Myelin deficiency in female rats due to a mutation in the PLP gene.

Myelin deficiency (md) in female rats due to a mutation in the X-linked proteolipid protein (PLP) gene is caused by X-chromosome monosomy. Cytogenetic analysis revealed a single X karyotype [41,X(md/0)]. An immunocytochemical, electron microscopic, and biochemical study was performed on male and female md rats. The central nervous system (CNS) of the female md rat [41,X(md/0)] revealed the same total lack of PLP as the CNS of the affected male littermate [42,XY(md/Y)]. Immunocytochemistry for myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNP) revealed "islands" of myelin sheath-like reaction product in both. Electron microscopy showed great paucity of compact myelin sheaths in 41,X(md/0) and 42,XY(md/Y). Reduced levels of MPB, MAG, and CNP were confirmed for both sexes but MAG and CNP were substantially higher in 41,X(md/0). Sexual differentiation of the brain may account for the observed differences since normal female reproductive organs are present in the md female rat.

How much difference does chromosome banding make? Adjustments in prevalence and mutation rates of human structural cytogenetic abnormalities.

A collaborative analysis was undertaken of 226 karyotypes with structural chromosome abnormalities diagnosed primarily with low level banding resolution, about 300 to 400 bands per karyotype. We estimate that in this series, use of low level banding was required to detect about 78% of pericentric inversions, about 51% of reciprocal translocations, about 47% of all balanced translocations, about 35% of unbalanced rearrangements other than rings, Robertsonian translocations and extra structurally abnormal chromosomes, about 11% of all unbalanced rearrangements, and about 35% of all structural abnormalities. Adjustment factors derived from these figures were applied to prevalence and mutation rates of structural mutation rates derived from published large scale studies of livebirths. Had low level banding been used in these earlier studies we estimate that the rate of all structural abnormalities would have been about 60% higher than those reported (3.8 per 1000 vs. 2.3 per 1000 in the original studies). The increase is much higher for balanced abnormalities, 75% (3.4 per 1000 vs. 1.9 per 1000), than for unbalanced abnormalities, 5% (0.42 per 1000 vs. 0.405 per 1000). The increase in mutation rates for de novo cytogenetic abnormalities was similarly, considerably higher after such adjustment: the rates per 100,000 gametes increased from 18.0 to 35.0 for balanced rearrangements, from 8.2 to 10.1 for unbalanced abnormalities and from 26.2 to 45.1 for all abnormalities. These estimates illustrate the difference even low level banding makes to detection of structural cytogenetic abnormalities and why contemporary studies using such methods cannot be compared with earlier large scale population studies or livebirths without some type of adjustment such as those suggested here.(ABSTRACT TRUNCATED AT 250 WORDS)

Inherited structural cytogenetic abnormalities detected incidentally in fetuses diagnosed prenatally: frequency, parental-age associations, sex-ratio trends, and comparisons with rates of mutants.

Rates of structural chromosome abnormalities were analyzed in 24,951 fetuses studied prenatally in which there were no grounds to suspect an inherited abnormality. In about one in 200 prenatal cytogenetic diagnoses, an unexpected structural abnormality was found. The observed rate was 5.3 per 1,000, of which 1.7 per 1,000 were unbalanced and 3.6 per 1,000 balanced. The rate of inherited abnormalities was 3.1-3.7 per 1,000 (0.4-0.9 per 1,000 for unbalanced abnormalities and 2.6-2.8 per 1,000 for balanced abnormalities). The rate of mutants in this series was, by contrast, 1.6-2.2 per 1,000 (0.8-1.2 per 1,000 for unbalanced abnormalities and 0.8-1.0 per 1,000 for balanced abnormalities). The rate of balanced Robertsonian translocation carriers was 0.6 per 1,000 (about 0.25 per 1,000 for mutants and 0.35 per 1,000 for inherited abnormalities), and for other balanced abnormalities, 3.0 per 1,000 (about 0.6 per 1,000 for mutants and 2.4 per 1,000 for inherited abnormalities). The rates of unbalanced Robertsonian translocations was about 0.1 per 1,000, almost all of which were mutants. For supernumerary rearrangements, the rate was 0.9 per 1,000 (about 0.4 per 1,000 inherited and 0.5 per 1,000 mutant). The rates of all unbalanced (nonmosaic) inherited abnormalities (4.0-5.2 per 10,000) were intermediate between higher rates estimated in all conceptuses (9.1-15.8 per 10,000) and rates observed in newborns (1.5-2.5 per 10,000). This trend is probably attributable to fetal mortality associated with unbalanced rearrangements. The rates of balanced (nonmosaic) inherited abnormalities (26.0-28.0 per 10,000), however, were considerably higher than the rates in all conceptuses (13-16.7 per 10,000) or in all live births (12.2-16.0 per 10,000). The major difference was in the rate of inversions. The use of "banding" methods in the studies of amniocentesis but not in most of the live births or abortus studies probably contributes to at least some of these differences. One trend in parental age among the inherited abnormalities was noteworthy. Paternal age was elevated for inherited balanced reciprocal structural abnormalities of paternal origin but not of maternal origin. With regard to sex ratio, there was a greater proportion of females than males among the unbalanced rearrangements both inherited and mutant. There was no obvious sex difference among the balanced rearrangements.

Decreased HLA heterogeneity in parents of children with Down syndrome.

HLA-A and B antigens were determined in a study of 37 couples and their children with trisomy 21 Down syndrome (DS), using a standard microlymphocytotoxicity test. The comparison groups included 76 couples and their healthy children. All individuals were Caucasians from the same geographical area, and there was no history of consanguinity. The parents of children with DS did not show an association with a specific HLA antigen or haplotype. Sixteen of the 37 couples (43.24%) having children with DS share two or more antigens at the A and/or B locus. This was significantly higher than the proportion in the control group (6/76, or 7.88%). Of the 16 couples having children with DS and sharing two or more antigens, eight had a haplotype in common, in contrast with only two couples in the control group. The data suggest that sharing of parental HLA-A and B antigens may be related either to the occurrence of trisomy 21 zygotes or to prenatal survival of affected embryos and fetuses.

Rates of mutant structural chromosome rearrangements in human fetuses: data from prenatal cytogenetic studies and associations with maternal age and parental mutagen exposure.

In 27,225 prenatal cytogenetic studies of amniotic fluid reported to the New York State Chromosome Registry and the United States Interregional Chromosome Register System, there were 61 cases with a structural chromosomal abnormality not known inherited, a rate per 1,000 of 2.24. Of these 33, 1.21 per 1,000 were known de novo and nonmosaic; consequently, the rate of events resulting from germinal mutation is highly likely to be between these two limits. The rates per 1,000 of unbalanced abnormalities were 0.59-1.29; of balanced abnormalities, 0.62-0.96; of balanced Robertsonian translocations, 0.22-0.29; and of unbalanced Robertsonian translocations, 0.07-0.11. The rates of fetuses with supernumerary markers and fragments were unexpectedly high: 0.26-0.70 per 1,000. These abnormalities were associated with increased maternal age (38.0 +/- 5.4 to 38.4 +/- 3.6 compared to 35.6 +/- 4.3 in controls), but even after adjustment for the bias to preferential study of older women, the observed rates of these supernumerary abnormalities were greater than would be expected from live-birth studies or rates estimated in all recognized conceptuses. There were trends to elevated maternal age for the group of all balanced rearrangements, and to diminished maternal age for the nonsupernumerary, non-Robertsonian unbalanced rearrangements. In 136 women studied primarily because of exposure to a putative mutagen, a de novo deletion and an inversion not known inherited were detected. The rate of abnormality in these 136, 1.47%, was significantly greater than the rate of abnormality in the remainder: 0.14%-0.22%.

Abortions because of unavailability of prenatal diagnosis.

PIP: Many women who seek amniocentesis will subsequently seek an abortion if an abnormality is found, yet it does not necessarily follow that such abortions are the only social consequences of the procedure. A survey of genetics centers in North America provides strong indirect evidence that, for many women, the test offers reassurance and encourages the continuation of pregnancy. Many women in the United States have sought an abortion because such diagnosis was unavailable to them or because the results were inconclusive. Many of the latter had a low risk (under 2%) of having a defective child. The 117 genetics centers responding (out of 152 in a national directory) reported 67 women who chose abortion because prenatal diagnosis was not available or practical. The number of abortions reported because of unavailability of prenatal diagnosis is a least estimate and does not include male fetuses detected prenatally in carriers of X-linked conditions such as hemophilia or muscular dystrophy. In addition, genetic centers and laboratories could only report cases that came to their attention, not women who many have aborted after their obstetricians or other physicians told them that no test was available. Some women choose abortion rather than run a very small increased risk of having a child with an abnormality. On the basis of the survey results it is believed that of the many women who agree to amniocentesis and for whom there are normal findings, a significant number would have chosen abortion in the absence of the reassurance provided by the normal results.^ieng