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Biomedical subjects

P A Jacobs

Publications and source records attributed to P A Jacobs.

At least 19 recordsLinked to original sources
PubMed2000

Distinctive patterns of memory function in subgroups of females with Turner syndrome: evidence for imprinted loci on the X-chromosome affecting neurodevelopment.

X-monosomy is a form of Turner syndrome (TS) in which an entire X chromosome is missing. It is usually assumed that neuropsychological deficits in females with TS result from insufficient dosage of gene products from alleles on the sex chromosomes. If so, then parental origin of the single X chromosome should be immaterial. However, if there are imprinted genes on the X chromosome affecting brain development, neuropsychological development will depend on the parental origin of the single X chromosome. We contrasted verbal and visuospatial memory in females with a single paternal X chromosome (45,X(p)) and those with a single maternal X (45,X(m)). Neither group showed any impairment on immediate story recall; if anything, performance was above control levels. Groups did not differ on a measure of delayed recall. However, when delayed recall was considered after adjusting for level of immediate recall, 45,X(m) females showed enhanced verbal forgetting relative to controls over a delay. On the Rey figure, both groups were poor at copying the figure, but, after adjusting scores for initial copy score and strategy, only the 45,X(p) females showed disproportionate forgetting relative to controls. We propose there may be one or more imprinted genes on the X chromosome that affect the development of lateralised brain regions important for memory function.

Adolescent↗
PubMed1999

The origin of the extra Y chromosome in males with a 47,XYY karyotype.

The presence of an extra Y chromosome in males is a relatively common occurrence, the 47,XYY karyotype being found in approximately 1 in 1000 male births. The error of disjunction must occur either during paternal meiosis II or as a post-zygotic mitotic error, both of which are rare events for other chromosomes. It is therefore of interest to determine when errors of Y chromosome disjunction occur. It is possible to distinguish between the different mechanisms of non-disjunction by analysing DNA polymorphisms at the distal tip of the Xp/Yp pseudoautosomal region in 47,XYY males, their parents and in some cases paternal grandparents. A cohort of 28 non-mosaic 47,XYY males was analysed. The results show that there are at least two mechanisms causing non-disjunction of the Y chromosome. In 16 of the 19 cases from which parents were available, the extra Y was generated by non-disjunction at meiosis II after a normal chiasmate meiosis I. Three cases were due to either a post-zygotic mitotic error or non-disjunction at meiosis II after a nullichiasmate meiosis I. Of the nine cases with no parental DNA available, at least four were due to meiosis II non-disjunction following a normal chiasmate meiosis I.

Base Sequence↗
PubMed1999

Is disomic homozygosity at the APECED locus the cause of increased autoimmunity in Down's syndrome?

AIMS: To examine the age of onset of insulin dependent diabetes mellitus (IDDM) in children with Down's syndrome compared with non-trisomic individuals, and to assess whether differences might be related to disomic homozygosity at the autoimmune polyglandular disease type 1 (APECED) gene locus. METHODS: Children with Down's syndrome and IDDM were identified through the Down's syndrome association newsletter and from paediatricians. DNA was extracted from mouthbrush preparations provided by the parents and patients using standard techniques. Mapping techniques were then used to identify areas of reduction to homozygosity, including a marker that overlaps the locus for APECED. The frequency of disomic homozygosity for all markers (n = 18) was compared with a control group of 99 patients with Down's syndrome and their parents. The families also answered a questionnaire concerning diabetes and related autoimmune conditions in the family. Details were compared with the British Paediatric Surveillance Group 1988 diabetes study. RESULTS: Children with Down's syndrome and IDDM were diagnosed significantly earlier than the general population (6.7 v 8.0 years) with a far higher proportion diagnosed in the first 2 years of life (22% v 7%). There was no evidence of increased disomic homozygosity in the region of the APECED locus in Down's syndrome patients with IDDM compared with simple Down's syndrome. CONCLUSIONS: The natural history of IDDM in Down's syndrome is different from that of the general population. Although children with Down's syndrome have features similar to cases of APECED, disomic homozygosity in this region does not explain the predilection for autoimmune disease.

Adolescent↗
PubMed1999

A molecular and FISH analysis of structurally abnormal Y chromosomes in patients with Turner syndrome.

Fourteen patients with Turner syndrome and a structurally abnormal Y chromosome were analysed by PCR amplification and fluorescence in situ hybridisation for the presence of sequences specific to defined regions of the Y chromosome. Thirteen patients had a mosaic karyotype including a 45,X cell line and one case was non-mosaic in cultured lymphocytes. Ten patients had a pseudodicentric Yp chromosome, two an isodicentric Yq, one a pseudodicentric Yq, and one a derived Y chromosome. Two of the patients with a psu dic(Yp) chromosome had complex karyotypes with more than two cell lines, one of which exhibited five morphologically distinct mar(Y) chromosomes, presumably derived from a progenitor psu dic(Yp). Nine of the ten psu dic(Yp) chromosomes were positive for all Yp and Yq probes used except DYZ1 which maps to Yq12, suggesting a common breakpoint near the Yq euchromatin/heterochromatin boundary. In the three patients with a dicentric Yq chromosome two different breakpoints were observed; in two it was between PABY and the subtelomeric repeat sequence and in one it was between DYZ5 and AMGY in proximal Yp. Our results suggest that the great majority of structurally abnormal Y chromosomes found in Turner syndrome mosaics contain two copies of virtually all of the functional Y chromosome euchromatin.

Chromosome Mapping↗
PubMed1998

FRAXA and FRAXE: evidence against segregation distortion and for an effect of intermediate alleles on learning disability.

There have been several claims of segregation distortion (meiotic drive) for loci associated with diseases caused by trinucleotide repeats, leading us to test for this phenomenon in a large study of the X-linked loci FRAXA and FRAXE. We found no evidence of meiotic drive in females and no convincing evidence in males, where the limitation of risk to daughters creates a testing bias for alleles of interest. Alleles for pre- and full mutation, intermediate alleles, and common alleles were analyzed separately, with the same negative results that are extended in the discussion to claims of meiotic drive for other diseases. On the other hand, an excess risk of learning difficulties was confirmed for intermediate FRAXA alleles (relative risk, 2.58 +/- .74) and suggested for intermediate FRAXE alleles. The penetrance of learning difficulty is low, the risk being estimated as .039 for FRAXA common alleles and .101 for intermediate alleles. Because of their lower gene frequency, full mutations are a less frequent cause of learning difficulty than intermediate alleles, which contribute .0020 to total prevalence and .0012 to attributable prevalence of learning difficulty.

Alleles↗
PubMed1998

A study of females with deletions of the short arm of the X chromosome.

We have undertaken a clinical and molecular study of 25 females with deletions of the short arm of the X chromosome. We have determined the deletion breakpoints, the parental origin and the activation status of the deleted X chromosomes. Genotype-phenotype correlations suggest that the presence of a single copy of the DFFRX gene, previously postulated as a gene involved in the ovarian failure seen in Turner syndrome, may be compatible with normal ovarian function, and that there may be a gene for Turner-like features located in distal Xp22.3.

Adolescent↗
PubMed1998

Fragile X premutation screening in women with premature ovarian failure.

We have screened 132 women with premature ovarian failure for fragile X (FRAXA) premutations. Three out of 23 (13%) pedigrees with the familial premature ovarian failure and 3/106 (3%) of women with the sporadic form of premature ovarian failure have FRAXA premutations compared with an expected prevalence of 1:590 (P=0.02). The mechanism of the association between FRAXA premutations and premature ovarian failure is unknown but as a genetic marker, FRAXA screening will be particularly valuable in predicting premature ovarian failure in some pedigrees and in the identification of families at risk of transmitting fragile X syndrome.

Adult↗
PubMed1997

Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function.

Turner's syndrome is a sporadic disorder of human females in which all or part of one X chromosome is deleted. Intelligence is usually normal but social adjustment problems are common. Here we report a study of 80 females with Turner's syndrome and a single X chromosome, in 55 of which the X was maternally derived (45,X[m]) and in 25 it was of paternal origin (45,X[p]). Members of the 45,X[p] group were significantly better adjusted, with superior verbal and higher-order executive function skills, which mediate social interactions. Our observations suggest that there is a genetic locus for social cognition, which is imprinted and is not expressed from the maternally derived X chromosome. Neuropsychological and molecular investigations of eight females with partial deletions of the short arm of the X chromosome indicate that the putative imprinted locus escapes X-inactivation, and probably lies on Xq or close to the centromere on Xp. If expressed only from the X chromosome of paternal origin, the existence of this locus could explain why 46,XY males (whose single X chromosome is maternal) are more vulnerable to developmental disorders of language and social cognition, such as autism, than are 46,XX females.

Adolescent↗
PubMed1997

A mathematical model for intracellular effects of toxins on DNA adduction and repair.

The process by which certain classes of toxins compounds or their metabolites may react with DNA to alter the genetic information contained in subsequent generations of cells or organisms are a major component of hazard associated with exposure to chemicals in the environment. Many classes of chemicals may form DNA adducts and there may or may not be a defined mechanism to remove a particular adduct from DNA independent of replication. Many compounds and metabolites that bind DNA also readily bind existing proteins; some classes of toxins and DNA adducts have the capacity to inactivate a repair enzyme and divert the repair process competitively. This paper formulates an intracellular dynamic model for one aspect of the action of toxins that form DNA adducts, recognizing a capacity for removal of those adducts by a repair enzyme combined with reaction of the toxin and/or the DNA adduct to inactivate the repair enzyme. This paper model illustrates the possible saturation of repair enzyme capacity by the toxin dosage and shows that bistable behavior can occur, with the potential to induce abrupt shifts away from steady state equilibria. The model suggests that bistable behavior, dose and variation between individuals or tissues may combine under certain conditions to amplify the biological effect of dose observed as DNA adduction and its consequences as mutation. A model recognizing stochastic phenomena also indicates that variation in within-cell toxin concentration may promote jumps between stable equilibria.

DNA Adducts↗
PubMed1997

Open compared with laparoscopic approach to Burch colposuspension: a cost analysis.

OBJECTIVE: To compare postoperative course and hospital charges of an open versus laparoscopic approach to Burch colposuspension for the treatment of genuine stress urinary incontinence. METHODS: A retrospective chart review was performed to identify all patients undergoing open or laparoscopic Burch colposuspension by the same surgeon over a 2-year period. Patients undergoing additional surgical procedures at the time of colposuspension were excluded from the study. Twenty-one patients underwent open Burch colposuspension and 17 patients underwent laparoscopic colposuspension. Demographic data including age, parity, height, and weight were collected for each group. Both groups also were compared with regard to operative time, operating room charges, estimated blood loss, intraoperative complications, change in postoperative hematocrit, time required to resume normal voiding, length of hospital stay, and total hospital charges. RESULTS: The laparoscopic colposuspension group had significantly longer operative times (110 versus 66 minutes, P < .01) and increased operating room charges ($3479 versus $2138, P < .001). There was no statistical difference in estimated blood loss or change in postoperative hematocrit between the two groups. No major intraoperative complications occurred in either group. Mean length of hospital stay was 1.3 days for the laparoscopic group and 2.1 days for the open group (P < .005). However, total hospital charges for the laparoscopic group were significantly higher ($4960 versus $4079, P < .01). CONCLUSION: Laparoscopic colposuspension has been described as a minimally invasive, cost-effective technique for the surgical correction of stress urinary incontinence. Although the laparoscopic approach was found to be associated with a reduction in length of hospital stay, it had significantly higher total hospital charges than the traditional open approach because of expenses associated with increased operative time and use of laparoscopic equipment.

Adult↗
PubMed1997

Molecular characterization of isochromosomes of Xq.

We have undertaken a study of 35 patients with i(Xq) to determine whether those that are maternally derived originate by similar mechanisms to those that are paternally derived. Isochromosome formation is not associated with increased parental age and > 90% of i(Xq) contain proximal Xp sequences suggesting that centromere misdivision is not a common mechanism of formation. Our results indicate that the majority of i(Xq) originate from a single X chromosome and the usual mechanisms of formation do not appear to differ according to the parent of origin.

Adult↗
PubMed1997

The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission.

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.

Alleles↗
PubMed1997

Evidence for a cryptic 46,XX cell line in a 45,X/46,X,psu idic(Xq) patient with normal reproduction.

Gonadal dysgenesis resulting in primary infertility is one of the most common features of Turner syndrome. There have been a number of cases described of pregnancy in 45,X subjects, but whether or not the fertility is associated with a 46,XX cell line in the germ cells is not known. We describe a 45,X/46,X,psu idic(Xq) female with normal fertility, in whom a cryptic 46,XX cell line was found in the germ cells.

Adult↗
PubMed1996

Molecular studies of the aetiology of trisomy 8 in spontaneous abortions and the liveborn population.

We have determined the parental origin in eight cases of constitutional trisomy+ 8. In all four cases of spontaneous abortion, the additional chromosome was maternal in origin and there was evidence for nullichiasmate meiosis I occurring in the genesis of this trisomy. In contrast, all four cases of liveborn trisomy 8 appear to have arisen by a mechanism consistent with the post-zygotic mitotic gain of the additional chromosome.

Abortion, Spontaneous↗
PubMed1996

Fertility, reproductive outcomes, and health of offspring, of patients treated for Hodgkin's disease: an investigation including chromosome examinations.

Reproductive outcomes and health of offspring were investigated in 340 patients with Hodgkin's disease first treated at Mount Vernon Hospital, Middlesex, England, at ages under 40 (females) or 45 (males) during 1970-91. Information on offspring was obtained from case-notes and postal questionnaires to the patients. Eleven men and 16 women who had conceived any children after treatment were then interviewed. There was no excess of stillbirths, low birthweight or cogenital malformations, and no cancers have occurred in the 49 offspring after treatment. There was a significant excess of twins, compared with national expectations, in offspring of female patients (RR = 8.52, P = 0.025). Aggregation of series from the literature also showed an excess of twins. Chromosomes from cultures of peripheral lymphocytes from 45 children born to 25 patients (11 men and 14 women) after treatment were examined for numerical abnormalities and for structural abnormalities at the 550 or greater band level of resolution. All were normal except in one child with Down's syndrome (47, XY, +21), for whom we found the origin of the trisomy was from the parent without Hodgkin's disease. The chromosome constitution was also abnormal in one miscarriage (69, XXY; originating from the parent without Hodgkin's disease) and one termination (45, X; for with the parental origin could not be determined) after treatment. The study adds to previous questionnaire data and for the first time provides data also from chromosome analysis, that offspring of patients treated in adulthood for Hodgkin's disease are not at greatly raised risk of genotoxic or other adverse outcomes as a consequence of their parent's treatment. The numbers of offspring assessed in the literature remains small, however, and surveillance of larger numbers of subjects is needed to enable reliable treatment-specific analyses.

Adult↗
PubMed1996

Haplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome.

To understand the origins of the fragile X syndrome and factors predisposing alleles to instability and hyperexpansion, we have compared the haplotype (using markers FRAXAC1, FRAXAC2, and DXS548) and AGG interspersion patterns of the FMR1 CGG repeat for 214 normal and 16 premutation chromosomes. Association testing between interspersion pattern and haplotype reveals a highly significant (P < 0.002) non-random distribution, indicating that all three markers are useful in phylogenetic reconstruction of mutational change. Parsimony analysis of the FMR1 CGG repeat substructure predicts that loss of AGG interruptions has occurred independently on many haplotypes associated with the fragile X syndrome, partially explaining the haplotype diversity of this disease. Among haplotypes found in linkage disequilibrium with the fragile X mutation, two different modes of mutation and predisposition to instability have been identified. One pathway has involved the frequent and recurrent loss of AGG interruptions from rare asymmetrical ancestral array structures. Intergenerational transmission studies suggest that these predisposed chromosomes progress relatively rapidly to the disease state. In contrast, the second mutational pathway involves a single haplotype which has maintained two AGG interruptions. Parsimony analysis of CGG repeat substructure within this haplotype suggests that larger alleles have been generated by gradual increments of CGG repeats distal to the most 3' interruption. Pedigree analysis of the intergenerational stability of alleles of this haplotype confirms a gradual progression toward instability thresholds. As a result, a large reservoir of chromosomes carrying large repeats on this haplotype exists. These chromosomes are predisposed to disease. The present data support a model in which there are at least two different mutational pathways predisposing alleles to instability and hyperexpansion associated with the fragile X syndrome.

Alleles↗