Penelope Roques

A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene

A series of mutations has been reported in the presenilin-1 (PS-1) gene which cause early onset Alzheimers disease (AD). The mutations reported to date have encoded missense mutations which alter residues conserved between PS-1 and the presenilin-2 (PS-2) gene. We have recently determined the intron/exon structure of the PS-1 gene and this information has been used to identify a mutation in the splice acceptor site for exon 9 in a family with early onset AD. Amplification of cDNA from lymphoblasts of affected individuals revealed that the effect of the mutation was to cause splicing out of exon 9, however it does not change the open reading frame of the mRNA. The importance of this observation is discussed.

Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease ☆

In order to establish whether positron emission tomography (PET) can identify metabolic changes in Alzheimers disease at a presymptomatic stage, we have examined 24 asymptomatic at risk individuals from families with Alzheimers disease. A significant reduction in global cerebral metabolic rate for glucose was found when compared with 16 age-matched controls. There was also a focal, parieto-temporal deficit similar to, although less extensive than, that found in 18 symptomatic individuals from familial Alzheimers disease (FAD) pedigrees. Follow up of this cohort will establish whether these metabolic changes relate to a presymptomatic stage of the disease.

Predisposing locus for Alzheimer's disease on chromosome 21

Linkage between Alzheimers disease and markers on the long arm of chromosome 21 was investigated in six families affected by disease of early onset. Linkage was confirmed and the disease locus shown to be centromeric to the locus D21S1/S11 on the long arm of the chromosome. It is argued that the data are consistent with the notion that all patients with Alzheimers disease of genetic aetiology have a predisposing locus on chromosome 21.

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimers disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

Familial dementia with swollen achromatic neurons and corticobasal inclusion bodies: A clinical and pathological study

Clinical, pathological and molecular genetic data are presented in two families in which 15 individuals have developed a progressive dementia. Clinical details are available in 10 individuals, neuropathological data in 2. Affected individuals presented between the ages of 43 and 59 years with personality change or memory loss. All individuals developed a progressive dementia with features of frontal lobe dysfunction. Affected individuals commonly developed additional features which included dysphasia, parkinsonism, limb clumsiness and disequilibrium. Duration to death was between 3 and 13 years. Pathological examination of one individual from each family revealed a combination of features not previously described in a familial dementia. Macroscopic examination revealed lobar atrophy. Microscopy revealed neuronal loss and gliosis with swollen achromatic neurons in the cortex and corticobasal inclusion bodies in the substantia nigra. On clinical assessment these families have many features of Picks disease but pathological examination reveals features more suggestive of corticobasal degeneration.

Familial progressive supranuclear palsy

A progressive extrapyramidal syndrome and dementia occurred in three members of one family. The age of onset was in the seventh decade and the affected individuals showed many of the clinical features of progressive supranuclear palsy (PSP). Necropsy of one individual revealed the neuropathological features of PSP. We propose that this family has a familial form of PSP and review the evidence in the literature that a familial form exists.

Association between autoimmune thyroid disease and Familial Alzheimers disease

Summary. objective To determine the prevalence of autoimmune thyroid disease in Familial Alzheimers Disease kindreds and to ascertain whether there is any evidence for genetic linkage between the two conditions.

Chromosome 14 familial Alzheimer’s disease: the clinical and neuropathological characteristics of a family with a leucine→serine (L250S) substitution at codon 250 of the presenilin 1 gene

BACKGROUND Seven affected members are described from a kindred with autosomal dominant familial Alzheimer’s disease associated with a novel mutation in the presenilin 1 (PS1) gene on chromosome 14 that results in a leucine to serine substitution at codon 250 (L250S). METHOD Clinical information on the pedigree was collected directly from family members including affected members and their carers and also from hospital records. RESULTS Detailed clinical information was available on five members. All had an early age at onset with a median age of 52 (95% confidence interval (95% CI) 49.4–54.9). Age at onset varied between 49 and 56 years, with duration of illness varying between six years and 15 years. Myoclonus, depression, and psychosis were features of this pedigree; seizures were not reported. CONCLUSIONS PS1 L250S familial Alzheimer’s disease is an early onset form of Alzheimer’s disease with clinical features similar to other reported familial Alzheimer’s disease pedigrees, except that seizures were absent.

Lewy bodies in the brain of two members of a family with the 717 (Val to Ile) mutation of the amyloid precursor protein gene

A second member of the original family with the valine to isoleucine substitution at codon 717 of the amyloid precursor protein died after the clinical diagnosis of Alzheimers disease had been made in life. Neuropathological examination of the brain revealed not only severe Alzheimer type pathology, with senile plaques and neurofibrillary tangles, but also Lewy bodies both in the cortex and brainstem. Lewy bodies also occurred in our first case, thus showing striking similarities in these two members of the same family. The possibility exists that the occurrence of Lewy bodies may not be coincidental, but could be genetically determined: the same genetic abnormality which determines the deposition of beta A4 protein, thus triggering of a chain of events leading to Alzheimers disease, may result in, or predispose to Lewy body formation.

Sequencing of exons 16 and 17 of the β-amyloid precursor protein gene in 14 families with early onset Alzheimer's disease fails to reveal mutations in the β-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 Alzheimers disease. Direct sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene in 14 families with familial early onset Alzheimers disease without the known pathogenic mutation (APP717) failed to reveal other mutations within the beta-amyloid sequence in this form of the disorder.