Biomedical subjects
Publications and source records attributed to E C Jenkins.
A 12 year-old mentally retarded girl with multiple congenital malformations presented with an apparently new chromosome abnormality involving a de novo balanced reciprocal translocation between part of the long arms of chromosomes 4 and 13. This was observed in 291 metaphase spreads derived from short-term leucocyte and skin fibroblast cultures.
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We conducted an experimental trial of high-dose folic acid given to five males, ages 8 to 26 years, with the fra(X) syndrome. In this double blind study, each subject received 250 mg per day of folic acid for 3 months, followed by placebo for 3 months, and folic acid again for an additional three months. Based on IQ tests, behavior ratings, the Autistic Descriptors Checklist, and parental ratings, there was little evidence to suggest any positive effects seen during the administration of high-dose folic acid. Therefore, this study has provided little support for a hypothesis of benefit of high-dose folic acid in the treatment of the fra(X) syndrome.
The fragile X chromosome has been identified in specimens from 17 male and 10 female fetuses in 11 laboratories throughout the world, obtained from at least 79 fetuses at increased risk for the fra(X) syndrome. Of these, 19 were confirmed, 6 were pending, 1 was negative and 1 could not be confirmed. Twenty-five of the 79 cases were studied in our laboratory (Institute for Basic Research [IBR]) and resulted in fra(X) demonstration in specimens from 3 male and 5 female fetuses. All 3 males and 2 of the 5 females have been confirmed. When amniocytes from the two confirmed female fetuses were exposed to FUdR after culturing in Chang medium, fra(X) frequencies were virtually negative indicating that Chang medium should not be used in fragile X studies at least when FUdR is used to induce fragility. Finally, amniocytes from a fra(X) male fetus studied in 3 different laboratories exhibited strikingly different frequencies. To date, we have experienced no false-positives or negatives, but the latter case was controversial. It is recommended that laboratories undertaking fra(X) prenatal detection use a combination of at least two different proven induction systems as well as complementary DNA marker studies to prevent false negative diagnosis.
We screened 183 autistic males for the fra(X) and found 24 (13.1%) to be positive. Adding the subjects of this study to those of 11 other surveys, of which 6 were positive and 5 were negative, a total of 614 autistic males have been screened. Overall 47 (7.7%) were positive. Based on this estimate and the prevalence of autism and fra(X), we estimate that 12.3% of fra(X) males are autistic. We have found that 17.3% of our fra(X) males were autistic and overall a 21.2% frequency has been reported, these higher figures are most likely due to biases in age and ascertainment. With an overall 7.7% frequency of fra(X) among autistic males and an estimated 12.3% of autism among fra(X) males, we conclude there is likely to be a significant association of fra(X) with autism. Because fra(X) appears to be the single most common cause of the condition, chromosomal testing is recommended for any autistic person with undiagnosed etiology.
The effect of cell density on expression of fra(X) was studied. A lymphoblast cell line from one fra(X) individual and whole blood from another individual was tested at various cell densities using RPMI-1640 with FUdR (0.1 microM) 24 hrs before harvest. Densities from 0.25 X 10(5) to 2 X 10(6) cells/ml were tested. Chromosomes were G-banded and analyzed for fra(X) frequency. Increased density caused fra(X) frequency to decline in lymphoblasts and whole blood. In the established line low density fra(X) frequency was 51.2% and decreased to 6.5% at the high density. In blood fra(X) frequency was 34.7% at low density and decreased to 18% fra(X) in high density. We suspect that decay of the FUdR effect may explain the results. Our results suggest that to maximize fra(X) frequency, cultures should be inititated at low density. This may be important in analysis of low-percentage fra(X) patients, nonexpressing female carriers, and obligate nonpenetrant males.
Fragile X frequencies differ widely between different fra(X)-positive individuals. The basis for this variation is unknown, but may reflect genetic differences or unknown environmental factors. To determine more fully the individual and familial variation in fra(X) frequencies, we studied 15 individuals. The present study showed that fra(X) frequency, with few exceptions, was consistent for the same individual both over time and within replicate cultures. This confirms previous observations by others on the consistency of fra(X) expression by others, and indicates the extent of expected variability within replicate cultures. Consideration of this variability should enable improved fra(X) identification.
Induction of some fragile sites including fragile X [fra(X)] depends on the depletion of thymidine monophosphate (TMP) from the culture medium. This can be accomplished by use of inhibitors such as 5-fluorodeoxyuridine (FUdR) and by culturing cells in medium deficient in folate and TMP. FUdR inhibits the activity of thymidylate synthase (TS), thereby depleting cells of TMP. To determine the degree of FUdR inhibition of TS under routine cytogenetic culture conditions, we modified the tritiated dUMP TS method for use in short-term whole blood cultures stimulated with phytohemagglutinin. TS inhibition was highly variable across whole blood cultures from 30 individuals exposed to FUdR during the last 24 hours of a 4 day culture. If an additional dose of FUdR was added 12 hours before harvest, TS inhibition usually increased. These findings have a potential impact on the use of FUdR for the diagnosis of the fra(X) syndrome.