Linkage studies of late-onset familial Alzheimer's disease.
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Alzheimer Disease↗
Biomedical subjects
P C Gaskell
Publications and source records attributed to P C Gaskell.
Genetic linkage mapping of chromosome 17 markers and neurofibromatosis type I.
The von Recklinghausen neurofibromatosis (NF1) gene has been localized to the pericentromeric region of chromosome 17. We have screened six multigenerational families with multiple, tightly linked markers to aid in mapping this region of the chromosome. More than 150 members in six families were typed with probes including HHH202, D17Z1, EW203, EW206, EW207, EW301, pA10-41, D17S37, and D17S36. Two-point lod scores for NF1 versus all markers were calculated. HHH202 demonstrated the tightest linkage to NF1 with theta = .0, z = 3.86 (95% confidence limits [CL] of theta = .0-.13), suggesting that HHH202 be considered as a potential candidate marker for use in carrier detection and prenatal diagnosis. Pairwise marker-to-marker lod scores were used in examining the most likely order of subsets of the markers. Of those tested, the most likely order was (pter)-pA10-41-EW301-D17Z1-HHH202-NF1-E W206-EW207-EW203-(qter). In addition, we have ascertained an NF1 x NF1 half-cousin mating in which there are four affected family members who are potentially homozygous for the disease gene. Two of these four individuals have been sampled and typed for marker loci. When their D17Z1 genotypes are considered, the probability that both these individuals are heterozygous is 85%.
Chromosome Mapping↗
Sib-pair linkage analysis in late onset Alzheimer's disease.
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Alzheimer Disease↗
Prenatal diagnosis using deletion studies in Duchenne muscular dystrophy.
Accurate carrier testing and prenatal diagnosis in Duchenne muscular dystrophy (DMD) families is facilitated when an Xp21 deletion is found to be segregating within a family. We discuss the results of the DNA testing in two families, one in which DNA from affected males was available for study and the other in which no DNA from an affected male was available. Factors complicating the counselling of DMD deletion families are outlined.
Chromosome Deletion↗
Genetic linkage studies in Alzheimer's disease families.
Alzheimer's disease is a devastating neurological disorder and the leading cause of dementia among the elderly. Recent studies have localized the gene for familial Alzheimer's disease to chromosome 21 in a series of early onset AD families (mean age of onset less than 60). Familial late onset AD (mean age of onset greater than 60) is a more common clinical form of the disorder. Thirteen families with multiply affected Alzheimer's disease family members were identified and sampled. Ten of these families were of the late onset Alzheimer's disease type. Simulation studies were used to evaluate the usefulness of these pedigrees in linkage studies in familial Alzheimer's disease. Linkage studies undertaken to test the localization of both early onset and late onset Alzheimer's disease families to chromosome 21 failed to establish linkage and excluded linkage from a large portion of the region where the early onset Alzheimer's disease gene was localized. These findings suggest that more than one etiology may exist for familial Alzheimer's disease and indicate the need for continued screening of the genome in familial Alzheimer's disease families.
Alzheimer Disease↗
Systematic gene mapping in man: data management considerations.
The application of recombinant DNA technology to linkage analysis is revolutionizing the gene mapping field through the availability of an increasing number of restriction fragment length polymorphisms (RFLP). The successful mapping of the human genome will lead to a new era of research in human genetics with implications for carrier detection and prenatal diagnosis in any number of disorders. In addition, the development of RFLP tightly linked to a disease is critical for the potential identification of the genetic defect. A systematic approach to human gene mapping whereby it is possible to simultaneously screen several disorders for linkage is discussed. Guidelines for the database management, field studies, DNA and lymphoblast cell transformation, family history and laboratory data are included. This methodology represents the integration and application of statistical and molecular genetic, clinical and tissue culture expertise to human gene mapping.
Chromosome Aberrations↗
Genetic linkage studies of chromosome 17 RFLPs in von Recklinghausen neurofibromatosis (NF1).
Recent localization of the gene for von Recklinghausen neurofibromatosis (NF1) to chromosome 17 has led to studies to identify additional tightly linked probes that can be used in defining the primary genetic defect in NF1. We have examined and obtained blood for DNA linkage studies on over 250 individuals from 10 multigeneration neurofibromatosis families. We have analyzed 130 members in 7 families with the available chromosome 17 NF1 linked probes, pE51, D17S71, and D17Z1, as well as two probes generated from our own chromosome 17/19 enriched library (LDR92, LDR152A). Tight linkage was found between NF1 and the centromeric probe D17Z1 (theta = 0.04) and between NF1 and D17S71 (theta = 0.08). A definite recombinant was seen for the D17Z1 marker, which previously had not exhibited crossingover. Chromosome 17 DNA markers pE51, LDR92, and LDR152A gave slightly positive scores, which were not statistically significant.
Chromosomes, Human, Pair 17↗
Linkage studies in peripheral neurofibromatosis.
Peripheral neurofibromatosis (NF) is one of the most common major genetic disorders in man. Its chromosomal location is unknown and questions regarding such factors as genetic heterogeneity remain unanswered. We have ascertained and sampled several large multi-generation families for linkage studies including one family of 66 subjects, 28 of whom were affected with NF. Recombinant DNA studies of several restriction fragment length polymorphisms (RFLPs) including C3, ApoC2, pBam34 (D19S6], HAUP[APRT], pE40-1 [D11521], Hp[Hp2 alpha], LDR92, and LDR111 failed to show a significant linkage (Z [lod score] greater than or equal to 3.00) in this family. In addition, the results excluded areas of the genome around the marker loci (Z greater than or equal to - 2.00) as potential sites for linkage. The maximum Z obtained with the markers was for Hp at theta (maximum recombination fraction) = 0.20 and Z = 0.399. We are now in the process of screening additional RFLPs and families for linkage to NF.
Genetic Linkage↗
Hereditary motor and sensory neuropathy, X-linked: a half century follow-up.
The existence of an X-linked sensorimotor peripheral neuropathy has been debated. We reevaluated the original family, and present data on 13 affected males and 25 obligate or probable heterozygous females, documenting the devastating nature of the disease in the men and the extremely variable degree of clinical involvement in the carriers. Use of DNA probes indicates that the gene lies in the DXYS1-p58-1 region of the X-chromosome.
Adolescent↗
The flick sign in carpal tunnel syndrome.
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Carpal Tunnel Syndrome↗
Tight linkage of apolipoprotein C2 to myotonic dystrophy on chromosome 19.
The cDNA and genomic probes for apolipoprotein C2 detect two restriction fragment length polymorphisms on chromosome 19. The combined estimated percentage of heterozygosity, assuming equilibrium, is approximately 75%, ie, apolipoprotein C2 is informative in 75% of matings. We have analyzed over 350 individuals in large multigenerational families for linkage of apolipoprotein C2 to myotonic muscular dystrophy. The maximum lod score was 16.29 with the maximum recombination fraction (theta) of 0.02, with 95% confidence limits for theta of 0.001 to 0.065. Thus, apolipoprotein C2 is useful in carrier detection and prenatal diagnosis with an accuracy of about 98%.
Apolipoproteins↗
Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs.
Factors that modify onset of Alzheimer's disease (AD) may be revealed by comparing environmental exposures in affected and unaffected members of discordant twin pairs or sibships. Among siblings at high risk of AD, sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with delayed onset and reduced risk of AD. After adjustment for use of NSAIDs, there was minimal effect on onset with reported history of any of three common illnesses (arthritis, diabetes, or acid-peptic disease). However, independent of exposure to NSAIDs, onset was unexpectedly delayed in those reporting extended use of histamine H2 blocking drugs. Randomized clinical trials will be needed to affirm the utility of these drugs for prevention, but the present findings may have implications for pathogenesis: because NSAIDs block the calcium-dependent postsynaptic cascade that induces excitotoxic cell death in NMDA-reactive neurons, and because histamine potentiates such events, excitotoxicity may deserve additional investigation in AD.
Age of Onset↗
Development of a microsatellite genetic map spanning 5q31-q33 and subsequent placement of the LGMD1A locus between D5S178 and IL9.
Limb-girdle muscular dystrophy (LGMD) is a genetically and clinically heterogeneous group of disorders. We previously localized an autosomal dominant form of the disorder (LGMD1A) to chromosome 5q22-31 by linkage analysis in a single large pedigree. After developing a microsatellite genetic map incorporating six loci in q31-33 of chromosome 5 and spanning 35 cM, we have refined the original localization. Using multipoint analysis, LGMD1A is localised to a 7 cM region between the markers IL9 and D5S178 with odds > 1000:1.
Chromosome Mapping↗
Complete genomic screen in late-onset familial Alzheimer's disease.
Alzheimer's disease (AD) is a complex genetic disorder. Linkage analysis has helped unravel a portion of the genetic component of AD by identifying four loci that play a role in the genetics of AD (amyloid precursor protein, presenilin 1, presenilin 2, and apolipoprotein E). These loci account for approximately 50% of the genetic etiology of AD. A total genomic screen is an efficient way to identify additional genetic effects in AD. A series of multiplex late-onset (>60 years) AD families were ascertained (NINDS-ADRDA diagnostic criteria) and sampled. A subset (n = 16) of the largest families (52 affecteds with DNA, 83 unaffecteds with DNA) were used to rapidly screen the genome (n = 280 markers) for additional major genetic effects. Critical values for regional follow-up were p < or =0.05 for SimIBD or sibpair analysis and/or a LOD score > or = 1.00. Fifteen regions warranted initial follow-up based on these criteria. An additional screening set was used (n = 38 families, 89 affecteds with DNA, 216 unaffecteds with DNA) for the follow-up analysis. These analyses revealed four regions of continued interest on chromosomes 4, 6, 12, and 20. Chromosome 12 presented the strongest results. Peak two point "affecteds only" LOD scores were 1.3, 1.6, 2.7, and 2.2 and (affected relative pair SimIBD) p values were 0.04, 0.03, 0.14, and 0.04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. These markers span approximately 30 cm near the centromeric region of chromosome 12. Sibpair analysis resulted in two point Maximum Lod Score (MLS) results of 0.4, 1.2, 3.2, and 1.0 for the above markers. Multipoint MLS analysis supported these findings. Saturation mapping of all available markers in the chromosome 12 region as well as further investigation of the regions on 4, 6, and 20 is ongoing with candidate gene analysis to follow.
Age of Onset↗