Dermatoglyphics of schizophrenics, patients with Down's syndrome and mentally retarded males as compared with Australian Europeans using multivariate statistics.

Dermatoglyphics of schizophrenics, patients with Down's syndrome and mentally retarded males were compared with those of normal Australian Europeans. A computer programme of multivariate analysis of fifteen dermatoglyphic features was utilized. This analysis produces two significant variates of each of the populations plotted in two-dimensional space. The distance, measured in arbitrary units, between any two populations was studied for its significance. It was noticed that the patients with Down's syndrome separated significantly from the rest of the groups. The importance of multivariate analysis in the study of dermatoglyphics in comparing two or more populations is discussed.     

Relationship between dermatoglyphic variability and finger length in genetic disorders: Down's syndrome]

Palmar and digital dermatoglyphics were compared in Down's syndrome patients with that in a control sample from a population. All dermatoglyphic changes characteristic of Down's syndrome were confirmed. The ridge counts along digital midlines were significantly lower in Down patients as compared to control data, especially, in little fingers, which corresponds to finger shortening in Down's syndrome. The findings agree with a suggestion that digital growth in man could be controlled by morphogenetic gradients which may be altered in genetic disorders.     

Dermatoglyphics of the relatives of children with congenital defects in development]

The localization of an axial triradius and the flexor creases were studied in 173 phenotypically normal mothers and 104 fathers of congenitally malformed children. The most pronounced changes ofdermatoglyphics were found in the parents of children with polygenic determined defects, less pronounced ones-- in the parents of children with multiple congenital non-chromosomal defects and with Down's syndrome. The frequency of the pathological features studied was similar both in children with polygenically determined isolated defects and with Down's syndrome. The frequency of the pathological determined isolated defects and in their parents. In multiple congenital defects and in Down's syndrome the abnormalities ofof the localization of an axial triradius and of the flexor creases were found in children more frequently than in the parents. It is suggested that the above mentioned peculiarities of parental dermatoglyphics may be useful for the genetic counsleling.     

Dermatoglyphics in childhood leukemia

The dermatoglyphics of 54 leukemic children do not differ significantly from those of 25 mothers and 592 unrelated controls with respect to frequency of digital pattern types, position of axial triradius, or type of palmar flexion creases. These findings do not support the hypothesis that children with leukemia have an increased frequency of unusual dermal patterns, but suggest that the dermatoglyphics of leukemic children are not distinctive and therefore have no practical value in the diagnosis of childhood leukemia. Whatever factors are responsible for the development of leukemia in children, these factors do not appear regularly to affect the differentiation of the dermal ridges.     

Red blood cell glucose metabolism in Down's syndrome

The specific activity of red blood cell glycolytic enzymes was determined in 20 Down's syndrome patients and compared with 20 normal controls. According to previous evidence, a 50% increase of phosphofructokinase and a 30% increase of glucose-6-phosphate dehydrogenase and glutathione peroxidase activity was found. Metabolic studies of the patients' erythrocytes revealed a decrease in fructose-6-phosphate and 2, 3-diphosphoglycerate concentrations, while fructose-1, 6-diphosphate and ADP both increased. Glucose utilization by intact erythrocytes from Down's syndrome patients did not differ from that of normal controls. However, addition of methylene blue or inorganic phosphate produced a higher stimulation of erythrocyte glycolysis in patients with Down's syndrome compared to controls. These metabolic abnormalities could be, at least in part, ascribed to the increased phosphofructokinase activity which is due to a gene-dosage effect.     

Dermal fibroblasts from Down''s syndrome patients share a cycloheximide-induced deficiency in collagen adhesion responses with normal aging cells

Human skin fibroblasts from three different Down's syndrome patients (trisomy 21) of very different ages have been tested for their adhesion responses on tissue culture substrata coated with type I collagen, fibronectin (FN), and their combination after or during treatment of cells with cycloheximide to evaluate limitations in specific responses. It was shown previously that in vitro-aged papillary and reticular dermal fibroblasts from normal individuals do not generate F-actin stress fibers when pretreated with cycloheximide on collagen substrata but do so on FN substrata, a deficiency linked to limiting amounts/function of collagen-specific receptors in aging cells. In these studies, all three Down's fibroblast populations demonstrated a similar deficiency in stress fiber formation, evaluated by rhodamine-phalloidin staining, upon cycloheximide treatment at all passage levels. They remained competent for stress fiber formation on FN substrata and for reorganization of microtubule and intermediate filament networks on all substrata, demonstrating the specificity for the collagen matrix and for the F-actin cytoskeleton in this deficiency. The cycloheximide-induced deficiency could be readily reversed in all three cell populations by further incubation of cells in drug-free medium and, in some cases, by prior growth of cells in ascorbate-supplemented medium to stimulate collagen and possibly collagen receptor production. However, several pieces of evidence indicate that reduced amounts of FN and collagen synthesized by fibroblasts do not contribute to the cycloheximide-induced deficiency, including the inability to reverse the effect by treatment of cells with TGF beta. Several conclusions are suggested from these studies: (a) Down's dermal fibroblasts become deficient in collagen-specific receptor(s) upon cycloheximide treatment, which leads to altered transmembrane signaling and inability to reorganize F-actin into stress fibers; (b) Down's dermal fibroblasts at all passage levels have matrix adhesive phenotypes similar to those of aging fibroblasts from normal individuals; and (c) these studies provide further support for cells from Down's patients as a genetic model of aging in normal populations.     

Dermatoglyphics in turner syndrome

Finger and Palmar dermatoglyphics in 25 karyotypically proven cases of Turner syndrome representing Northwestern region of India are presented and compared with those obtained on their 102 normal female counterparts. Predominance of ulnar loops over other patterns was recorded in turner patients. Mean total finger ridge count in Turner syndrome (147.4) remained higher than the normal females (121.1). c-d interdigital ridge count in turners remained significantly (p≤0.05) higher than their normal female counter-parts. In contrast to their western counterparts distal placement of axial triradius in both the palms of none of the Turner syndrome patients representing the current series was recorded. Occurrence of whorls and arches in hypothenar region of 12% and 4% was respectively noticed in right palm of patients. The use of distinctive dermatoglyphic features recorded amongst Turner syndrome patients representing this study may be made to corroborate diagnosis of this entity in settings where facilities to carry out karyotyping do not exist.     

Dermatoglyphic patterns in senile dementia of Alzheimer's type

Several reports suggest a genetic relationship between senile dementia of Alzheimer type (SDAT) and Down's syndrome. We have analyzed fingerprints and palmar patterns in an elderly female population comprising a group of 34 patients with probable SDAT, a group of 20 patients with other dementias, and a group of 20 non-demented controls. A bilateral Sydney line was found to be significantly more frequent in the SDAT group than in the two other groups (p less than 0.01, sensitivity 30%, specificity 95%, positive predictive value 91%, negative predictive value 61%). A bilateral Sydney line was as frequent in the SDAT group as in Down's syndrome. The limit value of the index of transversality equal or superior to 31, which is considered as a feature of Down's syndrome, was significantly more frequent in the SDAT group than in the two other groups (right hand p less than 0.05, left hand p less than 0.02). A bilateral discriminant value of this index was also significantly more frequent in the SDAT group than in the two other groups (p less than 0.02), as was an index of transversality higher than 31 on at least one hand (p less than 0.01). In contrast with other reports, we haven't found significantly different frequencies of digital ulnar loops and true hypothenar patterns between the SDAT group and the two others.     

Vitamin E concentrations in human brain of patients with Alzheimer's disease,fetuses with Down's syndrome,centenarians, and controls

The concentration of vitamin E (alpha-tocopherol) was measured in samples of cortex from patients with Alzheimer's disease (AD), fetuses with Down's syndrome (DS), and also in a group of centenarians. The mean tocopherol concentrations in the two patient groups did not differ significantly from appropriate controls. When expressed per lipid the mean tocopherol concentration of the centenarians was greater than that of the controls but this reflected a significant decrease in the lipid concentration of the former group. These results indicate that neither the normal aging processes, Alzheimer's disease, nor the increased in vitro lipid peroxidation reported in fetuses with Down's syndrome result from a gross lack of alpha-tocopherol, or cause a significant depletion of the vitamin.     

多重实时荧光PCR相对定量法快速诊断唐氏综合征

为了建立一种基于多重实时荧光相对定量PCR技术并应用之于唐氏综合征分子诊断, 选择21号染色体上唐氏综合征特异区域基因片段(DSCR3)为目的基因, 以12号染色体上的磷酸甘油醛脱氢酶基因(GAPDH)为参照基因, 设计合成两对引物以及分别以不同荧光标记的TaqMan探针, 在同一个反应管中进行扩增。以相对定量指标△CT值区分唐氏综合征患者与正常人。采用EB 病毒转化技术, 把唐氏综合征患者外周血B 淋巴细胞转化成永生淋巴母细胞系作为标准品。通过优化反应条件, 使得目的基因和参照基因的扩增效率基本一致, 接近100%, 模板浓度在3～300 ng/μL范围内, △CT值的变异系数小于15%, 浓度在30 ng/μL时, 变异系数最小(＜10%), 以该浓度的DNA作为模板进行批内和批间实验的△CT值重复性好, 变异系数分别为9.8%和13.3%。运用建立的方法检测20例唐氏综合征患者的血标本和30例正常人的血标本, 正常人△CT值范围是-1.90～-1.30, 患者的△CT值范围是-2.95～-2.15, 两组之间无交叉重叠, 有明显差异(P＜0.001)。唐氏综合征患者永生细胞系建系成功 ,染色体核型和DNA 分析表明建系前后遗传是稳定的。因此, 实时荧光定量PCR比较△CT值的相对定量法快速诊断唐氏综合征是可行的。     

Down's syndrome,Edwards' syndrome,Patau's syndrome —synthesis of glycosaminoglycans

Synthesis of glycosaminoglycans (GAGS) by fibroblasts derived from seven patients with Down's syndrome, five patients with Edwards' syndrome, and two patients with Patau's syndrome were studied in cell culture. The aneuploid strains were compared with diploid fibroblasts from age-matched controls. In terms of hyaluronic acid and sulfated GAG synthesis, the amount of synthesized hyaluronic acid was not significantly different between postnatal aneuploid strains and controls.     

BUdR-Giemsa labeling and satellite association in human leukocytes

Summary Satellite associations were analysed in differentially stained human leukocyte chromosomes, obtained from four patients with Down's syndrome and four normal probands. A particular type of close association between two acrocentrics, showing a non-random arrangement of sister chromatids in a concordant dark-to-dark and light-to-light alignment, was found to be more common in patients with Down's syndrome compared with the normal controls. Apart from this particular type of association, sister chromatids are randomly arranged in satellite associations between two acrocentrics in both groups of probands. Considerable differences in the mean frequencies of satellite associations between first and second metaphases of the same individual were found in some probands of both groups of individuals. Since a high degree of inter-individual variability in the proliferative response of human leukocytes in culture is well established, the use of BUdR-Giemsa labeling for comparative analysis of satellite association frequencies is suggested.     

Birth weight corrected for gestational age is related to the incidence of Down's syndrome pregnancies.

Three recent studies reported that early depletion of the primordial follicle pool is likely to be an independent risk factor for Down's syndrome pregnancies. The size of the primordial follicle pool at birth is determined by oogenesis and by the rate of follicle atresia during the intra uterine period. Since intra uterine growth retardation was reported to be associated with a significantly reduced primordial follicle pool at birth, we investigated the possibility of a relation between low birth weight for gestational age and the risk of a Down's syndrome pregnancy. In a case control study, 95 women with a history of a Down's syndrome pregnancy and 85 controls provided information on their own birth weight and length of gestation. Birth weight standard deviation scores, indicating the difference in birth weight from a reference group, were significantly lower in Down's syndrome mothers than in controls. These findings illustrate that the risk of a Down's syndrome pregnancy is related to a low birth weight corrected for gestational age, possibly by a causal relation between intra uterine growth retardation and the size of the primordial follicle pool.     

Proteomic evaluation of intermediary metabolism enzyme proteins in fetal Down's syndrome cerebral cortex

Trisomy 21 (Down's syndrome) is the most common genetic cause of human mental retardation. In Down's syndrome (DS) patients, deteriorated glucose, lipid, purine, folate and methionine/homocysteine metabolism has been reported. In our study, we used a proteomic approach to evaluate protein expression of enzyme proteins of intermediary metabolism in the brain of Down's syndrome fetuses. In fetal DS brain, we detected increased protein levels of mitochondrial aconitase as well as NADP-linked isocitrate dehydrogenase, decreased protein expression of citrate synthase and cytosolic aspartate aminotransferase. From two spots that corresponded to either pyruvate kinase M1 or M2 isozymes, significant elevation was observed only in one, while the second spot as well as the sum of the spots showed no differences between DS and controls. These results suggest derangement of intermediary metabolism during prenatal development of DS individuals.     

Synthesis of glycosaminoglycans in fibroblasts from abortuses with trisomy,triploidy, and from children with Down's syndrome

Summary A comparative study has been made of glycosaminoglycan (GAG) accumulation in human fibroblasts with trisomy 7 and triploidy from spontaneous abortuses, fibroblasts with triploidy from induced abortuses, fibroblasts from patients with Down's syndrome and diploid fibroblasts from age-matched controls. The study demonstrated that the incorporation of [³H]glucosamine into hyaluronic acid by fibroblasts with trisomy 7 and triploidy, established from spontaneous abortuses, and from two out of three induced abortuses with triploidy, was 2.6–5.3 times lower than control incorporation. One strain of fibroblasts from an induced abortus with triploidy (IMG-1062) did not show any differences in GAG production when compared with diploid fibroblasts. However, the strains from children with Down's syndrome revealed normal or even increased levels of hyaluronic acid production. The data support the contention that the decreased hyaluronic acid synthesis in fibroblasts with an abnormal karyotype is related to spontaneous abortion.     

Enzymuntersuchungen im Serum von schwachsinnigen Anstaltspatienten

Summary A number of enzymes alkaline and acid phosphatase, lactic acid dehydrogenase, glutamic oxalacetate transaminase (GOT), aldolase, glucose-6-phosphat dehydrogenase (G-6-PD) in the serum of 81 patients with Langdon Down's syndrome and mental deficiency (idiocy) were investigated and then compared with a sample of 37 healthy persons. The enzyme activities were determined spectrophotometrically.Statistically significant differences of alkaline and acid phosphatase, lactic acid dehydrogenase, and glutamic oxalacetate transaminase were demonstrated between oligophrenic patients and healthy persons; there was a distinct increase in the serum of patients. The values for aldolase and glucose-6-phosphat dehydrogenase were equal both in the serum of patients and of controls. There was no significant difference between the values of adult oligophrenics on one side and adult patients with Down's syndrome on the other. Until further notice children with serious mental deficiency — oligophrenics of unknown genesis as well as patients with Down's syndrome — demonstrated no definite evidence of enzymologically deviations compared with those of the control group.

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(Direktor: Prof. Dr. med. H. Schade)

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Nach einem am 22. 10. 1967 auf der 10. Tagung der Gesellschaft für Anthropologie und Humangenetik gehaltenen Vortrag.     

Thyroid hypofunction in Down’s syndrome

Oxidative stress affecting the thyroxin biosynthesis might explain the proneness of patients with Down's syndrome (DS) (trisomia 21) to develop hypothyroidism. Thyroideal cells are exposed to endogenous H2O2 that acts as a cofactor for the iodination of thyroxin precursors. The gland has high levels of selenium-containing proteins, including peroxide-detoxicating enzyme proteins. The object of the present study was to explore the hypothesis of a role of an imbalance between toxic oxygen production and protective metalloenzymes during the development of thyroid hypofunction in DS patients. We analyzed serum levels of thyroid hormones and trace metals in 38 institutionalized adults with DS, using mentally retarded subjects matched for age, sex, and behavioral function as controls. The DS patients had significantly lower mean values of free thyroxin (fT4) and increased TSH (thyroid stimulating hormone), as compared to the controls. They had lower serum selenium than the controls. A positive correlation was observed between serum concentrations of fT4 and selenium in the DS patients (r = 0.393, p < 0.05). No significant differences were found between the fT4 or the TSH concentrations in the patients with and without circulating antithyroid autoantibodies. Our results support the suggestion that thyroid hypofunction in patients with Down's syndrome in some way is linked to the low serum levels of selenium found in these patients. It is suggested that selenium-containing proteins are involved in thyroid hormonal synthesis, by protecting biosynthetic processes against the toxicity of free oxygen radicals.     

Non-random centromere division: a mechanism of non-disjunction causing aneuploidy?

Early centromere separation was investigated in 12 normal children, 14 patients with Down's syndrome and in 12 patients of children with autosomal trisomies. A significantly non-random centromere division of chromosomes was found in each of the cases. A higher frequency of early separated G chromosomes was observed in Down's syndrome. In 2 mothers of trisomy-18 patients, the early division of chromosomes 18, generally seen in normal individuals, could not be demonstrated. The possible assoication between altered sequence of centromere disision and non-disjunction needs further confirmation.     

Radiosensitivity of chromosomes in lymphocytes from Down's syndrome patients

A study was made of the yield of chromosome aberrations in gamma-irradiated G0 peripheral blood lymphocytes from 6 patients with different forms of Down's syndrome. The doses used were from 0.25 to 3.0 Gy. Seven healthy donors of different age made the control group. There was a significant increase in the yield of chromosome exchanges in lymphocytes from all the patients as compared to control. The spontaneous level of chromosome aberrations and the frequency of radiation-induced fragments did not differ from the control values. The yield of exchanges in diploid and trisomic cells from patients with the mosaic form of Down's syndrome did not change significantly as the time of cultivation was raised. The origin of DNA repair defects leading to the increased chromosome radiosensitivity in Down's syndrome is discussed.     

Dermatoglyphics in phenylketonuria

Dermatoglyphics of 100 phenylketonurics and 200 controls matched for ethnic origin and sex were compared. The present study of dermatoglyphics in phenylketonurics is consistent with results showing that single gene disorders have fewer and less striking anomalies of ridge development than diseases with gross chromosomal defects.Analysis revealed a decreased frequency of whorl patterns on the finger tips and a wider mean summed atd angle among affected females as compared to normal females. The males showed no significant differences. Limited as they were to one sex, the differences seem unlikely to be attributable to the effect of the phenylketonuric gene.This research was supported by the Minnesota Association for Retarded Children, The Graduate School of the University of Minnesota and United States Public Health Service Grant Number HD 01507-01.