in several epidemiological studies has been a positive family history of the disease (14,21). In addition, many large pedigrees have been described in which AD appears to be inherited as an autosomal dominant disorder. In one such pedigree (F23) a point mutation within the beta-amyloid precursor protein (APP) gene at codon 717 was identified and hypothesized to be pathogenic (10). The mutation results in a valine to isoleucine change in APP (APP717 Val-->Ile). Subsequent screening has revealed four other pedigrees, detailed in this study, in which this mutation co-segregates with AD (13,26,37). In addition, one other pedigree (Tor3) with this mutation has been described (15) and detailed clinical, neuropsychological, and neuropathological data are reported. Tor3 is discussed below in comparison to the findings in the families in this study. The five families we report with the mutation were identified in Britain (1 family), the United States (1 family), and Japan (3 families). The mutation has not been reported in the general population of any of these countries (3,13,26,33). On this basis alone it seems this mutation is pathogenic. Other APP codon 717 mutations have been identified which co-segregate with the disease (4,25). Also, a double mutation in APP at codons 670/671 has been shown to cosegregate with the disease in two large Swedish pedigrees (22). In all cases, there is complete co-segregation of the APP mutation with early onset AD, providing overwhelming statistical evidence that these mutations are pathogenic. We present the clinical features and limited neuropathology of AD in these families with the APP 717 Val-->Ile mutation.

Adult↗
PubMedDate not supplied

CD40 signaling and Alzheimer's disease pathogenesis.

The interaction between CD40 and its cognate ligand, CD40 ligand, is a primary regulator of the peripheral immune response, including modulation of T lymphocyte activation, B lymphocyte differentiation and antibody secretion, and innate immune cell activation, maturation, and survival. Recently, we and others have identified CD40 expression on a variety of CNS cells, including endothelial cells, smooth muscle cells, astroglia and microglia, and have found that, on many of these cells, CD40 expression is enhanced by pro-inflammatory stimuli. Importantly, the CD40-CD40 ligand interaction on microglia triggers a series of intracellular signaling events that are discussed, beginning with Src-family kinase activation and culminating in microglial activation as evidenced by tumor necrosis factor-alpha secretion. Based on the involvement of microglial activation and brain inflammation in Alzheimer's disease pathogenesis, we have investigated co-stimulation of microglia, smooth muscle, and endothelial cells with CD40 ligand in the presence of low doses of freshly solubilized amyloid-beta peptides. Data reviewed herein show that CD40 ligand and amyloid-beta act synergistically to promote pro-inflammatory responses by these cells, including secretion of interleukin-1 beta by endothelial cells and tumor necrosis factor-alpha by microglia. As these cytokines have been implicated in neuronal injury, a comprehensive model of pro-inflammatory CD40 ligand and amyloid-beta initiated Alzheimer's disease pathogenesis (mediated by multiple CNS cells) is proposed.

Alzheimer Disease↗