X;14 translocation:an exception to the critical region hypothesis on the human X-chromosome.

We report on a family in which an X;14 translocation has been identified. A phenotypically normal female, carrier of an apparently balanced X-autosome translocation t(X;14)(q22;q24.3) in all her cells and a small interstitial deletion of band 15q112 in some of her cells had 2 offspring. She represents a fifth case of balanced X-autosome translocation with the break point inside the postulated critical region of Xq(q13 q26) associated with fertility. The break point in this case is located in Xq22, the same band as in four previously published exceptional cases. In most of her cells, the normal X was inactivated. Her daughter, the proposita, has an unbalanced karyotype 46,X,der(X), t(X;14)(q22;q24.3)mat, del(15)(q11.1q11.3)mat. She is mildly retarded and has some Prader-Willi syndrome manifestations. She has two normal 14 chromosomes, der(X), and deletion 15q11.2. Her clinical abnormalities probably could be attributed to the deletions 15q and Xq rather than 14q duplication. In most of cells, der(X) was inactivated. We assume that spreading of inactivation was extended to the 14q segment on the derivative X. Late replication and gene dose studies support this view. Another daughter, who inherited the balanced X;14 translocation and not deletion 15 chromosome, is phenotypically normal.

Moving satellites and unstable chromosome translocations: clinical and cytogenetic implications.

We describe 2 families in which acrocentric short arm material moved from one chromosome to another. In case 1, a meiotic event resulted in movement of an unusually large paternal 21p to chromosome 13 in the fetus. In case 2, a mitotic event resulted in fetal mosaicism. The short arm material from a paternal chromosome 15 moved to chromosome 14 in some of the fetal cells. Movement of acrocentric short arm material resulted from breakage and exchange in centromeric areas of repetitive DNA. We suggest the mechanism may be similar to that of previously reported "jumping" translocations. Failure to recognize movement of the short arms of acrocentric chromosomes can result in erroneous interpretation of prenatal cytogenetic results and of other cytogenetic assays dependent on acrocentric short arm polymorphisms.

Trisomy 15 mosaic derived from trisomic conceptus: report of a case and a review.

We report on a fetus with 47,XX,+15 chromosome abnormality detected on chorionic villus sampling (CVS). The pregnancy was terminated at 15.5 weeks of gestation and chromosome analysis done on amniocytes and fetal tissues showed a karyotype 46,XX/47,XX,+15. Autopsy showed multiple abnormalities. Short-arm polymorphisms of the three number 15 chromosomes were highly informative in the delineation of parental origin and the stage of meiotic error. Using fluorescent in situ hybridization (FISH) with D15Z1 and a chromosome 15 painting probe, in addition to DA/DAPI and G-banding, we were able to show that the trisomic conceptus was derived through maternal meiosis I error. The trisomic state was then partially corrected by the loss of one of the two maternal 15s resulting in mosaicism without uniparental disomy (UPD). Striking differences in the proportion of trisomic cells in kidneys, blood, intestine, and skin, and lower proportions of trisomic cells in transformed and frozen than in fresh tissues, illustrate the continuing cell selection in this fetus in favour of the normal cell line. Trisomy 15 conceptions are usually aborted spontaneously in the first trimester of pregnancy. The longer survival of this fetus is most probably the result of a chromosome 15 loss from the trisomic zygote. To the best of our knowledge, the presence of this lethal trisomy has been reported in only five live-born infants, and in five fetuses including the present case, it was detected prenatally and the pregnancies were terminated.

Family with 22-derived marker chromosome and late-onset dementia of the Alzheimer type: I. Application of a new model for estimation of the risk of disease associated with the marker.

We have identified 2 sisters with probable dementia of the Alzheimer type who have an unusual 22-derived marker chromosome with a greatly elongated short arm containing 2 well-separated nucleolus organizer regions. A marker chromosome similar in appearance is uncommon in the general population. Eleven of 24 of their biological relatives were also found to have the marker. The known pedigree of this family encompasses 6 generations in 2 of which there is evidence of 10 cases of dementia of the Alzheimer type. The average age-at-onset of dementia is 65.8 +/- 5.5 years; the average age-at-death among those apparently affected is 74.9 +/- 8.3 years. A new model for the estimation of risk was applied to the family data. Persons in this family with the marker were found to be 4 times more likely to develop dementia than those without the marker, the 95% confidence interval for this risk being 1-50. The probability that the association of dementia and the marker is due to chance alone is .05 (1 in 20).

Red cell superoxide dismutase, glutathione peroxidase and catalase in Down syndrome patients with and without manifestations of Alzheimer disease.

The activities of red blood cell enzymes that scavenge the superoxide radical and hydrogen peroxide were measured in severely to profoundly retarded adult Down syndrome (DS) patients with and without manifestations of Alzheimer disease (AD), and control individuals matched for sex, age, and time of blood sampling. Cu,Zn superoxide dismutase (SOD-1) and glutathione peroxidase (GSHPx) activities were significantly elevated (1.39-fold and 1.24-fold, respectively) in DS individuals without AD. When an adjustment was made for the SOD gene dosage effect, DS patients with AD manifestations had significantly lower SOD levels than the matched control individuals. In contrast, DS patients with and without AD had a similar elevation in GSHPx (an adaptive phenomenon). The mean catalase (CAT) activity was no different in DS and control individuals; however, in a paired regression analysis, DS patients without AD had marginally lower CAT activity than control individuals, whereas DS patients with AD had slightly but not significantly higher CAT activity. Thus, AD manifestations in this DS population are associated with changes in the red cell oxygen scavenging processes.

Age-associated chromosome 21 loss in Down syndrome: possible relevance to mosaicism and Alzheimer disease.

We previously observed low level mosaicism (2-4% normal cells) in phytohemagglutinin-stimulated peripheral blood lymphocytes (PBL) in 29% of a small group of elderly persons with Down syndrome (DS). An analysis of cytogenetic data on 154 trisomy 21 cases (age 1 day to 68 years) showed that the proportion of diploid cells in such cultures significantly increased (P < 0.005) with advancing age. Thus, the "occult" mosaicism in PBL of the elderly persons with DS is likely due to the accumulation of cells that have lost a chromosome 21. A consequence of chromosome 21 loss could be uniparental disomy of the 2n cells, a factor that might have significant biological consequences if some chromosome 21 genes are imprinted. Loss of a chromosome 21 from trisomic cells might result in tissue-specific mosaicism and "classical" mosaicism in different age groups. Chromosome 21 loss might also be relevant to the development of Alzheimer-type dementia in DS and in the general population.

Autoimmune thyroiditis associated with mild "subclinical" hypothyroidism in adults with Down syndrome: a comparison of patients with and without manifestations of Alzheimer disease.

Serum tests of thyroid function were compared in Down syndrome (DS) patients with and without manifestations of Alzheimer disease (AD). Relative to control individuals, DS patients had, overall, lower mean total T4 (P = 0.070) and T3f (P = 0.015), higher T3U (P = 0.013) and TSH (P = 0.020), no difference in free T4, and higher thyroid antithyroglobulin (ATA) (P = 0.033) and antimicrosomal autoantibody (AMA) titres (P = 0.0097). Similar trends were apparent in DS males and females, and in DS patients off all drugs. In an analysis of case/control pairs with corrections for age and sex, DS patients with AD manifestations (n = 9) had significantly lower T3 (P = 0.029) and higher AMA (P = 0.043) than paired control individuals, whereas DS patients without AD manifestations (n = 20) had significantly lower T3 (P = 0.013) but higher ATA (P = 0.0065). T3 was significantly lower in the DS patients with AD manifestations than in the unaffected (P = 0.0013). These data suggest that autoimmune thyroiditis associated with a mild "subclinical" form of hypothyroidism is common in adult DS patients and more pronounced in patients with AD manifestations than in those without. This "subclinical" hypothyroidism may contribute to cognitive deficits in ageing DS patients.

Evidence for the inheritance of silver-stained nucleolus organizer regions.

The inheritance of nucleolus organizer regions (NORs) was investigated by examining the degree of silver-staining in individual acrocentric chromosomes in two successive generations. The study was undertaken in six Down's syndrome children and their respective parents. Quinacrine fluorescent polymorphisms were used to identify individual acrocentrics and to determine which of the child's acrocentrics were informative as to parental homologue of origin. Of the 66 acrocentrics in the six children, 31 were informative. The correlation between the degree of silver=staining in the child's chromosomes and the respective parental chromosomes of origin was highly significant (P less than 0.001), with a correlation coefficient of 0.90. The results suggest that the degree of Ag-AS staining is characteristic for a particular chromosome and that this characteristic is an inherited property.

Dic(21;21) in a Down's syndrome child with an unusual chromosome 9 variant in the mother.

A child with characteristic clinical features of Down's syndrome and raised red cell SOD-1 activity was found to have, in addition to a single chromosome 21, a reverse dicentric tandem translocation of two No 21s with dual NORs and C band regions. The breakpoints on the chromosomes involved in the translocation were at the most distal end of the long arms (21q223). The phenotypically normal mother carried a rare variant of a chromosome 9.

Methylation of the 5' flanking sequences of the ribosomal DNA in human cell lines and in a human-hamster hybrid cell line.

In a human lymphoblastoid cell line (Z83) in which rDNA genes on chromosome 22 are amplified but transcribed at a low level, immunocytological studies with antibodies to 5 methylcytidine provided evidence for hypermethylation of the rDNA. The extent of methylation of the 5' flanking sequences of the ribosomal DNA was examined by comparing the size of restriction fragments obtained by digestion of genomic DNA with EcoRI and HpaII or EcoRI and MspI. Southern blots indicated hypermethylation of the 5' flanking sequences of many copies of rRNA genes in these cells, but not in a control lymphoblastoid cell line without rDNA amplification. Results obtained with a somatic hybrid human-hamster cell line, in which the rRNA genes on the single human chromosome 22 are inactive, showed that only a small fraction of the CCGG sites in the 5' flanking sequences of the transcriptionally silent rRNA genes in this hybrid were methylated. Since inactive rRNA genes can show such a minimal level of methylation, it is likely that the extreme hypermethylation of the amplified rRNA genes in Z83 occurred in association with their inactivation rather than following it.

Expression of an X-linked muscular dystrophy in a female due to translocation involving Xp21 and non-random inactivation of the normal X chromosome.

A young female was diagnosed as having X-linked muscular dystrophy of the Duchenne type. Chromosome studies, including trypsin-Giemsa banding, Quinacrine fluorescence, and nucleolus organizer region (NOR) silver staining revealed an X-autosome reciprocal translocation t(X;21) (p21;p12). Utilizing both [3H] thymidine autoradiography and the BrdU-Hoechst 33258-Giemsa technique, lymphocytes and fibroblasts were found to show a preferential inactivation of the normal X suggesting the presence of a single mutant gene on the translocated X. This patient is one of seven reported cases of an X-linked muscular dystrophy associated with an X-autosome translocation. In all seven cases the exchange point in the X chromosome is in band p21 at or near the site of the Duchenne gene.