Gertrude Kohn

Cytogenetic investigations in families with ataxia-telangiectasia

Chromosomal studies were performed on peripheral blood lymphocytes and cultured skin fibroblasts from five Israeli-Moroccan families with ataxia-telangiectasia. A total of 24 individuals, including seven propositi, was investigated. Among the probands, significantly elevated rates of chromosome damage were observed in both blood and skin. Skin fibroblasts of affected individuals showed several orders of magnitude more chromosome breakage than lymphocytes. Increased rates of chromosome damage were also observed in the fibroblasts of some phenotypically normal family members (obligate heterozygotes and sibs) when compared to normal controls. An apparent abnormal clone of cells, possessing a large acrocentric marker chromosome (14q+), was observed in varying proportions among cells of all the propositi (2-5% of lymphocytes; 1-9% of fibroblasts).

Male pseudohermaphroditism due to 17β-hydroxysteroid dehydrogenase deficiency: Studies on the natural history of the defect and effect of androgens on gender role☆

Studies within the Arab population in Israel revealed 25 pseudohermaphrodites due to 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) deficiency. Twenty-three individuals, presently living in the Gaza strip, belong to a very large inbred kinship which extends over 8 generations. All affected subjects (46, XY) were born with mild to moderate degrees of ambiguity of an apparently normal-looking female genitalia and therefore were reared as girls. In childhood, genital abnormalities consisted of a clitoral-like phallus surrounded by a chordee, non-fused labial-scrotal folds and a urogenital sinus. The testes were in the inguinal canals, or rarely, in the labial-scrotal folds. Wolffian structures were normally differentiated while Mullerian structures were absent. At puberty, subjects developed a male body habitus with abundant body hair and beard. Gynecomastia was absent. The phallus and testes enlarged to adult proportions while the prostate remained small. Together with the physical change from girls to boys they developed a male identity having erections and ejaculations, which in 7 cases led to the spontaneous adoption of a male gender role. In adults the hormonal abnormalities consisted of greatly elevated delta 4-androstenedione (delta 4) (350-1267 ng/dl) associated with subnormal testosterone (T) levels (0.9-3.1 ng/ml). Dihydrotestosterone (DHT) levels, with the exception of 1 patient, were relatively low in all cases (27-35 ng/dl). Children had low levels of delta 4, T and DHT, which were normal for age. Although from puberty on there was a significant rise of the 3 androgens, delta 4 always remained extremely elevated and T and DHT relatively low when compared to normal controls. Dexamethasone failed to suppress the androgen pattern while HCG augmented the defect, making the diagnosis possible in 2 prepubertal children. Dehydroepiandrosterone (DHEA) and 17-hydroxyprogesterone (17-OHP) levels were normal or moderately elevated. Estradiol (E2) levels were normal in children and all but 2 adults, who had high levels. LH and FSH levels were very high after puberty, but normal before. However, there was an overresponse to LHRH in all age groups. The contrast between the lack of intrauterine virilization of the external genitalia in fetuses with 17 beta-HSD deficiency versus the marked masculinization that occurs after puberty still remains a puzzling phenomenon. It is conceivable that the postpubertal development of a male phenotype with change of gender identity and role occurs due to the joint effect of delta 4, T and DHT, even though secreted in inadequate proportions. Thus masculinization in these individuals is a slow process requiring a longer period of time than that of normal puberty to be completed.

Abnormal ganglioside accumulation in cultured fibroblasts from patients with mucolipidosis IV.

Abstract Extracts of cultured skin fibroblasts derived from patients with mucolipidosis IV showed a marked increase and altered distribution of GM 3 and GD 3 gangliosides. GD 3 is elevated 1.5–2 times that of normal whereas GM 3 is elevated to a lesser extent. No abnormalities were found in the neutral glycolipids. These two gangliosides apparently comprise most of the accumulated lipid-like material observed on ultrastructural analysis in this disease.

Mucolipidosis type IV: ganglioside sialidase deficiency.

Summary A solubilized sialidase is partially deficient in cultured fibroblasts derived from skin biopsies of four mucolipidosis IV patients. Fibroblasts from two obligate heterozygotes also have sialidase activity lower than normal controls. Membrane-bound sialidase activity is not affected in this disease. Based on previous and present findings, we propose that this solubilized activity is probably lysosomal origin. Sialidase activity in mucolipidosis IV cells is normal when neuraminlactose is used as substrate. Mixing cell homogenates from mucolipidosis IV patients and from controls results in the expected combined sialidase activity, indicating the absence of an internal inhibitor in the deficient cells. It is therefore suggested that the mutation in mucolipidosis IV specifically affects a lysosomal ganglioside sialidase, while the remaining non-lysosomal sialidases partially mask this deficiency.

Ataxia telangiectasia: chromosomal stability in continuous lymphoblastoid cell lines

Chromosomal breakage in peripheral lymphocytes, cultured fibroblasts and long-term lymphoblastoid cell lines was investigated in five hitherto undescribed patients with ataxia telangiectasia (AT). Increased chromosomal instability was observed in lymphocytes and fibroblasts, and clones possessing a Dq+ marker were observed. Breakage rates were significantly higher in the fibroblasts than in the lymphocytes of AT patients or in similar tissues from patients with Bloom syndrome or Fanconi anemia. However, chromosome breakage in lymphoblastoid lines established from these five AT patients and six others did not differ from controls. These observations suggests that selection pressures, in vivo or in vitro, or both, act differently on the expression of chromosomal instability in these various cell types.

Prenatal diagnosis of ataxia telangiectasia

INCREASED SPONTANEOUS CHROMOSOME BREAKAGE rates in peripheral blood lymphocytes and cultured skin fibroblasts is characteristic of ataxia telangiectasia. 1 Recently, we have shown the presence of a clastogenic factor, a low molecular weight peptide, in plasma of patients with AT and in conditioned medium from their cultured skin flbroblasts2 ~ Normal human lymphocytes cultured in AT fibr0blast conditioned medium or in plasma from AT patients show an increased chromosome breakage rate (0.10 breaks per cell) as compared to controls (0.00 to 0.03 breaks per cell). In this report we describe the prenatal diagnosis of a fetus at risk for AT, based on the presence of the clastogenic factor in the amniotic fluid, as well as on spontaneous chromosome breakage and a chromosomal translocation involving chromosome 14 in the cultured amniotic fluid cells. The diagnosis has been confirmed by an increased spontaneous chromosome breakage rate in the fetal amniotic membrane cells.

Prenatal diagnosis of mucolipidosis IV by electron microscopy

Mucolipidosis IV, a recently recognized metabolic storage disease, is characterized clinically by corneal opacity in infancy, full facial features, and psychomotor retardation. Electron microscopy of cells from a 2-year-old affected girl revealed multiple cytoplasmic storage bodies. Cultured amniotic fluid cells, in two subsequent pregnancies, demonstrated similar abnormal storage bodies. Electron microscopic examination of various uncultured tissues from one abortus demonstrated abnormal inclusions in the cells of the brain, cornea, conjunctiva, and other epithelial tissues, thus confirming the prenatal diagnosis. This suggests that mucolipidosis IV is an autosomal recessive trait and demonstrates the efficacy of electron microscopy in the prenatal diagnosis of metabolic storage diseases whose biochemical defect is yet unknown.

THE PLACENTAL SEPTA

THE human placenta is divided into about 15-20 cotyledons, these divisions being visible on its maternal surface. Between the cotyledons, there extends a groove deep into the placental tissue in which lies a thin membrane, the placental septum, whose origin and composition has long been the subject of controversy. This membrane does not reach to the chorionic membrane, and does not form a complete separation between two cotyledons. On the average, however, it covers more than half the depth of the intercotyledon groove, and it is to be seen most easily from the side of the decidual plate. Grosser (1927) reviewed the varying opinions then held as to whether the septum is of maternal or foetal origin. He was of the opinion that the part of the septum nearest to the maternal surface can be found to contain decidual cells, and that most of the rest of the septum is an empty network, into which trophoblastic cells have invaded. He thinks that many septa, towards the end of pregnancy, especially those parts distant from the decidual plate, are composed of foetal elements. Schroeder (1 930) also stated that the septum was of foetal origin. More recently, other investigators have continued the controversy, and in the FIAT Review of German Science (1948) the statement is made that the septa are undoubtedly foetal in origin, an opinion agreed to by Stieve (1940). Eastman (1956) has described the placental

Farage, a Novel Early B Cell Lymphoma Cell Line with Trisomy 11

Farage, a new cell line established from a lymph node biopsy of a patient with non-Hodgkins lymphoma (NHL), constitutes a clonal expansion of cells at a distinct stage of B-cell differentiation. The cells lack both T and myeloid surface markers, express B cell surface antigens including CD19, CD20, CD22, HLA-DR, were positive for C3 receptors and EBNA and expressed BCL-2. No immunoglobulin determinants could be demonstrated on the cell surface. Intracellular IgM and kappa chains were detected, in an unusual but distinct localization and appeared to be localized to the nucleus or to the perinuclear area without any spread to the cytoplasm, as seen in the early B cells. Southern blot DNA analysis showed rearrangement of one of the IgJH alleles. The Farage cells were negative for B cell activation antigens including CD25, CD11b, HC2 and Bly-7. The cells were negative for two anti CD-10 (CALLA) reagents but weakly positive with one. Interestingly they were strongly positive for both nuclear and cytoplasmic T...

Spondyloepiphyseal dysplasia tarda: a new autosomal recessive variant with mental retardation.

A new variant of spondyloepiphyseal dysplasia tarda with mild to moderate mental retardation is described in three daughters born to healthy, consanguineous parents. The mode of inheritance is compatible with that of an autosomal recessive disorder. The identification of this variant is important, as it enables more precise counselling in families in which sporadic cases with this form of presentation are found.