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M Hutton

Publications and source records attributed to M Hutton.

At least 73 records · Page 4Linked to original sources
PubMed1998

Exclusion of genetic linkage to 4q21-23 and 17q21 in a family with Lewy body parkinsonism.

Genetic analysis of markers from chromosomes 4q21-23 and 17q21 in a family with apparently autosomal dominant Lewy body parkinsonism is presented. This analysis shows that the locus leading to this disease is not allelic with that previously shown to lead to Lewy body parkinsonism on chromosome 4 or to the locus on chromosome 17 leading to frontotemporal dementia with parkinsonism. A brief clinical comparison of this family with families showing linkage to these loci is presented. The data suggest that at least one other major genetic determinant for Lewy body parkinsonism remains to be identified.

Adult↗
PubMed1998

ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer's disease families.

The apolipoprotein E (ApoE) genotype is a significant risk factor and modulator of age of onset of Alzheimer's disease (AD). We analyzed the effect of the ApoE genotype in two distinct early-onset familial AD groups: families with a mutation in the presenilin-1 gene (PS-1) on chromosome 14, and families without a mutation detectable in the PS-1, presenilin-2 (PS-2), and the amyloid precursor protein (APP) gene (non-PS early-onset familial AD). The ApoE genotype is clearly shown not to modulate age of onset in families with a mutation in the PS-1 gene and families with no lesion detectable in either the presenilin or APP gene. The effects of a double dose of ApoE4 on age of onset were not assessed in the PS-1 AD families due to the lack of any affected ApoE4 homozygotes in the sample set; this insufficiency will need to be assessed in further studies. There was no association between the ApoE4 allele and AD in the PS-1 families. Non-PS early-onset AD families were shown to have a significantly higher frequency of ApoE4 compared to controls and the PS-1 AD group. These observations are important and suggest that 1) other genetic and environmental factors modify the AD phenotype in PS-1 and non-PS early-onset families; and 2) the ApoE4 allele is a significant risk factor in the etiology of non-PS early-onset AD and will be a useful adjunct in the diagnosis of unaffected family members.

Alleles↗
PubMed1998

Increased Abeta42(43) from cell lines expressing presenilin 1 mutations.

Mutations in the presenilin 1 (PS1) gene on chromosome 14 are a major cause of autosomal dominant, early-onset Alzheimer's disease. Here, we show that transfecting cells with several mutant, but not wild-type, PS1 cDNAs alters the processing of the amyloid precursor protein (APP) such that more Abeta42(43) is produced, confirming and extending several recent reports. The most effective mutation in this regard was the exon 9 splice-out mutation (delta9). The correlation between the size of the effect on APP processing and the age of onset of disease assessed in families with the mutations was not informative, and the possible reasons for this are discussed.

Age of Onset↗
PubMed1998

Cloning and characterization of the presenilin-2 gene promoter.

Mutations in the presenilin-2 (PS-2) have been shown to cause early onset Alzheimer's disease (AD) in a series of families known as the Volga Germans and in an unrelated Italian kindred. Expression of the PS-2 gene is regulated during AD, aging, development and brain injury. Although expressed primarily in neurons, enhanced levels of PS-2 have been reported in astrocytes activated by neuronal damage. Understanding the regulation of the PS-2 gene may thus provide an insight into its role in AD. We have isolated a 3635 bp DNA fragment that contains 2934 bp of DNA sequence upstream from the PS-2 gene. Primer extension analysis was used to map three major transcriptional start sites within the PS-2 gene. The promoter sequence, upstream of each transcriptional start site, does not contain TATA or CAAT boxes but does contain several GC rich sites (Sp-1 and AP-2). A reporter gene construct containing the PS-2 promoter (PS2P, -2934 to +702) transfected into M17 cells drives basal transcription to 20% of the levels of the SV-40 viral promoter. Addition of NGF to PC-12 cells was found to upregulate the PS2P promoter and an NGF-responsive element was localized by deletional analysis between -403 and +13 within the promoter. Since the PS-2 gene has multiple start sites and the upstream sequence is GC rich with no TATA box, the PS-2 promoter is consistent with the GC class of 'housekeeping' genes.

5' Untranslated Regions↗
PubMed1998

Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau.

Molecular genetic analysis is revealing the etiologies of Alzheimer's disease (AD) and related dementias. Here we review genetic and molecular biological evidence suggesting that the peptide A beta 42 is central to the etiology of AD. Recent data also suggests that dysfunction in the cytoskeletal protein tau is on the pathway that leads to neurodegeneration and dementia. Tau is produced either indirectly, by A beta 42, or directly, in some forms of frontotemporal dementia by mutations in tau itself. These data support are refine the amyloid cascade hypothesis for AD and suggest that understanding the causes and consequences of tau dysfunction is an important priority for dementia research.

Alzheimer Disease↗
PubMed1998

A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.

Age of Onset↗
PubMed1998

Genetics of Alzheimer's disease.

Mutations in any one of three genes can cause autosomal dominant, early-onset Alzheimer's disease: these genes are the amyloid precursor protein (APP) gene on chromosome 21, the presenilin-1 (PS-1) gene on chromosome 14 and the presenilin-2 (PS-2) gene on chromosome 1. Pathogenic mutations at all these loci cause mismetabolism of APP such that more of the peptide A beta 42 is produced. This peptide is deposited in the plaques in the brains of Alzheimer's patients. These facts have led to the dominant hypothesis for the disease process: the 'amyloid cascade hypothesis', which proposes that overproduction or failure to clear the peptide A beta 42 is always central to the disease. Genetic variability at the apoliprotein E locus is a major determinant of late onset Alzheimer's disease. The mechanism by which apoliprotein E is involved in the pathogenesis of Alzheimer's disease is not yet known. There are likely to be other genetic factors which impinge on Alzheimer's disease.

Age of Onset↗
PubMed1998

Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease.

Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.

Aged↗
PubMed1998

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.

Age of Onset↗
PubMed1998

Clinical and genetic aspects of progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is, after Parkinson's disease, the most common form of degenerative parkinsonism. Several clinical features are used in the recognition of this disorder as well as in the differentiation from related disorders. Clinical criteria that could increase diagnostic accuracy in research studies are also emphasized. Due to a better understanding of the genetic aspects of PSP, recent studies have suggested that it is a recessive disorder in linkage disequilibrium with the tau (tau) gene, rather than a sporadic disorder. In addition, the recent identification of mutations in the tau gene associated with a similar neurodegenerative condition (frontotemporal dementia and parkinsonism linked to chromosome 17) has further strengthened the argument that tau dysfunction is somehow involved in the pathogenesis of PSP. Nongenetic factors that could trigger or perpetuate the cascade of events leading to neuronal degeneration in PSP are also reviewed.

Aged↗
PubMed1997

Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation.

We describe a new mutation causing Alzheimer's disease (AD) in presenilin-1 (N135D) that is at the homologous site to the presenilin 2 mutation (N141I) in Volga German kindreds. The phenotype of PS1 N135D is an early-onset (34-38 years) disease. The mutation forms part of, and extends, the alpha-helical array of mutations in transmembrane 2 of the presenilins and leads to the suggestion that disruption of this helical face is the molecular insult that leads to disease.

Adult↗
PubMed1997

Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22.

An Australian family with autosomal dominant presenile nonspecific dementia was recently described. The disease results in behavioral changes, usually disinhibition, followed by the onset of dementia accompanied occasionally by parkinsonism. Twenty-eight affected individuals were identified with an age of onset of 39 to 66 years (mean, 53 +/- 8.9 years). We mapped the disease locus to an approximately 26-cM region of chromosome 17q21-22 with a maximum two-point LOD score of 2.87. Affected individuals share a common haplotype between markers D17S783 and D17S808. This region of chromosome 17 contains the loci for several neurodegenerative diseases that lack distinctive pathological features, suggesting that these dementias, collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in the same gene. The entire coding region of five genes, mapped to the FTDP-17 candidate region, were also sequenced. This analysis included the microtubule-associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease. No pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.

Adult↗
PubMed1997

Regional and cellular localization of presenilin-2 RNA in rat and human brain.

In situ hybridization probes selective for presenilin-2 (PS-2) were used to determine the regional and cellular expression pattern of PS-2 mRNA in rat and human brain. In rat brain, the greatest expression of PS-2 mRNA is in the granule cell layers of the dentate gyrus and cerebellum. Molecular layers within these structures are virtually devoid of signal. Cortical expression of PS-2 message is restricted to neuronal layers, while the hybridization signal is weak or absent in molecular layers and white matter. Kidney, liver, and spleen display moderate levels of PS-2 message. A PS-2 sense strand probe produced no specific signals in any tissue. In human brain, the greatest hybridization signal for PS-2 is present in the granule cells of the cerebellum. Within hippocampus, the granule cell layer of dentate is strongly labeled, with CA3 pyramidal neurons also clearly visible. A laminar expression pattern is seen in the neuronal layers of human frontal and temporal cortex, with the deeper laminae having the strongest signals. These data are consistent with a primarily neuronal localization of PS-2 mRNA within the brains of both rat and human. Within the limitations of the analysis, it appears that virtually every neuron is labeled, and differences in the intensity of labeling are associated with both neuron size/density and brain region. The distribution of PS-2 RNA is not restricted to those regions having the greatest pathology in Alzheimer's disease. However, one unusual pathological feature of PS-2 mutations causing AD is the presence of cerebellar amyloid plaques in some cases. It is intriguing, in this context, that PS-2 RNA is enriched in the cerebellum, especially in human specimens.

Animals↗
PubMed1997

Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor.

Sixteen affected individuals are described from two families with early onset autosomal dominant familial Alzheimer's disease. A mutation at codon 139 in the presenilin 1 gene on chromosome 14 results in a methionine to valine substitution which cosegregates with the disease in these families. Onset of dementia was before the age of 50 years in all individuals. The ages at onset within each family were tightly clustered but were significantly different between the families; this difference could not be accounted for by apolipoprotein E status and suggests the existence of a further genetic factor that modifies age at disease onset. The pattern of cognitive decline was similar in both families: early memory loss (initially selective for verbal memory in some individuals) was followed soon after by loss of arithmetic skills while naming and object perception skills were relatively preserved. A speech production deficit was observed in three members of one family but not in the other. Seizures were common and usually predated by myoclonic jerks by a number of years. Serial MRIs showed progressive cortical atrophy with periventricular white matter change appearing 3-4 years into the disease. PET revealed parieto-temporal hypometabolism in all individuals scanned. The diagnosis of Alzheimer's disease was confirmed with typical histopathology in one individual from each family.

Adult↗
PubMed1997

The presenilins and Alzheimer's disease.

The presenilin 1 and presenilin 2 genes have been identified as pathogenic loci involved in the majority of early onset, autosomal dominant Alzheimer's disease. A series of (predominantly) missense mutations have been identified in the two genes which lead to disease. The presenilins are probably eight transmembrane domain proteins with both termini in the cytoplasmic compartment. They have a wide tissue distribution and are found in the endoplasmic reticulum and early Golgi. The mechanism of pathogenesis of the mutations is not clear although, both in patients and in in vitro systems, the effects of presenilin mutations are reminiscent of the effects of the pathogenic mutations in the amyloid precursor protein gene which lead to increases in the amount of amyloid-beta42(43) being produced from the metabolism of the amyloid protein precursor. Thus, the presenilin data provide independent support for the amyloid cascade hypothesis of Alzheimer's pathogenesis. Work on the Caenorhabditis elegans homologues of the presenilins, spe-4 and sel-12, suggests that the presenilins may have a more general and direct role in the processing and trafficking of membrane-bound proteins and that, in part, the pathogenic mutations may disrupt this role.

Alzheimer Disease↗
PubMed1997

A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43).

We report a novel mutation in the amyloid precursor protein gene (APP I716V) which probably leads to familial early onset Alzheimer's disease with an onset age in the mid 50s. Cells transfected with cDNAs bearing this mutation produce more A beta 1-42(43) than those transfected with wild-type APP and this effect is additive with that of the previously reported APP V717I mutation thus providing a novel approach for further increasing A beta 1-42(43) in model systems.

Age of Onset↗
PubMed1997

Mycobacterium tuberculosis transmission from a pediatrician to patients.

UNLABELLED: The following report describes the contact investigation of a pediatrician with tuberculosis (TB). The pediatrician's disease was discovered in late February 1993 after tuberculin skin testing (TST) of his 15-month-old son was positive (13-mm induration). Further investigation to identify the source of the child's infection revealed a positive (15-mm induration) TST in the pediatrician. The pediatrician had been symptomatic with a cough since September 1992. The pediatrician had a chest radiograph that revealed numerous cavitary lesions and a sputum smear that was positive for acid-fast bacilli. An investigation was initiated to assess whether the transmission of Mycobacterium tuberculosis had occurred in the pediatrician's office to patients, families, or other visitors. The investigation was later extended to include the hospitals and the day care center where the pediatrician worked. METHODS: A letter was mailed to parents of children served by the practice, explaining the potential exposure to TB and requesting that all persons who visited the office after September 1, 1992 complete an interview and Mantoux TST. Mass interviewing, testing, and test interpretation within the practice took place seven times during March and April 1993. RESULTS: At the completion of screening, 181 (87%) of 208 children who had close contact with the index case were reliably skin-tested and returned for interpretation. Three (1.7%) of the 181 children were TST-positive (>/=5 mm). Thirty-seven (13%) of the 286 adults tested and returning for interpretations were TST-positive (>/=10 mm). Thirty-two (86%) of the 37 adults who tested positive were foreign-born. CONCLUSION: This investigation highlighted the need for identifying childhood TB infection as a sentinel event for adult disease. It also demonstrated the difficulty associated with deciding the extent of contact investigation of a health care worker with TB. Finally, the investigation emphasized the importance of maintaining regularly scheduled and appropriate testing for TB infection in health care workers and the need for health care workers to be cognizant of their own risk and be able to identify, especially in themselves, signs and symptoms of potential TB disease.

Adolescent↗