Biomedical subjects
Publications and source records attributed to A Milunsky.
A Turkish family is described with two members suffering from familial amyloidotic polyneuropathy. Their transthyretin genes were examined using the polymerase chain reaction, and both patients possessed the met30 mutation in both of their transthyretin genes. In this family, only individuals who are homozygous for the met30 mutation have developed symptoms.
We examined the relation of multivitamin intake in general, and folic acid in particular, to the risk of neural tube defects in a cohort of 23,491 women undergoing maternal serum alpha-fetoprotein screening or amniocentesis around 16 weeks of gestation. Complete questionnaires and subsequent pregnancy outcome information was obtained in 22,776 pregnancies, 49 of which ended in a neural tube defect. The prevalence of neural tube defect was 3.5 per 1000 among women who never used multivitamins before or after conception or who used multivitamins before conception only. The prevalence of neural tube defects for women who used folic acid-containing multivitamins during the first 6 weeks of pregnancy was substantially lower--0.9 per 1000 (prevalence ratio, 0.27; 95% confidence interval, 0.12 to 0.59 compared with never users). For women who used multivitamins without folic acid during the first 6 weeks of pregnancy and women who used multivitamins containing folic acid beginning after 7 or more weeks of pregnancy, the prevalences were similar to that of the nonusers and the prevalence ratios were close to 1.0.
The DNA from an individual with familial amyloidotic polyneuropathy was examined. It did not possess any of the mutations which have previously been associated with familial amyloidotic polyneuropathy. However, a novel 7.0 kb Sph I restriction fragment was discovered, and the mutation creating it was localized to exon 3 of the transthyretin gene. This mutation was inherited from a parent, and may result in an amino acid substitution for glu89, his90 or ala91. The patient's transthyretin has a lower pI than normal transthyretin.
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Here we report on three patients with dup (7p) and review the previously published 17 cases. Characteristic manifestations include severe/profound psychomotor retardation, dolichocephaly or microbrachycephaly, gaping fontanels and wide sagittal and metopic sutures, hypertelorism, large apparently low-set ears, micrognathia, choanal atresia/stenosis, hyperextensible joints subject to dislocation, joint contractures, and a high rate of cardiac septal defects. Our analysis suggests that dup(7p) is associated with a recognizable characteristic phenotype.
High resolution chromosome analysis was done on lymphoblastoid cell lines, established during the past decade from affected males with X-linked lymphoproliferative disease (XLP) or from obligate female carriers, from 14 families. One cell line, from a male with XLP, has a partial deletion of band Xq25. The constitutional nature of the deletion is confirmed in chromosome studies of peripheral blood from the affected individual and represents the first such structural defect to be described in this disorder. Cell lines from the remaining 13 families do not have cytogenetically detectable deletions. This observation will facilitate precise localization, cloning and sequencing of the gene causing XLP.
Friedreich ataxia is a progressive neurodegenerative disorder affecting the peripheral and central nervous systems. One in 50,000 of the population are affected by this recessively inherited disorder, with onset usually before puberty. The recent localization of the disease locus to chromosome 9 has made it possible to provide genetic counselling to families with at least one affected child. Tight linkage of the disease mutation to an anonymous DNA marker MCT112 (D9S15) has been shown with a pairwise lod score of 36.1 at 0 = 0. We report here the first prenatal diagnosis in Friedreich ataxia. Using MCT112 and the confidence interval approach, we have calculated risks for a fully informative family with one affected sib.
The X-linked lymphoproliferative syndrome (XLP) results in fatal infectious mononucleosis, hypogamma-globulinemia, and malignant lymphoma. The mutation has been mapped relative to several restriction fragment length polymorphism (RFLP) markers in the Xq21-Xq27 vicinity. The DXS37 locus was found to be near both the DXS42 and XLP loci.
Analysis of seven kindreds indicates that the XLP locus exhibits 1% recombination with DXS42 (lod = 17.5) and no recombination with DXS37 (lod = 13.3).
In a prospective study of maternal serum alpha-fetoprotein screening for both high and low values, we assessed the overall predictive value, sensitivity, specificity and relative risks for congenital defects and complications of pregnancy. Among 13,486 women with singleton pregnancies interviewed at the time of screening (15 to 20 weeks of gestation), 3.9% had high and 3.4% had low values. A high maternal serum alpha-fetoprotein value was associated with the following adverse outcomes: neural tube defects (relative risk = 224), other major congenital defects (relative risk = 4.7), fetal deaths (relative risk = 8.1), neonatal death (relative risk = 4.7), low birth weight (relative risk = 4.0), newborn complications (relative risk = 3.6), oligohydramnios (relative risk = 3.4), abruptio placentae (relative risk = 3.0) and preeclamptic toxemia (relative risk = 2.3). A low maternal serum alpha-fetoprotein value was associated with chromosomal defects (relative risk = 11.6) for fetal death (relative risk = 3.3). Either high or low maternal serum alpha-fetoprotein values were associated with 34.2% of all major congenital defects, 19.1% of all stillbirths and fetal-neonatal deaths, 11.0% of major pregnancy complications, and 15.9% of serious newborn complications. Maternal serum alpha-fetoprotein screening provides an important adjunctive tool for the identification of high-risk pregnancy and adverse neonatal outcome.
A cDNA coding for histatin 1 was isolated from a human submandibular-gland library and sequenced. This cDNA was used to probe RNAs isolated from a variety of tissues to investigate tissue-specific regulation and to determine whether histatins might play a role other than in the oral cavity. The same probe was also used for Southern blot analysis of human genomic DNA restricted with various enzymes, and it showed that the genes coding for histatins are on the same chromosome. In situ hybridization of the cDNA probe to metaphase chromosome spreads was performed to determine chromosomal location of the genes for histatins. A genomic fragment isolated using the cDNA probe was also hybridized to chromosome spreads, and the same chromosome was identified. The genes for histatins are located on chromosome 4, band q13. We have shown that three histatin mRNAs are expressed in human parotid and submandibular glands but in none of the other tissues studied. These results suggest that histatins are specific to salivary secretions.
Low maternal serum alpha-fetoprotein values during the second trimester of pregnancy are associated with an increased risk of Down syndrome in the fetus. In this study a sensitive, monoclonal-based radioimmunoassay for alpha-fetoprotein was used to determine whether such an association also applies to the first trimester and if maternal serum alpha-fetoprotein screening could successfully detect a significant number of pregnancies in which the fetus had a trisomy or other chromosome disorder. Sera were obtained prospectively from 540 women just before chorionic villus sampling for prenatal diagnosis of chromosome defects (largely because of advanced maternal age) at 8 to 12 weeks' fetal age and assayed for alpha-fetoprotein under code without knowledge of the cytogenetic results. Eight of 27 (29.6%) of all serious chromosome defects were associated with low maternal serum alpha-fetoprotein values (less than or equal to 0.6 multiples of the median). Overall, 59 of 540 patients (10.9%) had maternal serum alpha-fetoprotein values less than or equal to 0.6 multiples of the median, eight of whom had a fetus with a serious chromosome defect. Women whose maternal serum alpha-fetoprotein value was less than or equal to 0.6 multiples of the median had one in eight odds of carrying a fetus with a trisomy and one in seven odds of the fetus having any serious chromosome defect. From this study of a group of women at higher risk, we conclude that first-trimester maternal serum alpha-fetoprotein screening for chromosome defects is feasible. A prospective study to determine detection efficiency is now required of a consecutive routine pregnancy population in whom gestational age is determined by menstrual dates as is usually the case in clinical practice.
We measured intact hCG, free alpha hCG, and free beta hCG levels in amniotic fluid and maternal serum using specific monoclonal antibody-based immunoradiometric assays. Compared to maternal serum, amniotic fluid had low levels of intact hormone along with high levels of its free subunits. The mean amniotic fluid hCG level was 1 mg/L at 13 weeks, and it progressively decreased to 0.100 mg/L by the 23rd week. Amniotic fluid alpha hCG levels were highest at 15 and 16 weeks (0.340 mg/L) and rapidly declined to concentrations less than 0.050 mg/L at 21 weeks. Amniotic fluid beta hCG concentrations were about 0.200 mg/L between 13 and 16 weeks and progressively decreased until the 23rd week. In vitro stability studies of hCG and its subunits demonstrated that dissociation of hCG into its subunits was not responsible for these results. Both hCG and free subunits detected in amniotic fluid were indistinguishable from standard hCG and free subunit preparations, as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Our findings are consistent with the hypothesis that the presence of hCG and free subunits in the amniotic fluid represents secretion from the trophoblastic tissue into the amniotic fluid compartment. Furthermore, high serum hCG levels in association with low levels of its free subunits are probably the result of polarized secretion of the intact hormone from the syncytiotrophoblasts into the maternal circulation.
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The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predict which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.
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Low maternal serum alpha-fetoprotein levels have been associated with fetal aneuploidies. Amniotic fluid alpha-fetoprotein levels have been reported to be low with Down syndrome (trisomy 21) but not with other fetal trisomies. We compared the amniotic fluid alpha-fetoprotein levels from 25 cases of autosomal trisomy (18 of trisomy 21, four of trisomy 13, three of trisomy 18) diagnosed by midtrimester fetal cytogenetic studies with those from matched, cytogenetically normal pregnancies. With these normal pregnancies used as controls, statistical analyses were performed on the data for all the trisomic fetuses, on the data for trisomy 21 only, and on the data for trisomies 13 and 18 combined. Amniotic fluid alpha-fetoprotein levels were significantly lower in the 25 trisomic cases compared with controls, 0.77 +/- 0.34 versus 1.03 +/- 0.34 mg/dl (p less than 0.001). However, further analysis revealed that the difference was due to the trisomy 21 data alone. In the trisomy 21 cases there was a significant difference for alpha-fetoprotein levels between cases and controls (p less than 0.001), whereas there was no difference for the combined trisomy 13 and 18 cases compared to controls (p greater than 0.40). These findings suggest that the low maternal serum levels of alpha-fetoprotein reported in cases of Down syndrome may be related to reduced amniotic fluid concentrations. However, the reduced maternal serum alpha-fetoprotein levels reportedly associated with trisomies 13 and 18 do not seem to be explained by low amniotic fluid concentrations.
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