Edmund C. Jenkins

A profile of cognitive deficit in females from fragile X families

Fragile X, a recently discovered X-linked syndrome, is usually associated with mental retardation in affected males. Less consistent findings have been described for females. neuropsychological evaluation of seven nonretarded females from fragile X families suggested a characteristic profile: on Wechsler IQ tests, a positive Verbal-Performance score difference and lower subtest scaled scores on Arithmetic, Digit Span, Block Design, and Object Assembly; on the Wide Range Achievement Test, a lower score on Arithmetic than on Reading or Spelling; and on the Benton Visual Retention Test, defective recall. These results suggest the existence of X-linked learning disability in females.

Localization of a human gene homologous to the PrP gene on the p ARM of chromosome 20 and detection of PrP-related antigens in normal human brain

Infectious fractions prepared from scrapie-infected hamster brains contain a protein, PrP 27-30, which shares antigenic determinants with polypeptides found in similarly prepared fractions from patients with Creutzfeldt-Jakob disease. cDNA sequences encoding the hamster PrP 27-30 identified homologous sequences in the human genome as well as in normal human brain mRNA preparations. Antibodies raised against the mouse PrPs identified antigenically related peptides in both normal hamster and human brain as well as in scrapie-infected hamster brain and CJD-affected human brain. By using in situ hybridization we localized the homologous human genomic sequences on the short arm of chromosome 20. Our results indicate that the reportedly unique proteins detected in human CJD preparations derive from normal human gene products.

Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia

Telomere shortening has been recently correlated with Alzheimers disease status. Therefore, we hypothesized that a possible association might exist for adults with Down syndrome (DS). Using blind, quantitative telomere protein nucleic acid FISH analyses of metaphase and interphase preparations from 18 age-matched trisomy 21 female study participants with and without dementia, we have observed increased telomere shortening in adults with DS and dementia (p < .01). From this initial study, we conclude that telomere shortening is associated with dementia in this high-risk population and suggest that additional research may show that telomere shortening may be a biological marker of dementia status.

Polymerase chain reaction analysis of fragile X mutations

SummaryThe mutation that underlies the fragile X syndrome is presumed to be a large expansion in the number of CGG repeats within the gene FMR-1. The unusually GC-rich composition of the expanded region has impeded attempts to amplify it by the polymerase chain reaction (PCR). We have developed a PCR protocol that successfully amplifies the (CGG)n region in normal, carrier and affected individuals. The PCR analysis of several large fragile X families is presented. The PCR results agree with those obtained by direct genomic Southern blot analyses. These favorable comparisons suggest that the PCR assay may be suitable for rapid testing for fragile X mutations and premutations and genetic screening of at-risk individuals.

Autism severity is associated with child and maternal MAOA genotypes.

Cohen IL, Liu X, Lewis MES, Chudley A, Forster‐Gibson C, Gonzalez M, Jenkins EC, Brown WT, Holden JJA. Autism severity is associated with child and maternal MAOA genotypes.

Multilocus analysis of the fragile X syndrome

SummaryA multilocus analysis of the fragile X (fra(X)) syndrome was conducted with 147 families. Two proximal loci, DXS51 and F9, and two distal loci, DXS52 and DXS15, were studied. Overall, the best multipoint distances were found to be DXS51-F9, 6.9%, F9-fra(X), 22.4%; fra(X)-DXS52, 12.7%; DXS52-DXS15, 2.2%. These distances can be used for multipoint mapping of new probes, carrier testing and counseling of fra(X) families. Consistent with several previous studies, the families as a whole showed genetic heterogeneity for linkage between F9 and fra(X).

Analysis of the fragile-X chromosome: localization and detection of the fragile site in high resolution preparations.

SummaryFragile X chromosome preparations were analyzed at levels of up to 850 bands per haploid set. We were able to consistently sublocalize the Xqter fragile site to band Xq27.3 using high-resolution methods. Chromosome length versus the frequency of fragile X expression was also compared. The fragile site appeared at a higher percentage in more condensed chromosome preparations. The importance of this finding is that high-resolution chromosome preparations do not optimize fragile-X detection.

Alzheimer's Disease in Adults with Down Syndrome.

Abstract Down syndrome is associated with increased mortality rates due to congenital cardiac defects and leukemia early in life, and with Alzheimers disease and a tendency toward premature aging later in life. Alzheimers disease was once considered an inexorable result of growing old with Down syndrome, but recent data indicate that risk does not reach 100%. Although some individuals exhibit signs and symptoms of Alzheimers disease in their 40s, other individuals have reached the age of 70 without developing dementia. This chapter presents a wealth of data from a longstanding longitudinal study with the overall objective of understanding and recounting the mechanisms responsible for these substantial individual differences.

Cholesterol level, statin use and Alzheimer's disease in adults with Down syndrome

Adults with Down syndrome (DS) are at significantly higher risk of Alzheimers disease (AD) than the general population, but there is considerable variability in age at onset. This study tested the hypothesis that total cholesterol (TC) levels are related to vulnerability, and that the use of statins may decrease risk. The relation of TC level and statin use to risk of AD was investigated in 123 Caucasian adults with DS. Evaluations included serial assessments of cognitive, adaptive and maladaptive behavior, medical records, and neurological examinations. Mean length of follow-up was 5.5 years [1.2-7.1] for the entire sample, 5.1 years [1.2-7.1] for subjects who developed dementia, and 5.6 years [1.5-7.1] for those who did not develop dementia. Controlling for covariates, participants with TC>or=200mg/dL were more than two times as likely to develop AD than subjects with lower TC [hazard rate (HR)=2.59, p=.029, 95% CI: 1.1, 6.1]. In contrast, participants with higher TC levels who used statins during the study, had less than half the risk of developing AD than participants with higher TC levels who did not use statins (HR=.402, p=.095, 95% CI: .138, 1.173). If the protective effects of statins can be further validated, these findings suggest that their use may delay or prevent AD onset in vulnerable populations.

Reverse mutations in the fragile X syndrome.

Three females were identified who have apparent reversal of fragile X premutations. Based on haplotype analysis of nearby markers, they were found to have inherited a fragile X chromosome from their premutation carrier mothers, and yet had normal size FMR1 repeat alleles. The changes in repeat sizes from mother to daughter was 95 to 35 in the first, 145 to 43 in the second, and 82 to 33 in the third. In the first family, mutations of the nearby microsatellites FRAXAC2 and DXS548 were also observed. In the other two, only mutations involving the FMR1 repeats were found. We suggest differing mutational mechanisms such as gene conversion versus DNA replication slippage may underlie such reversions. We estimate that such revertants may occur among 1% or less of premutation carrier offspring. Our results indicate that women identified to be carriers by linkage should be retested by direct DNA analysis.