Biomedical subjects
Publications and source records attributed to E Engel.
Between 1972 und 1983 85 children with myelomeningocele were treated according to the criteria for selective treatment as given by Lorber. The results of children with early or delayed operation and of those who had only supportive care are presented. Survival time and causes of death in the group of children not operated on are in particular given, the sequelae of selective treatment are discussed.
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Direct analysis of fetal DNA using restriction endonucleases constitutes a major area of progress in prenatal diagnosis. This recent technology may permit the precise identification of a mutant allele for some diseases, whereas in others it allows the familial segregation of a pathogenic allele to be followed by its linkage to a DNA sequence polymorphism. This type of analysis, available in a few centers, is currently used, among others, for the prenatal diagnosis of hemoglobinopathies such as sickle cell anemia. After fetal cells have been obtained by choriocentesis or amniocentesis, the extracted DNA is exposed to selected restriction enzymes. In the diagnosis of sickle cell anemia the mutant codon responsible for the substitution of glutamic acid by valine in the beta hemoglobin chain is no longer cut by the enzyme Mst II, due to its variance with the normal codon; this difference in fragment length is detected by DNA electrophoresis, and the particular fragments are identified by molecular hybridization with appropriate radioactive probes. Utilizing these methods the genotype of a homozygous normal fetus can be distinguished from that of a homozygote affected or a heterozygote for the sickle mutation of the beta hemoglobin chain. We have recently applied this prenatal methodology to the pregnancies of two couples from Zaire, in which each member was a proven sickle cell carrier. Fetal material was obtained in both cases by amniocentesis at the 16th week of gestation and followed by cell culture. In the first case, a 46, XX fetus, DNA (10 mcg) revealed a heterozygous sickle cell carrier genotype.(ABSTRACT TRUNCATED AT 250 WORDS)
Chromosomal syndromes may result from extremely small cytogenetic alterations, involving as little as one chromosomal sub-band. An example is the cri-du-chat (cat cry) syndrome, in which the critical deletion appears to involve the sub-bands 5p15.1-3. Aside from a sporadic deletion of 5p, the loss of material may result from an interstitial deletion, caused by the malsegregation of a balanced parental translocation, or, in exceptional cases, as the consequence of a sporadic or familial chromosomal inversion which has been modified by unequal crossing-over (recombination aneuploidy). In addition, in certain children with the clinical syndrome (11 of 331 in a recent review) the deletion cannot be proven cytogenetically and is presumed to be submicroscopic. In the case described here, an intrachromosomal rearrangement of chromosome 5--an invper(5)(p15q14 or 15) or an ins(5) (p15q12q12)--is segregating in the maternal family. Three of the four children born to the couple were abnormal. The first boy, affected with cleft lip, pyloric stenosis and inguinal hernias, died at 4 months of age. The second died at 3 weeks with microcephaly and agenesis of the corpus callosum, cleft palate, heart malformation, and sexual ambiguity. A third boy, now 14 years old, is phenotypically normal and has a normal karyotype. The female proband, seen by us at 9 years of age, showed the clinical features of the cri-du-chat syndrome, with severe psychomotor and staturoponderal retardation, facial dysmorphism, congenital heart defect, and the peculiar voice for which she had received the nickname of "kitten". Her karyotype shows the same variation of chromosome 5 present in her mother and grandmother, characterized on G bands by an additional dark band on 5p15. As there is no evidence for a reciprocal translocation in the mother, the most probable explanation is that of a familial inversion or insertion within chromosome 5. This rearrangement, subject to meiotic modifications, could have been responsible for the complex malformations observed in 3 of the 4 children, including our proband who has a clinical diagnosis of the cri-du-chat syndrome.
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Bloom syndrome (BS) was diagnosed in a 7-year-old boy during hospitalization for acute lymphoblastic leukemia (ALL). The patient had most of the signs of BS along with some atypical manifestations: absence of telangiectases, obesity, and moderate mental retardation. Results of the cytogenetic studies were fully consistent with the diagnosis of BS: the occurrence of quadriradial figures and a very high incidence of sister-chromatid exchanges (SCE). This child's ALL was of non-B, non-T type with the presence, at the time of diagnosis, of a marrow clone including two markers. A Yq - chromosome was detected in about 10% of PHA-stimulated lymphocytes but neither in bone marrow cells nor in skin fibroblasts. This case is the fifth instance of ALL out of 104 registered cases of BS.
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Secretion of HCO-3 by the gastric epithelium has been thought to lower the concentration of H+ in the gastric mucus layer. This has been analyzed mathematically to include the HCO-3-H+ reaction, bulk water flow, diffusion, ion-ion electrical interaction, and ion-fixed charge interaction. The reaction-electrodiffusion problem is solved by use of singular perturbation theory. We show that there is a very thin layer for the reaction, equivalent to a sink of H+. In this layer there is negligible HCO-3 accumulation. A steady-state model is satisfactory if gastric mixing motions are more frequent than every 3 min. H+ concentration at the epithelium decreases with increased bicarbonate secretion, increased volume flow associated with bicarbonate secretion, increased thickness of the mucus layer, increased fixed negative charge of the mucus, and decreased cation flux into the lumen. The resultant lowering of H+ concentration may be as small as 5 mM but is probably considerably larger. Determining the actual drop will depend on more precise experimental measurements of the parameters of the problem.
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A 3 1/2-year-old boy is described whose Down syndrome resulted from partial 21 trisomy through unbalanced de novo translocation between the long arm of chromosome 21 and the short arm end of a No. 5: 46,XY,t(5;21)(p15;q11). This case is discussed and compared with 17 others collected from the literature, some of which derived from a maternal balanced translocation.
Simplified "overnight" and longer term primary culture techniques are described for obtaining chromosome preparations from tiny chorionic villi samples (5-15 mg).
In the nearly last two years, using ten different media combinations in our research for the fragile X, we have observed cytogenetic variations, the knowledge of which may be useful for correct diagnosis. This experience, based on more than 6000 metaphases in 41 cases, includes 5 typical probands, 4 obligate and 4 possible heterozygotes, 19 deficient psychopaths, and 9 controls. Three main techniques were retained as shown in the text. In this study a fragile site was documented on 239 chromosomes of the C or X group, among which 180 could be specifically identified by trypsin Giemsa banding. Of these 180 fragile sites, X involvement was shown in 101 cells, and 55 other lesions were found to affect a chromosome 6. In our experience, none of 1180 cells from 9 control individuals were positive. It thus may be that under rigorous culture conditions the occurrence of one single fragile X at q27 or q28 is suggestive of the presence of the underlying mutation. In 19 cases studied because of mental and psychotic problems, nonetheless considered as clinically negative, only 2 out of 2510 cells had a fragile X, whereas frequency among cytogenetically verified X in our positive cases varied from 4 to 20% cells. We have come to distinguish five variations in the cytogenetic aspect of this site on the X, shown from A to E in a figure, two of which (D and E) may not have been described before. In rare cases this fragility usually seen as a chromatid or isochromatid gap may be present as a break with a resulting "double minute" found elsewhere in the metaphase field.(ABSTRACT TRUNCATED AT 250 WORDS)
A congenital chromosome abnormality was found in two unrelated children with acute lymphoblastic leukemia (ALL). In the first case, a pericentric inversion of chromosome No. 11, inv(11)(p15q13), was observed and discovered to be familial, being present in five other members of the family over two generations. In the second case, the presence of a congenital ring chromosome No. 21, 46,XX,r(21), was considered to be the result of a de novo mutation. The possible relation between these congenital chromosome anomalies and a predisposition to neoplasia is discussed and could be explained by different mechanisms: (1) amplification of oncogenic determinants by gene duplication, and/or (2) alteration of the effects of wildtype alleles through deletion or changes in position.
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