William J. Mellman

The fetal trimethadione syndrome

Three families are described in which each of the mothers took trimethadione during pregnancy. From a comparison of siblings in each family and of others exposed to trimethadione in utero, a specific phenotype is delineated. Features included in the fetal trimethadione syndrome are developmental delay, speech difficulty, V-shaped eyebrows, epicanthus, low-set ears with anteriorly folded helix, palatal anomaly, and irregular teeth. Additional anomalies in some of the patients include intrauterine growth retardation, short stature, microcephaly, cardiac anomaly, ocular anomaly, hypospadias, inguinal hernia, and simian creases.

A familial syndrome of renal, genital, and middle ear anomalies.

A family is described in which 4 female siblings showed varying degrees of renal dysgenesis, ranging from unilateral hypoplasia to bilateral agenesis. This was associated with internal genital malformation, in particular vaginal atresia, and with anomalies of the ossicles of the middle ear.

Familial spongy degeneration of the central nervous system (Van Bogaert-Bertrand disease) - An ultrastructural study

SummaryLight and electron microscopy study of skeletal muscle and cerebral biopsies from a case of spongy degeneration of central nervous system is reported. The multiple vacuoles present in cerebral gray and white matter correspond to (a) clefts within myelin sheaths resulting from splitting at the intraperiod line and (b) swollen astrocytic perikarya and processes. Unusual mitochondria containing crystalline-like material were observed only in astrocytes. The ultrastructural findings are consistent with cerebral edema. It is suggested that the astrocytes play a primary role in the fluid accumulation while the myelin swelling is a secondary lesion. The possible role of the abnormal astrocytic mitochondria is discussed.ZusammenfassungEs wird über licht- und elektronenoptische Untersuchungen an Muskel-und Hirnbiopsien eines Falles von spongiöser Degeneration des ZNS berichtet. Die in der grauen und weißen Hirnsubstanz enthaltenen Vacuolen entsprechen a) Spalten in den Markscheiden infolge Aufsplitterung an der intraperiodischen Linie und b) geschwollenen Astrocytenperikaryen und-fortsätzen. Ungewöhnliche Mitochondrien mit Gehalt an kristallinem Material fanden sich nur in Astrocyten. Die ultrastrukturellen Befunde entsprechen denen des Hirnödems. Es wird angenommen, daß die Astroglia eine primäre Rolle in der Flüssigkeitsansammlung spielt, während die Markscheidenschwellung als eine Sekundärläsion aufgefaßt wird. Die mögliche Bedeutung abnormer Astrocyten-Mitochondrien wird diskutiert.

Galactosemia: Evidence for a Structural Gene Mutation

Identical immunoprecipitin reactions appeared in double immunodiffusion between rabbit anltibodies to human galactose-1-phosphate uridyl transferase and red cell preparations from both normal and galactosemic individuals. The galactosemic erythrocyte preparations quantitatively absorbed the antiboy that immunoprecipitates enzymatically active galactose-1-phosphate uridyl transferase.

Galactosemia: Symptomatic and asymptomatic homozygotes in one Negro sibship

The case histories of 2 Negro brothers are presented. Neither child hasgalactose-1-phosphate uridyl transferase activity in his circulating red cells, and thus each fulfills the laboratory criterion for the diagnosis of congenital galactosemia. One sibling demonstrated a classic galactosemic picture in infancy, while the other brother has never exhibited any signs or symptoms which could be attributed to galactosemia. Metabolic studies on the asymptomatic brother appear to place him in a subgroup of atypical “galactosemic patients,” as previously delineated by Segal and co-workers.5

Turner's syndrome in the male***

Summary 1. Five patients with the symptom complex described as Turners syndrome in the male are presented. Sixteen additional cases have been collected from the literature. The associated anomalies are summarized. 2. Chromosomal counts in 2 of our patients showed the diploid number of 46 without recognizable abnormalities. This is in accord with other reports. 3. It is suggested that the so-called Turners syndrome in the male is not a well-defined entity supported by objective chromosomal aberrations. Rather, it may represent several loosely related clinical conditions of unknown etiology. The marked clinical similarity, in some instances, to gonadal dysgenesis may signify that the somatic anomalies in the latter are not clearly attributable to the observed chromosomal defect.

ABNORMAL LYMPHOCYTE FUNCTION IN TRISOMY 21

The effect of trisomy 21 on cellular function has been a continuing concern of our laboratory since we observed, in 1964, that the leukocytes in the circulation of individuals with mongolism frequently had higher enzyme activities than did those of nonmongoloid subjects with mental retardati0n.l Originally, we had undertaken these studies in an attempt to localize to chromosome 21 the genetic determinants of specific enzymes. When we found that the measured activity of an X-linked enzyme, glucose-6-phosphate dehydrogenase, was increased in direct proportion to that of other enzymes, we concluded that the enzyme hyperactivity detected in leukocytes of mongols probably reflected a disorder of cellular physiology rather than the expression of dosage for gene determinants controlling specific enzymes. This contention was reinforced by our next study on this subject which revealed that the circulating granulocytes of four out of five adults with mongolism had a significant shortening of their half-life in the circulation.2 On the basis of measurements of total body granulocyte pools, we concluded that the shortened circulating half-life reflected an increase in granulocyte turnover rate. In support of this conclusion was the correlation that we found between circulating granulocyte half-life and urinary excretion of uric acid. The study reported here represents our attempt to determine if there is also a disorder of lymphocyte function in individuals with mongolism. We were aware of several reports that have appeared in the past two years which suggest that there are atypical responses in vitro of lymphocytes from mongols in both the mixed leukocyte reaction and after exposure to phytohemagglutinin (PHA)..?s4 There are also studies of the enzyme activities of both cultured and uncultured lymphocytes from mongols that show increased activities of enzymes similar in proportion to those found in the Our study has compared the response to PHA of lymphocytes in culture from mongols and controls. We have estimated DNA synthetic rates at varying doses of PHA, and after different periods of incubation in the presence of PHA.

Standardized karyotype of deer mice, Peromyscus (Rodentia)

£A standard G-band karyotype is proposed for the genus Peromyscus . G-banded chromosomes of Peromyscus boylii glasselli (NF = 56), numbered and arranged according

Mosaic mongolism. II. Cytogenetic studies

Cytogenetic studies were performed on 8 persons with mosaic mongolism (46/47, 21+). It was found that the leukocyte culture can be used with confidence to determine the proportion of trisomic and normal cells at a single point in the life of the individual. However, we observed that in 7 subjects who had leukocyte cultures analyzed after periods of up to 7 years, there were significant shifts in the proportion of trisomic cells in 4 (3 had decreased and the other had increased percentages of trisomic cells). Long-term cultures of skin fibroblasts led to marked increases in the percentage of trisomic cells after several months of serial subculture. This information seriously challenges any attempts to correlate data on the proportions of trisomic cells in cultured tissues of persons with mosaic mongolism with the phenotype of mongolism.

Galactose-1-phosphate uridyltransferase and galactokinase activity in cultured human diploid fibroblasts and peripheral blood leukocytes: I. Analysis of transferase genotypes by the ratio of the activities of the two enzymes

The specific activities of galactokinase and galactose-1-phosphate uridyltransferase were determined in peripheral blood leukocytes directly after separation from whole blood, and in cultured skin fibroblasts at various times during the subculture growth period. Growth curves were obtained for fibroblasts based on three different parameters: direct cell counts, total protein, and total deoxyribonucleic acid (DNA) content. At the time in culture when the specific activity of both enzymes was maximal and least variable, the ratio of transferase to galactokinase correlated well with the transferase genotypes of the original tissue donors. Leukocyte transferase: galactokinase ratios gave a similar distribution pattern. Whereas transferase activity in both fibroblasts and leukocytes was similar, galactokinase was approximately three times as active in fibroblasts as in leukocytes. All fibrobast cell strains tested had similar galactokinase activity regardless of transferase genotype.The kinetic properties of fibroblast galactokinase were examined. Galactose-1-phosphate inhibits galactokinase activity in both normal and galactosemic cell strains, whereas other glycolytic intermediates have no effect. There was no detectable transferase activity in eight galactosemic (Gt(G)/Gt(G)) cell strains when transferase activity was maximal in cell strains of other transferase genotypes. Inhibitors responsible for the absence of transferase activity could not be demonstrated. In addition, transferase activity in galactosemic cell lysates was not observed in cells during logarithmic growth; measurable uridine diphosphate galactose (UDPgal) pyrophosphorylase activity was found in human diploid fibroblast cultures, as well as significant levels of endogenous uridine triphosphate (UTP) in lysates of fibroblast cultures.