New Orleans, LA
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September 13-14, 2003 New Orleans, LA | |
Posted with the permission of the Trisomy 21 Research Foundation Board of Directors. Conference DVD & VHS Cassette orders |
Down syndrome (DS) or trisomy 21 is a complex genetic and metabolic disorder due to the presence of 3 copies of Chr 21. The extra chromosome derives from the mother in 93% of cases and is due to the failure of normal segregation during meiosis. Except for advanced age, maternal risk factors for having a child with DS are not known. Our preliminary study suggested that increased homocysteine associated with low folate and a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR C677T) gene may increase the risk of having a child with DS. A subsequent larger study confirmed increased risk associated with the MTHFR polymorphism and also found that a second polymorphism in the methionine synthase reductase gene (MTRR A66G) also increased maternal risk. The combined presence of both polymorphisms conferred a greater risk than either alone. DS is also a major cause of pregnancy failure with an estimated 80% fetal loss. It is unclear, however, whether fetal survival is a chance event or whether a maternal-fetal interaction could promote survival. The cystathionine beta synthase gene is located on Chr 21 and its overexpression in DS reduces homocysteine levels. We evaluated the within family transmission of the MTHFR 677 T allele to liveborn infants with DS and found a preferential transmission of the T allele that could provide a survival advantage in the context of elevated maternal homocysteine. Our most recent work has focused on mechanisms of abnormal chromosome segregation with folate deficiency. Experiments with in vivo and in vitro models suggest that DNA hypomethylation in pericentromeric repeats promotes a decondensed chromatin structure that may predispose to abnormal chromosome segregation.
Humans utilize folic acid for a complex array of metabolic reactions that maintain a fine balance between the processes of DNA synthesis, RNA synthesis, genomic stability, amino acid synthesis, DNA methylation pattern maintenance, and cellular integrity. More than a dozen key enzymes are involved in cellular folate metabolism and genetic variants of a number of these enzymes have been identified that may disrupt the fine balance of cellular processes. The methylene-tetra-hydro-folate reductase (MTHFR) gene plays a key role in folate metabolism and MTHFR variants have been associated with both genetic disease susceptibility and resistance. Interestingly, only about 5% of Caucasians are homozygous for the pristine wild type MTHFR gene. It is our thesis that this ancient folate biochemical pathway interconnects energy metabolism with biosynthesis and growth, and represents an extensive evolutionary experiment that is still in progress.
CBS, like superoxide dismutase (SOD) is located in the Down Syndrome Critical Region of Chromosome 21. Previous research has suggested that overexpression of CBS, which converts homocysteine to cystathionine, may cause the "trapping" of folic acid species in the form of 5-methyltetrahydrofolate. Secondarily, the lack of homocysteine compromises the S-Adenosylmethione (SAM) cycle, which is involved in critical biomethylation pathways. We have begun a new project in metabonomics in which we are evaluating the impact of CBS on folate metabolites and on other metabolites, particularly those downstream from CBS action, including cystathionine and cysteine. The potential impact of overexpression of CBS in Down Syndrome in the production of toxic metabolites is a focus of this new project, and will be the central focus of this presentation.
[Abstract not available]
It is today well known, that the metabolism of persons with Down syndrome differs from persons with a normal complement of chromosomes. Pathological workups for purine, carbohydrate and homocysteine - cysteine metabolism are typical in persons with Down syndrome. These distinctive features correlate, at least partially, with gene over-expression caused by the additional 3rd chromosome 21 characteristic of persons with Down syndrome. We can found some clinical correlates of this pathological metabolism, in the immune system, growth, lipoprotein metabolism, brain metabolism. We demonstrate, that modified nutrition, Targeted Nutrition and regular physical exercise is a great benefit for people with Down syndrome. The children and adolescents have profits on different levels. Reducing body weight, optimizing their blood-checks, reduction of infections rates, increase of ability, progress in mobility and fun!
I will be presenting the results of a 2-year cohort study on 400 patients with Down syndrome using NuTriVene-D or using an over-the-counter vitamin preparation. The study will present data on growth, infection rate and development in this study population. After attending this presentation the attendee will understand the results of the study and its implications.
The incidence of DS in Egypt is 1:650 live births. Mental retardation due to multiple etiologies represents 40% of all referred cases to our Department. Down syndrome was the etiological cause in 12% of all mentally retarded cases and represented 5% of the total referred cases. Our Department in NRC is a referral Center for physicians from all over Egypt. In our effort to provide help to those desperate children and their families, we were the first to introduce the early intervention service for children with DS in 1995, for this we used special evaluation programs to teach and assess the cognitive, language and motor skills. We have already succeeded in reducing the decline in the intellectual development that occurs in the absence of intervention. Also we constructed a computer assisted procedure of Multimedia Instruction Program to assist children with DS based on what normal children should know. This project was applied for the first time in Egypt. In this presentation, I will focus on the following outputs of our research on these patients:
Detailed results will be presented.
Down syndrome (DS) caused by trisomy 21 is associated with an increased incidence of congenital anomalies, neurodevelopmental impairment and accelerated ageing. DS receives the highest ranking among genetic conditions (above Werner and Cockayne syndromes) for its association with premature aging. The most salient physical features associated with precocious aging in individuals with DS include: immune deficiencies and dysfunction, cataract formation, hearing-loss, skin atrophy and Alzheimer's-type neuropathology. The oxidative stress hypothesis of aging proposes that cellular senescence is mediated thru the cumulative effects of oxygen radicals, superoxide anions (·02-), hydroxyl radicals (·0H) and hydrogen peroxide (H202) which are generated as a byproduct of normal oxidative phosphorylation.
Evidence suggesting that increased oxidative stress is related to the early cognitive manifestations of DS has been argued for over a decade. The source of reactive oxygen in DS remains unknown. One hypothesis that gene dosage for SOD1 represents the most important source of free radicals in this condition has been questioned; as increased gene dosage for SOD1 has repeatedly been shown to confer protection from oxidative stress in a number of different experimental paradigms.
Respiring mitochondria represent the major source of superoxide production in most cell types, and superoxide anions have been shown to function as direct precursors of mitochondrial hydrogen peroxide formation. Superoxide is generated within mitochondria when electrons are released out of sequence in the electron transport chain and transferred directly to molecular oxygen. Recent methods allow for the measurement of intramitochondrial superoxide anion formation by respiring macrophages using lucigenin-derived chemiluminescence (LDCL).
A three-group, cross-sectional design was utilized to compare LDCL measurements from young children with DS (n=46) with children with cognitive impairment (CI) of unknown etiology (n=30), and typically developing (Nl) children (n=43). Data was analyzed using Pearson's zero-order correlations and multivariate analysis of variance (MANOVA). DS subjects had significantly elevated LDCL signal compared to Nl subjects (p=.03). This study provides new and direct evidence regarding the source of reactive oxygen species in this condition. The role of the mitochondria as a primary source of superoxide anion production and the mechanisms underlying its generation in DS deserves further study.
The purpose of this paper is to illustrate the value and need of some common optometric treatments not often considered in the Down syndrome population to enhance visual function and performance. The talk will discuss the difference between sight and vision, and point out some of the common functional visual problems associated with Down syndrome and how they can affect behavior, development, and learning. The speaker provides a unique perspective as a father of a child with DS, and on how these treatments work at home. The talk will include several select case studies from numerous consulting cases to demonstrate the above situations and how practical clinical applications can offer a better opportunity for this population to integrate academically, socially, and occupationally. The format of this presentation will attempt to relate to the lay as well as professional community. Specifically, the paper will discuss the visual problems of accommodation (focusing), strabismus (misaligned eye), diplopia (double vision), binocular vision (using both eyes together to gain depth perception) and visual perception (visual interpretation and understanding) and how the use of lenses, prisms, patching, and vision therapy can help. The results of which can vary considerably, and yet can have profoundly positive results allowing improvement in ability to read, work on midline, execute a more appropriate gait, and move more deliberately.
This session will present an overview of the nature of sensory processing and its effect on learning, communication, and motor skills. Teaming, as well as the benefits of a sensory/communication based approach to programming in the home and school setting will be emphasized.
This presentation will give parents an overview of the development of Down Syndrome "myths" related to feeding and speech development within this population. Parents will gain understanding of what Oral-Motor and Feeding therapy is and how exercises in both areas can improve speech clarity. Parents will leave with 2 therapy techniques that they can implement at home based on information in Oral-Motor Exercises for Speech Clarity by Sara Rosenfeld-Johnson.
A brief summary of nutrients, herbs and pharmaceuticals that enhance particular aspects of cognitive performance, with special relevance to Down syndrome and brain development.
I will be presenting the results of my 4-year cohort study on the use of Targeted Nutritional Intervention in Trisomy 21 along with the use of essential fatty acids and medication intervention. In addition, I will be presenting my medical guidelines for medical intervention in children and adults with Trisomy 21. At the end of this presentation the attendee will understand some of the reasoning and protocols for using Targeted Nutritional Intervention and how to medically manage children and adults with Trisomy 21.
[Abstract not available]