ISSN:0148-7299    

DOI:10.1002/ajmg.1320370702

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370703

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThe most relevant data and stimulating ideas presented and discussed at the symposium are briefly summarized. They centered around four major foci: the genotype, the phenotype, the pathogenesis of Down syndrome (DS), and the Down person. The molecular genetic approaches to the isolation of genes encoded by chromosome 21, the definition of a possible “critical region,” and the acquisition of further insights on the origin of trisomy 21 were the main topics of the analysis of the genotype. The study of the phenotype concentrated essentially on three complex traits related to the nervous, immune, and hematologic systems, which show great sensitivity to developmental disturbances, with major effects on DS subjects' health and behavior. The difficulties of investigating the pathogenesis of the syndrome were outlined, but the theoretical bases for devising sound and complete experimental approaches were also delineated. Finally, the special attention that in the last decade the medical and sociopsychological sciences gave to Down persons was also underlined, and future developments indicated. DS still remains a challenge to science and medicine; however, from the symposium emerged a less pessimistic view on actual potentialities for a decisive advancement in its basic knowle

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370704

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractIn trisomy 21, pathogenesis of mental retardation is still poorly understood although the knowledge of the genic content of chromosome 21 is steadily increasing. Short of discovering how to silence selectively one of the 3 chromosomes 21, no rational medication can be envisaged before pathogenesis has been unraveled, at least partially.A biochemical scheme of impairment of mental efficiency is presented. Secondarily, the possible deleterious effects of a given gene overdose are discussed. Cu/Zn SOD, cystathionine beta synthase, S 100β protein, phosphofructokinase, purine synthesis and adenosine pharmacology, thyroid disturbance, and elevated TSH with low rT3as well as biopterine metabolism interferences are reviewed.It is observed that the metabolic paths controlled by these genes, although unrelated at first glance, are in fact tightly related by their effects, just as if synteny was in some way related to biochemical cooperation or mutually controlled regulation.Experiments in vitro have demonstrated a peculiar sensitivity of trisomic 21 lymphocytes to methotrexate. From this starting point, systematic research of special sensitivities has begun.Clinical observations and relevant statistical methods allow study of the speed of mental development under various medications. The interest of regulating thyroid metabolism, when needed, is exemplified. Reequilibration of monocarbon metabolism is discussed and the seemingly favourable effect of folinic acid medication in pseudo‐Alzheimer complication is present

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370705

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractReview of the clinical cytogenetic literature provides compelling evidence for a specific relationship between imbalance of particular chromosomes or chromosomal regions and the appearance of defined patterns of phenotypic abnormalities. In many instances, detailed phenotypic mapping has made it possible to assign portions of a phenotype to relatively small chromosome segments, which are sometimes referred to as “critical regions.” However, since these regions are usually defined by a subset of the phenotypic manifestations of an aneuploidy syndrome—generally those anomalies that are regarded as most characteristic or readily observable—it is important not to fall into the trap of thinking that it is imbalance of only these regions that has deleterious effects on development and function. Thus, in Down syndrome, the presence of an extra copy of the proximal part of 21q22.3 appears to result in the typical physical phenotype—as defined principally in terms of the characteristic facial and hand anomalies and congenital heart defect—in addition to mental retardation. But, duplication of proximal 21q also affects mental development, and the regions responsible for many other aspects of the Down syndrome phenotype, including Alzheimer disease, have not been defined at all. Therefore, it remains likely that loci present on many parts of the long arm of chromosome 21 play a role in the development of the overall phenotype of Down syndrome.The immediate effect at the molecular level of an aneuploidy‐caused alteration in gene dose appears to be a non‐compensated commensurate change in the production of gene products. Therefore, the mechanisms invoked to explain the genesis of the phenotype must be based on 50% increases and decreases in gene product synthesis in trisomies and monosomies, respectively. Despite the specificity of patterns of phenotypic abnormalities, there is both a considerable degree of variability in the expression of the individual components that constitute these patterns and a significant degree of overlap among the patterns of different aneuploid states. This variability is presumed to be the result of a combination of stochastic, environmental, and other genetic factors which impinge on but do not obscure the overall pattern of abnormalities. The overlap of phenotypes may be attributable to the involvement of many gene products of different chromosomal origin in any particular developmental pathway, and hence the susceptibility of such pathways to a variety o

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370706

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractPresent efforts to identify, isolate, and characterize in molecular terms the “consensus” segment of 21q sufficient to cause most of the major and some of the most characteristic minor manifestations of Down syndrome will soon provide answers to many questions. However, we think that a reductionist approach to explain the Down syndrome phenotype in a “linear” manner from the DNA sequence of the segment will be doomed to failure from the outset because of the open, complex, nonlinear, hierarchical nature of morphogenetic systems. Neo‐Darwinism is under strong attack; most genetic changes accumulated over time may very well be of neutral effect, and detailed studies in several related groups of vertebrate species has shown that molecular and organismal evolution are largely independent of one another. It has been pointed out recently that biology lacks a theory of ontogenetic and phylogenetic development, and that a purely “genocentric” view of biology at the expense of the complexly hierarchical intrinsic epigenetic attributes of developmental systems is “out of focus with respect to … biological organization and morphogenesis,” and may be “a residue of nineteenth century romantic idealism.”Down syndrome impresses us as a paradigm of increased developmental variability due to a deceleration of the rate of development (neoteny) with many anomalies of incomplete morphogenesis (vestigia), atavisms, increased morphometric variability with many decreased means, increased variances, and increased fluctuating asymmetry. These abnormalities, together with highly increased risk of prenatal death and postnatal morbidity, impaired growth, and abnormal CNS and gonadal structure and function characteristic of most aneuploidy syndromes, suggest to us that the pathogenesis of Down syndrome is best viewed in terms of the mechanisms of speciation. Transgenic experiment involving sequential or overlapping pieces of “the consensus segment” on distal 21q22.1–22.3 may help decide to what extent the Down syndrome phenotype can be resolved into the additive effect of several pleiotropic oligogenes with epistatic interaction or the indirect secondary “mass” effect of a specific segment of 21q with epistatic interaction involving multiple

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370707

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractIn past decades, most individuals with Down syndrome were usually not afforded adequate medical care. Many children with Down syndrome were institutionalized and they were often deprived of all but the most elementary medical services. Fortunately, there have been major improvements in the health care provision during the past 20 years.Professionals who are providing services to persons with Down syndrome need to be aware of those clinical conditions that are more often observed in this populations. Certain congenital anomalies (congenital cataracts, anomalies of the gastrointestinal tract, and congenital heart disease) often require immediate attention, as some of them may be life threatening. During the subsequent childhood years a number of clinical conditions and disorders such as infectious diseases, increased nutritional intake, periodontitis, seizure disorders, sleep apnea, visual impairment, audiologic deficits, thyroid dysfunction, and skeletal problems usually occur at a higher prevalence. During adolescence specific aspects of maturation and certain health issues (skin infections, thyroid disorders, increased weight gain, and others) as well as mental health concerns need to be taken into consideration. Similar concerns may also be observed during adulthood which in addition is often marked by accelerated aging and the threat of Alzheimer disease in some persons with Down syndrome.Special attention needs to be paid to these disorders and conditions during the lifetime of a person with Down syndrome. Appropriate medical care should be withheld from a person with Down syndrome that would be given unhesitatingly to an individual without this chromosome disorder.

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370708

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractWe investigated thyroid function of 108 home‐reared Down syndrome (DS) patients.Five had overt hypothyroidism, 2 were hyperthyroid, and 33 had high TSH values with an exaggerated response to TSH values with an exaggerated response to TRH test despite hormone levels in the normal range. This finding indicated subclinical hypothyroidism. Antithyroid antibodies (antimicrosome and antithyroglobulin) were present in 13 patients.At the same time we investigated 73 parents: only one mother was hypothyroid and antithyroid autoantibodies were found in only 8% of Down syndrome parent

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370709

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractGrowth retardation is a cardinal characteristic of Down syndrome (DS). It is most pronounced from the age of 6 months, when growth starts to become growth hormone (GH) regulated. DS children have normal serum levels of GH. GH regulates the production of insulin‐like growth factors (IGFs), which act as growth hormones. Therefore, the serum IGF pattern and the level of their receptors were studied in fetuses with trisomy 21 and in patients with DS throughout life. Serum levels of IGF were determined by radio‐immunoassays for insulin‐like growth factors 1 and 2 (RIA‐IGF‐1 and RIA‐IGF‐2) showing normal serum RIA‐IGF‐2 levels throughout life. However, serum RIA‐IGF‐1 did not rise during childhood and remained at a low level throughout life. Determination of serum IGF by a radioreceptor assay (RRA‐IGF), which detects both IGF‐1 and IGF‐2 as well as enhanced activity in the fetal circulation, showed a deficit in serum RRA‐IGF in fetuses with trisomy 21, but at birth and throughout life elevated serum RRA‐IGF levels. In spite of this, no differences were observed in fetal brain or liver binding sites for IGF‐1, IGF‐2, or insulin. Since in the RRA‐IGF method IGF‐1, IGF‐2, and a fetal form of IGF‐1 cross‐react, it is possible that there is a delayed maturation with incomplete switching from production of the fetal form of IGF to production of the GH‐regulated IGF‐1 in DS. The deficit in IGF‐1‐like peptides might account for the growth retardation in DS. In order to study the effect of human growth hormone (hGH) therapy in DS,5 growth‐retarded children with DS were treated with hGH for 6 months. During this period the growth velocity doubled and the serum IGF‐1 levels were resto

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370710

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractChildren affected with Down syndrome (DS) show deficient growth, immunodeficiency—especially concerning T‐cell population—and low plasma zinc levels. New growth charts have been recently proposed, and zinc supplementation to the diet the diet has been reported to improve transiently the efficiency of the immune system. The aim of this study was to evaluate if in DS children zinc sulphate therapy could improve the growth rate and affect some endocrine parameters. We studied 22 patients (16 males and 6 females) who received zinc sulphate for 6 to 9 months. Fifteen of 22 patients studied reached a higher centile in their growth rate, whereas the remaining seven showed no change, at least to date. The average heighty velocity changed from 23.84 ± 7.98 mm/6 months t 40.80 ± 7.68 mm/6 months. Growth hormone serum level mwas 5.94 ± 4.89 ng/ml compared with 7.49 ± 6.75 ng/ml before and after therapy, respectively. Somatomedin serum level was 160.27 ± 68.88 after therapy, respectively. In conclusion, zinc sulphate therapy of patients with DS affects not only the immune system, as previously reported, but can also acceler

ISSN:0148-7299    

DOI:10.1002/ajmg.1320370711

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY