Biogerontology 7 (4): 211-220 (Aug 2006)
Multiple evidence for an early age pro-oxidant state in Down Syndrome patients
Pallardó FV¹, Degan P, d'Ischia M, Kelly FJ, Zatterale A, Calzone R, Castello G, Fernandez-Delgado R, Dunster C, Lloret A, Manini P, Pisanti MA, Vuttariello E, Pagano G
¹Department of Physiology, University of Valencia, E-46010, Valencia, Spain
Oxidative stress has been associated with Down syndrome (DS) and with its major phenotypic features, such as early ageing. In order to evaluate an in vivo pro-oxidant state, the following analytes were measured in a group of DS patients aged 2 months to 57 years: (a) leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG); (b) blood glutathione; (c) plasma levels of: glyoxal (Glx) and methylglyoxal (MGlx); some antioxidants (uric acid, UA, ascorbic acid, AA and Vitamin E), and xanthine oxidase (XO) activity. A significant 1.5-fold increase in 8-OHdG levels was observed in 28 DS patients vs. 63 controls, with a sharper increase in DS patients aged up to 30 years. The GSSG:GSHx100 ratio was significantly higher in young DS patients (< 15 years), in contrast to DS patients aged ≥15 years that showed a significant decrease in the GSSG:GSHx100 ratio ratio vs. controls of the respective age groups. Plasma Glx levels were significantly higher in young DS patients, whereas no significant difference was detected in DS patients aged ≥15 years. Unlike Glx, the plasma levels of MGlx were found to be significantly lower in DS patients vs. controls. A significant increase was observed in plasma levels of UA in DS patients that could be related to an increased plasma XO activity in DS patients. The plasma concentrations of AA were also increased in young (< 15 years) DS patients, but not in older patients vs. controls in the same age range. The levels of Vitamin E in DS patients did not differ from the values determined in control donors. The evidence for a multiple pro-oxidant state in young DS patients supports the role of oxidative stress in DS phenotype, with relevant distinctions according to patients' ages.
Clin Chem Lab Med 44 (3): 306-10 (2006)
Markers of oxidative stress in children with Down syndrome
Zitnanova I, Korytar P, Sobotova H, Horakova L, Sustrova M, Pueschel S, Durackova Z
Institute of Chemistry, Biochemistry and Clinical Biochemistry, Medical Faculty, Comenius University, Bratislava, Slovakia.
BACKGROUND: Persons with Down syndrome have increased vulnerability to oxidative stress caused by overexpression of superoxide dismutase, an antioxidant enzyme coded on chromosome 21. Increased oxidative stress may lead to oxidative damage of important macromolecules. We monitored this damage by measuring levels of different biomarkers of oxidative stress (protein carbonyls and 4-hydroxy-2-nonenal), as well as plasma antioxidant capacity, in children with Down syndrome. A total of 20 children with Down syndrome and 18 healthy individuals were recruited for this purpose. METHODS: Plasma protein carbonyls were measured using an ELISA technique, 4-hydroxy-2-nonenal was monitored by HPLC and the antioxidant capacity was evaluated using a ferric reducing ability of plasma (FRAP) assay. RESULTS: We found that children with Down syndrome had significantly elevated levels of protein carbonyls compared to healthy controls (p < 0.01). Levels of 4-hydroxy-2-nonenal and antioxidant capacity were similar in both groups. CONCLUSION: Our results on oxidative damage to proteins confirm the assumption of increased oxidative stress in individuals with Down syndrome.
Mayo Clin Proc 80 (12): 1607-11 (2005 Dec)
Oxidative stress and hematologic and biochemical parameters in individuals with Down syndrome
Garcez ME, Peres W, Salvador M
Instituto de Biotecnologia e Departamento de Ciencias Biomedicas, Universidade de Caxias do Sul, RS, Brazil
OBJECTIVE: To evaluate the levels of thiobarbituric acid reactive substances (TBARS), uric acid, and seric superoxide dismutase and catalase activities, as well as total serum iron, total iron-binding capacity (TIBC), erythrocyte osmotic fragility, and hemograms in people with Down syndrome. PARTICIPANTS AND METHODS: The study sampled (July to December 2003) 50 people with Down syndrome and 50 individuals without Down syndrome (control group) matched by age and sex. The levels of TBARS were measured by the TBARS method. Serum superoxide dismutase and catalase activities and uric acid levels were determined spectrophotometrically. Erythrocyte osmotic fragility was assessed by the percentage of hemolysis. Hemograms, total serum iron level, and TIBC were determined with automated systems. RESULTS: The results showed that levels of TBARS, uric acid, and seric superoxide dismutase and catalase activities were higher in the Down syndrome group compared with the control group. We also observed a slight increase in erythrocyte osmotic fragility in the Down syndrome group, but the total serum iron levels, TIBC, and hemograms for both groups were within the age-related reference values. CONCLUSION: This was the first time, to our knowledge, that increases in seric superoxide dismutase and catalase activities were observed in people with Down syndrome. Although other studies are necessary, our results add to the understanding of the mechanisms responsible for the increased oxidative stress observed in individuals with Down syndrome and may be useful in supporting future antioxidant therapies that will improve the lives of people with Down syndrome.
Life Sci 76 (12): 1407-26 (2005 Feb 4)
Anti-oxidant gene expression imbalance, aging and Down syndrome
Department of Biotechnology, Brain Insights, Inc., 17801 Sky Park Circle # K, Irvine, California 92614, USA
The expression of copper zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), glutathione peroxidase (GPx), and catalase (CAT) genes have been detected in human skin fibroblast cells for 2 year normal child (control), 50 year old normal male and female and a 1 year old Down Syndrome (DS) male and female with established trisomy karyotype using the RT-PCR technique. Differential expression of these genes is quantified individually against a beta-Actin gene that has been employed as an internal control. The immunoblotting of cell lysate proteins with polyclonal antibodies exhibit SOD1 (16 kD), SOD2 (40 kD), GPx (23 and 92 kD), CAT (64 kD), and Actin (43 kD) as translational products. The results demonstrate that the enhancement in the level of mRNAs encoding SOD1 in DS male and female, as well as aged male and female are 51, 21, 31 and 50% respectively compared to the normal child (control). In SOD2, DS male and female display higher (176%) and lower (26%) levels of expression whereas aged male and female exhibit enhanced levels of expression (66 and 119%) respectively compared to the control. This study demonstrates that DS affects the female less than the male whereas in the aging process, the female is more prone to oxidative damage than the male. These results not only indicate that the level of GPx mRNA is constant except in DS male, which shows a downward regulation but that even CAT mRNA is upward regulated in aged as well as in DS males and females. These disproportionate changes in anti-oxidant genes, which are incapable of coping with over expressed genes, may contribute towards the aging process, dementia and Down syndrome.
Med Hypotheses 64 (3): 524-32 (2005)
Thiel R, Fowkes SW
Center for Natural Health Research, Down Syndrome-Epilepsy Foundation, 1248 E. Grand Avenue, Suite A, Arroyo Grande, CA 93420, USA
Individuals with Down syndrome have signs of possible brain damage prior to birth. In addition to slowed and reduced mental development, they are much more likely to have cognitive deterioration and develop dementia at an earlier age than individuals without Down syndrome. Some of the cognitive impairments are likely due to post-natal hydrogen peroxide-mediated oxidative stress caused by overexpression of the superoxide dismutase (SOD-1) gene, which is located on the triplicated 21st chromosome and known to be 50% overexpressed. However, some of this disability may also be due to early accumulation of advanced protein glycation end-products, which may play an adverse role in prenatal and postnatal brain development. This paper suggests that essential nutrients such as folate, vitamin B6, vitamin C, vitamin E, selenium, and zinc, as well as alpha-lipoic acid and carnosine may possibly be partially preventive. Acetyl-L-carnitine, aminoguanidine, cysteine, and N-acetylcysteine are also discussed, but have possible safety concerns for this population. This paper hypothesizes that nutritional factors begun prenatally, in early infancy, or later may prevent or delay the onset of dementia in the Down syndrome population. Further examination of these data may provide insights into nutritional, metabolic and pharmacological treatments for dementias of many kinds. As the Down syndrome population may be the largest identifiable group at increased risk for developing dementia, clinical research to verify the possible validity of the prophylactic use of anti-glycation nutrients should be performed. Such research might also help those with glycation complications associated with diabetes or Alzheimer's.
Ital J Biochem 52 (2): 72-9 (2003 Jun)
Aminoacid profile and oxidative status in children affected by Down syndrome before and after supplementary nutritional treatment
Ciaccio M, Piccione M, Giuffre M, Macaione V, Vocca L, Bono A, Corsello G
Cattedra di Biochimica Clinica, Facolta di Medicina e Chirurgia, Sezione di Biochimica Medica, Dipartimento di Biotecnologie Mediche e Medicina Legale, Universita degli Studi di Palermo, Palermo, Italy
Down syndrome is the most common autosomal aberration among liveborns, characterised by several clinical features and metabolic disturbances. Aminoacid pathways abnormalities and defective oxidative balance are the most common metabolic problems in Down Syndrome. To evaluate the biochemical responses of children with Down Syndrome to a nutritional regimen supplemented with aminoacids, vitamins and polyunsaturated fatty acids, we submitted 86 subjects divided in two groups (0-6 and 6-12 years) to the dosage of plasma levels of aminoacids, antioxidant enzymes activities and reactive oxygen species, before and after 12 months of such nutritional supplementation and in relation to normal controls. The results obtained showed a tendency towards the values of normal subjects with statistically significant differences. Although other studies must be performed to confirm and define such report, our experience supports the usefulness of a nutritional supplementation with aminoacids, vitamins and polyunsaturated fatty acids, also considering the absence of side effects.
J Pediatr 142 (5): 583-5 (2003 May)
Glutathione metabolism and antioxidant enzymes in children with Down syndrome
Pastore A, Tozzi G, Gaeta LM, Giannotti A, Bertini E, Federici G, Digilio MC, Piemonte F
Laboratory of Biochemistry, Molecular Medicine Unit, Children's Hospital and Research Institute Bambino Gesu, Rome, Italy
Oxidative stress has been proposed as a pathogenic mechanism of atherosclerosis, cell aging, and neurologic disorders in Down syndrome. This study demonstrates a systemic decrease of all glutathione forms, including glutathionyl-hemoglobin, in the blood of children with Down syndrome. Furthermore, we obtained a disequilibrium, in vivo, between the antioxidant enzyme activities.
J Neural Transm Suppl 67: 67-83 (2003)
An altered antioxidant balance occurs in Down syndrome fetal organs: implications for the "gene dosage effect" hypothesis
de Haan JB, Susil B, Pritchard M, Kola I.
Monash Institute of Reproduction and Development, Centre for Functional Genomics and Human Disease, Monash University, Clayton, Victoria, Australia
Down syndrome (DS) is the congenital birth defect responsible for the greatest number of individuals with mental retardation. It arises due to trisomy of human chromosome 21 (HSA21) or part thereof. To date there have been limited studies of HSA21 gene expression in trisomy 21 conceptuses. In this study we investigate the expression of the HSA21 antioxidant gene, Cu/Zn-superoxide dismutase-1 (SOD1) in various organs of control and DS aborted conceptuses. We show that SOD1 mRNA levels are elevated in DS brain, lung, heart and thymus. DS livers show decreased SOD1 mRNA expression compared with controls. Since non-HSA21 antioxidant genes are reported to be concomitantly upregulated in certain DS tissues, we examined the expression of glutathione peroxidase-1 (GPX1) in control and DS fetal organs. Interestingly, GPX1 expression was unchanged in the majority of DS organs and decreased in DS livers. We examined the SOD1 to GPX1 mRNA ratio in individual organs, as both enzymes form part of the body's defense against oxidative stress, and because a disproportionate increase of SOD1 to GPX1 results in noxious hydroxyl radical damage. All organs investigated show an approximately 2-fold increase in the SOD1 to GPX1 mRNA ratio. We propose that it is the altered antioxidant ratio that contributes to certain aspects of the DS phenotype.
Pediatr Neurol 27 (1): 36-8 (2002 Jul)
Perinatal growth of prefrontal layer III pyramids in Down syndrome
Vuksic M; Petanjek Z; Rasin MR; Kostovic I
Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000, Zagreb, Croatia
We analyzed the dendritic differentiation of layer IIIc pyramidal neurons of prefrontal cortex (prospective area 9) in the brains of a premature infant and a 2.5-month-old infant with Down syndrome and two age-matched control subjects during the peak period of dendritic growth and differentiation. Our quantitative analysis supports qualitative observation and revealed no significant differences in the tempo and mode of dendritic differentiation between normal and Down syndrome cases. Thus we have concluded that the children with Down syndrome from our study begin their lives with morphologically normal layer III pyramidal neurons. Our findings suggest that pathologic changes of key prefrontal input-output neuronal elements begin to develop in Down syndrome after 2.5 months of postnatal age.
Eur J Paediatr Neurol 6 (4): 213-9 (2002 Jul)
Systematic review of the effect of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome
Department of Paediatric Neurosciences, King's College Hospital, London, UK
The objective was to evaluate the effects of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome. The study design was a systematic review of randomized controlled trials of dietary supplements and/or drugs reporting any assessment of cognitive function in subjects with Down syndrome. Eleven trials were identified with 373 randomized participants. None of the trials reported cognitive enhancing effect in subjects with Down syndrome. Meta-analysis was not conducted due to the heterogeneous nature of the population, interventions and outcome measures used. Overall, the quality of the trials was poor with few subjects and generally inadequate allocation concealment of the treatments given. This comprehensive systematic review provides no positive evidence that any combination of drugs, vitamins and minerals enhance either cognitive function or psychomotor development in people with Down syndrome. However, because of the small number of subjects involved and the overall unsatisfactory quality of the trials, an effect cannot be excluded at this point. At present there is no justification for the use of such regimes outside the context of large well designed trials. Parents of children with Down syndrome should be actively discouraged from giving these 'miracle drugs' to their children.
Free Radic Biol Med 31(4): 499-508 (2001 Aug 15)
Influence of age on activities of antioxidant enzymes and lipid peroxidation products in erythrocytes and neutrophils of Down syndrome patients
Muchova J, Sustrova M, Garaiova I, Liptakova A, Blazicek P, Kvasnicka P, Pueschel S, Durackova Z
Institute of Medical Chemistry, Biochemistry, and Clinical Biochemistry, Faculty of Medicine, Comenius University, Bratislava, Slovakia
Thirty-seven individuals with Down syndrome (DS) were divided into four age categories: (i) 1 to < 6 years, (ii) 6 to < 13 years, (iii) 13 to < 20 years, and (iv) over 20 years. Activities of antioxidant enzymes found in individual age categories were different, but the differences between age groups were not statistically significant. We confirmed significantly higher activities of Cu/Zn superoxide dismutase (SOD) and glutathione peroxidase (GPx) in blood cells of people with DS as compared to 35 controls, which consisted, for the first time, of siblings of children with DS. No significant differences were found in activities of catalase and glutathione reductase in DS vs. controls. A significant difference was observed in serum concentration of malondialdehyde (MDA) in DS vs. controls (8.39 ± 0.34 micromol/l vs. 7.34 ± 0.27 micromol/l; p = .021) and concentration of MDA in erythrocytes of individuals with DS between the third and fourth age group (p = .05). In DS persons, an elevated ratio of SOD to catalase plus GPx with respect to the controls in all age categories was found, suggesting oxidative imbalance, potentially contributing to accelerated aging observed in these persons.
Am J Hum Genet 69 (1): 88-95 (2001 Jul)
Homocysteine metabolism in children with Down syndrome: in vitro modulation
Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, James SJ
Division of Biochemical Toxicology, Food and Drug Administration National Center for Toxicological Research, Jefferson, AR, 72079, USA
The gene for cystathionine beta-synthase (CBS) is located on chromosome 21 and is overexpressed in children with Down syndrome (DS), or trisomy 21. The dual purpose of the present study was to evaluate the impact of overexpression of the CBS gene on homocysteine metabolism in children with DS and to determine whether the supplementation of trisomy 21 lymphoblasts in vitro with selected nutrients would shift the genetically induced metabolic imbalance. Plasma samples were obtained from 42 children with karyotypically confirmed full trisomy 21 and from 36 normal siblings (mean age 7.4 years). Metabolites involved in homocysteine metabolism were measured and compared to those of normal siblings used as controls. Lymphocyte DNA methylation status was determined as a functional endpoint. The results indicated that plasma levels of homocysteine, methionine, S-adenosylhomocysteine, and S-adenosylmethionine were all significantly decreased in children with DS and that their lymphocyte DNA was hypermethylated relative to that in normal siblings. Plasma levels of cystathionine and cysteine were significantly increased, consistent with an increase in CBS activity. Plasma glutathione levels were significantly reduced in the children with DS and may reflect an increase in oxidative stress due to the overexpression of the superoxide dismutase gene, also located on chromosome 21. The addition of methionine, folinic acid, methyl-B(12), thymidine, or dimethylglycine to the cultured trisomy 21 lymphoblastoid cells improved the metabolic profile in vitro. The increased activity of CBS in children with DS significantly alters homocysteine metabolism such that the folate-dependent resynthesis of methionine is compromised. The decreased availability of homocysteine promotes the well-established "folate trap," creating a functional folate deficiency that may contribute to the metabolic pathology of this complex genetic disorder.
Biol. Trace Elem. Res. 1 (81): 21-8 (2001 Jul)
Evaluation of superoxide dismutase and glutathione peroxidase enzymes and their cofactors in Egyptian children with Down's syndrome
Meguid Nagwa Abdel, Kholoussi NM, Afifi HH.
Department of Human Genetics, National Research Centre, Cairo, Egypt
The present work investigated the activity of Cu/Zn superoxidedismutase enzyme (SOD) in red blood cells and glutathione peroxidase enzyme (GPx) in whole blood by spectrophotometric methods. Plasma levels of the cofactors copper and zinc and whole-blood selenium were evaluated using atomic absorption spectrophotometer. The study included a population of 18 Down's syndrome (DS) patients with complete trisomy 21 (group 1), translocations (group 2), and mosaicism (group 3), and their 15 matched controls. The purpose of this work was to study the gene dosage effect of SOD and its consequence on GPx enzyme and the various cofactors, and to find out correlations with developmental fields. Our results showed that in the population with complete trisomy 21 and translocations, SOD and GPx activities were increased, whereas in cases with mosaicism, the enzymes activities were within normal limits. Plasma copper concentrations were increased, whereas whole-blood selenium concentrations were significantly decreased in the three DS groups. Plasma zinc levels were within normal in all patients. We concluded that changes in trace elements and enzyme activities were not related to age or sex. Also, there was no correlation between the enzyme levels and the developmental activities. Our results are useful tools for identifying nutritional status and guiding antioxidant intervention.
Int J Clin Pharmacol Res 21 (2): 79-84 (2001)
Reactive oxygen metabolites and prooxidant status in children with Down's syndrome
Carratelli M, Porcaro L, Ruscica M, De Simone E, Bertelli AA, Corsi MM.
Diacron S.r.l., Diagnostic Division, Grosseto, Italy
Children with Down's syndrome suffer many diseases among which cardiovascular diseases, increased susceptibility to infections, leukemia, endocrine alterations, immune defects, nutritional disturbance and mental retardation have clinical relevance. It has been suggested that the pathogenesis of Down's syndrome involves reactive oxygen species arising from a mutation in gene encoding, which disproportionately elevates superoxide dismutase activity. Reactive oxygen species and total antioxidant capacity were evaluated using two new spectrophotometric methods in a selected group of 40 children with Down's syndrome and in 20 apparently healthy children used as controls. Reactive oxygen species were significantly higher ( < 0.05) in children with Down's syndrome than in controls: 452 (± 72) U.Carr vs. 270 (± 66) U.Carr respectively. Total antioxidant capacity was significantly higher (< 0.05) in controls than in children with Down's syndrome: 380 (± 52) micromol hypochlorous acid (HCLO)/ml vs. 281 (± 33) micromol HCLO/ml, respectively. In fact, thiol groups (sulfhydryl) were significantly higher (< 0.05) in controls than in children with Down's syndrome: 644 (± 78) micromol/l vs. 462 (± 54) micromol/l, respectively Our data show how to simply measure chemical indices of oxidative status in serum samples from children with Down's syndrome. We determined the plasmatic activities of reactive oxygen metabolites and oxidative defense molecules. Accumulated macromolecular damage may be one of the causes of some of the abnormalities that are considered part of the syndrome. Therefore, children with Down's syndrome have to cope with a significant prooxidant environment. Oxidative stress causes alterations such as atherosclerosis, early aging, immunological default and neurologic disorders in Down's syndrome patients. The new test available for measuring reactive oxygen species in serum proved to be reliable and useful as an early marker of tissue damage.
Pädiatrische Praxis 59: 703-708 (2001)
Matthias J. Gelb
Gemeinschaftspraxis für Kinder- und Jugendmedizin, Schwerpunktpraxis Down-Syndrom, Jörg-Schwarzerd-Str.8, 75015 Bretten
The metabolism of persons with Down syndrome differs, sometimes considerably, 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. This gene-over-expression can result in an increase of chromosome 21-encoded gene products. Gene dosage studies have shown an increase of gene products of up to 40-50% from genes located on chromosome 21. Two of these proteins in special interest are Zn/Cu peroxide-dismutase (POD) and cystathionine-ß-synthetase (CBS).
Zn/Cu peroxide-dismutase catalyzes the dissimilation of peroxide that occurs with the metabolism to hydrogen peroxide, which is then processed in to water by the enzymes catalase or glutathionine peroxidase. A surplus of Zn/Cu peroxide-dismutase results in a surplus of hydrogen peroxide, which adversely reacts with cell membranes, DNA and enhances lipid peroxidation, especially in the presence of iron. Further investigations are needed to elucidate whether over-expression of this enzyme is also clinically correlated with disorders of maturation, aging and various degenerative diseases, like Alzheimer's.
The over-expression of cystathionine-ß-synthetase interferes with methionine-homocysteine metabolism. This may be biochemically expressed as increased concentrations of cysteine or disorders in the metabolism of folate. Decreases in homocysteine can result in a reduction of the resynthesis of methionine.
Acta Medica Mediterranea 3-4: 151-6 (2001)
La Sindrome di Down: valutazione di nuovi parametri biochimici
M. Ciaccio, F. Di Gaudio, M. Giuffrè, V. Macaione, G. Cusumano, A. Bono
Università degli Studi di Palermo, Facoltà di Medicina e Chirurgia, Dipartimento di Biotecnologie Mediche e Medicina Legale, Sezione di Biochimica Medica
*Università degli Studi di Palermo - Facoltà di Medicina e Chirurgia, Dipartimento Materno Infantile
**Università degli Studi di Messina, Facoltà di Medicina e Chirurgia, Dipartimento di Scienze Biochimiche, Fisiologiche e della Nutrizione
La Sindrome di Down è la più frequente anomalia cromosomica autosomiale, caratterizzata da gravi alterazioni cliniche e metaboliche. II metabolismo aminoacidico e la produzione di Specie Radicaliche dell'Ossigeno costituiscono una delle maggiori modifiche biochimiche. Scopo del nostro studio è stato la valutazione biochimica del profilo aminoacidico plasmatico, delle Specie Radicaliche dell'Ossigeno e di specifiche attività enzimatiche antiossidanti in 159 soggetti in età evolutiva (0-12 anni) affetti da Sindrome di Down. I risultati ottenuti mostrano una alterazione delle concentrazioni plasmatiche dei parametri biochimici considerati confrontati con una popolazione di soggetti normali di pari età.
Ann Neurol 48(5): 795-8 (2000 Nov)
Down's syndrome is associated with increased 8,12-iso-iPF2alpha-VI levels: evidence for enhanced lipid peroxidation in vivo
Pratico D, Iuliano L, Amerio G, Tang LX, Rokach J, Sabatino G, Violi F.
The Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia 19104, USA
Postmortem and in vitro studies have shown that oxidative stress plays a role in the pathogenesis of many of the clinical features of Down's syndrome. The isoprostane 8,12-iso-iPF2alpha-VI is a specific marker of lipid peroxidation. We found elevated levels of this isoprostane in urine samples of subjects with Down's syndrome compared with those of matched controls, which correlated with the duration of the disease. These results suggest that increased in vivo lipid peroxidation is a prominent component early in the course of Down's syndrome.
Proceedings of the International Conference: Women, Science and Technology for Sustainable Development: 251-4 (1999 Feb 8-11)
Assessment of Children with Down Syndrome Attending Early Intervention Program in Egypt
Meguid, Nagwa Abdel; Afifi, H.; Ismail, S.; Bassuoni, R.
Human Genetics Department, National Research Centre, Tahir Sir, Dohki, Cairo, Egypt
The present study investigated the role of antioxidant nutritional support in conjunction with a training Portage programme designed to improve the capabilities of patients with Down Syndrome (DS). The study included 60 children with DS aged between 2 and 45 months. 20 cases were included in an early intervention portage project and supported with antioxidants. Another 20 cases only attended the early intervention programme. The remaining group of 20 children with DS did not attend at all. The portage early intervention programme was used to evaluate the development of various fields of activity. The present authors organized a 1 year follow-up study of the first and second stages of evaluation. Initial growth parameters and development assessment were done, and then again at 6 month intervals. Complete blood analysis, T3, T4 and TSH were carried out every 6 months. Parents were asked to stop any additional vitamins, and to keep illness logs and follow-up the incidence of upper respiratory, ear and GIT infections. The most striking finding was the marked improvement in the health and growth of the group of children with DS attending the intervention programme in conjunction with antioxidant treatments. There was a significant decrease in the incidence of all infections, and upper respiratory and ear infections in particular. The authors also noticed a significant improvement in cognitive and gross motor development in comparison to the other groups. This study emphasizes the therapeutic effect of antioxidant nutritional intervention on the quality of life of people with DS.
Free Radic Biol Med 25(9): 1044-8 (1998 Dec)
Biomarkers of Oxidative Stress are Significantly Elevated in Down Syndrome
Slobodan V. Jovanovic, Debbie Clements and Kent MacLeod
International Center for Metabolic Testing, 1305 Richmond Road Ottawa Ontario Canada K2B 7Y4
There is convincing epidemiological and in vitro evidence of chronic oxidative stress in individuals with Down syndrome (DS). These individuals develop Alzheimer like changes in the brain in their 30s and 40s. The incidence of autoimmune diseases and cataracts is significantly increased, and the overall ageing process is accelerated. In vitro studies show that impaired viability of DS neurons may be amended by simple chemical antioxidants, such as vitamin E, BHT and propyl gallate, clearly indicative of oxyl radical involvement. However, because of the lack of in vivo experiments, the role of oxidative stress in DS remains controversial. We report here on the results of the chemical analyses of urine samples of 166 individuals, where DS subjects were matched by their siblings. The levels of 8-hydroxy-2'-deoxyguanosine (2.35 ± 1.69 in DS vs. 1.35 ± 1.04 in controls, P = 0.00011), a biomarker of oxidative damage to DNA, and malondialdehyde (0.255 ± 0.158 in DS vs. 0.204 ± 0.128 in controls, P = 0.033), a biomarker of lipid peroxidation, are significantly elevated in individuals with DS. Dietary influences failed to show any significant correlation with the oxidative stress biomarkers. These results provide direct evidence for increased oxidative stress in individuals with DS.
Mutat Res 409(2): 81-9 (1998 Nov 12)
Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome
Druzhyna N, Nair RG, LeDoux SP, Wilson GL
Department of Structural and Cellular Biology, University of South Alabama, Mobile 36688, USA
Recent evidence indicates that oxidative DNA damage may be a major cause of aging. One of the more sensitive targets is the mitochondrial genome which is 10 times more susceptible to mutation than is the nuclear genome. A number of age-related neuromuscular degenerative diseases also have been associated with mutations in mitochondrial DNA (mtDNA), and progressive accumulation of oxidative damage in mtDNA from neuronal tissues over time has been shown. In support of the notion that oxidative stress leads to aging is the finding in Down's syndrome (DS), which is characterized by premature aging, that there is enhanced oxidative stress resulting from the aberrant expression of CuZn superoxide dismutase (CuZn SOD). On the basis of these observations, we hypothesized that there may be defective repair of oxidative damage in mtDNA which would ultimately lead to defective electron transport and concomitant enhanced production of reactive oxygen species (ROS). This effect would heighten the oxidative burden in the cell and accelerate the development of phenotypes associated with aging. To evaluate repair of oxidative damage in mtDNA, fibroblasts from several DS patients were treated with the reactive oxygen generator menadione. Oxidative damage was assessed at 0, 2, and 6 h after exposure using a Southern-blot technique and a mtDNA specific probe. The results of these studies show that DS cells are impaired in their ability to repair oxidative damage to mtDNA compared to age-matched control cells. Therefore, this data supports the possibility that increased production of ROS from mitochondria plays a crucial role in the development of aging phenotypes.
Biochem Biophys Res Commun 243(3): 849-51 (1998 Feb 24)
Early glycoxidation damage in brains from Down's syndrome
Odetti P, Angelini G, Dapino D, Zaccheo D, Garibaldi S, Dagna-Bricarelli F, Piombo G, Perry G, Smith M, Traverso N, Tabaton M
Department of Internal Medicine (DIMI), University of Genova, Italy
In Down's syndrome, the presence of three copies of chromosome 21 is associated with premature aging and progressive mental retardation sharing the pathological features of Alzheimer disease. Early cortical dysgenesis and late neuronal degeneration are probably caused by an overproduction of amyloid beta-peptide, followed by an increased cellular oxidation. Interestingly, chromosome 21 codes for superoxide-dismutase and amyloid beta precursor resulting, in Down's syndrome, in an overflow of these gene products and metabolites. We studied Down's fetal brain cortex to evaluate the presence and amount of lipid and protein oxidation markers; moreover, we quantified two forms of glycation end products that are known to be involved in the process of cellular oxidation. All these parameters are significantly increased in Down's fetal brains in comparison to controls, providing the evidence that accelerated brain glycoxidation occurs very early in the life of Down's syndrome subjects.
It. Biochem. Soc. Transactions 11: 446 (1998)
Plasma amino acids and status of free radicals in children with Down's syndrome
M. Ciaccio, G. Corsello, M. D'Ancona, M. Piccione, A. Saia, M. Lo Giudice, G. Cusumano, L. Giuffrè, A. Bono
Life Sci 59(7): 537-44 (1996)
Evidence against the involvement of reactive oxygen species in the pathogenesis of neuronal death in Down's syndrome and Alzheimer's disease
Hayn M, Kremser K, Singewald N, Cairns N, Nemethova M, Lubec B, Lubec G
Department of Biochemistry, University of Graz, Austria
It has been proposed that the pathogenesis of Down's Syndrome (DS) involves reactive oxygen species (ROS) arising from a gene dosage effect that disproportionately elevates superoxide dismutase (SOD1) activity. It was also suggested that generation of ROS might be responsible for neuronal death in Alzheimer's Disease (AD). Little data on brain ROS in DS and AD exist; therefore, we determined activities of choline acetyltransferase (ChAT) and of the oxidative defense enzymes SOD1 and glutathione peroxidase (GSHPx) in frontal cortex of aged patients with DS and AD. We also measured levels of malondialdehyde, which reflects lipid peroxidation, and o-tyrosine, which represents the hydroxyl radical attack. ChAT was significantly reduced in cortex of patients with DS (-68%) and AD (-66%) as compared to controls. There were no statistically significant differences, however, between controls and both neurodegenerative disorders for SOD1, GSHPx, malondialdehyde and o-tyrosine. Our data contradict the only previous finding on increased SOD1 and ROS in brains of patients with DS: age as well as methodological differences might account for the discrepancy. In conclusion, no evidence for a pathogenetic role of SOD1, GSHPx, lipid peroxidation or hydroxyl radical attack in aged patients with DS and AD could be provided.
Nature 378 (6559): 776-9 (1995 Dec 21-25)
Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro
Busciglio J., Yanker BA.
Department of Neurology, Harvard Medical School, Children's Hospital, Boston, MA 02115
Down's syndrome (DS) or Trisomy 21 is the most common genetic cause of mental retardation. Development of the DS brain is associated with decreased neuronal number and abnormal neuronal differentiation, and adults with DS develop Alzheimer's disease. The cause of the neurodegenerative process in DS is unknown. Here we report that cortical neurons from fetal DS and age-matched normal brain differentiate normally in culture, but DS neurons subsequently degenerate and undergo apoptosis whereas normal neurons remain viable. Degeneration of DS neurons is prevented by treatment with free-radical scavengers or catalase. Furthermore, DS neurons exhibit a three to fourfold increase in intracellular reactive oxygen species and elevated levels of lipid peroxidation that precede neuronal death. These results suggest that DS neurons have a defect in the metabolism of reactive oxygen species that causes neuronal apoptosis. This defect may contribute to mental retardation early in life and predispose to Alzheimer's disease in adults.
APMIS Suppl 40: 57-70 (1993)
Association of phenotypic abnormalities of Down syndrome with an imbalance of genes on chromosome 21
Becker LE; Mito T; Takashima S; Onodera K; Friend WC
Department of Pathology (Neuropathology), University of Toronto, Ontario, Canada
The phenotype of the brain in Down syndrome is different from that of a normal child both in its reduced size and altered gyral configuration. Underlying the mental retardation are neuronal abnormalities, including alterations of cortical lamination, reduced dendritic ramifications, and diminished synaptic formation. However, cholinergic enzymes such as choline acetyl transferase and acetyl cholinesterase have shown no abnormalities in young children with Down syndrome. The pace of dendritic maturation is altered in Down syndrome. In infancy, the normal dendritic tree continuously expands; in Down syndrome, at 4 months of age, the neurons show a relatively expanded tree, but during the first year, the dendrites stop growing and become atrophic relative to control neurons. To relate these phenotypic alterations to chromosome 21, we examined the gene products of several genes localized to chromosome 21. Identification of such genes and determination of their gene product allow the production of specific antibodies and the identification, through immunohistochemical techniques, of the expression of these proteins in both normal development and Down syndrome. Specifically, the localization and appearance during development of proteins such as S100 beta, beta A4-amyloid, superoxide dismutase, and OK-2 are providing links between genotype and phenotype. S100 beta protein is of particular interest because of its effect in vitro on neuritic outgrowth and its increased expression in the temporal lobe in Down syndrome. The brains of transgenic mice bearing multiple copies of the human S100 gene show some comparable changes to those in Down syndrome. These experimental approaches provide the means for better understanding the cellular and molecular basis for the mental retardation in Down syndrome.
Somat Cell Mol Genet 18: 143-161 (1992)
Gene dosage and Down's syndrome: metabolic and enzymatic changes in PC12 cells overexpressing transfected human liver-type phosphofructokinase
Elson A, Bernstein Y, Degani H, Levanon D, Ben-Hur H, Groner Y
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel
Down's syndrome (DS) is a human genetic disease caused by triplication of the distal third of chromosome 21 and overexpression of an unknown number of genes residing in it. The gene for the liver-type subunit of phosphofructokinase (PFKL), a key glycolytic enzyme, maps to this region and the product is overproduced in DS erythrocytes and fibroblasts. These facts, together with abnormalities which occur in DS glycolysis, make PFKL overexpression a candidate for causing some aspects of the DS phenotype. A cellular model for examining the consequences of PFKL overexpression in DS was constructed by transfecting rat PC12 cells with the human PFKL cDNA. Phosphofructokinase (PFK) isolated from PFKL-overexpressing clones was more inhibited by ATP and citrate and less activated by fructose-6-phosphate than control PFK; similar results were obtained when PFK preparations from DS and control fibroblasts were compared. In vivo NMR measurements determined that cells overexpressing PFKL performed glycolysis 40% faster than controls. These results show that overexpression of PFKL is the cause for altered biochemical regulatory characteristics of PFK in DS fibroblasts and can result in enhancement of glycolysis rates. It is also shown that increased gene dosage can exert its influence not merely by enhancing the amounts of gene products but also by altering their biochemical nature.
Neurosci Lett 132 (2): 154-8 (1991 Dec 9)
Developmental pattern of muscarinic receptors in normal and Down's syndrome fetal brain—an autoradiographic study
Bar-Peled O; Israeli M; Ben-Hur H; Hoskins I; Groner Y; Biegon A
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
The ontogeny of muscarinic cholinergic receptors in developing human brain was analyzed by in vitro receptor autoradiography with [3H]Quinuclidinyl Benzilate. It was found that muscarinic receptors develop relatively early; the levels at 24 weeks of gestation were comparable or even higher then the values in the adult brain, and that the levels of both M1 and M2 receptors increase with age. M1 receptors were concentrated mainly in forebrain regions while M2 receptors dominated in the thalamus. Scatchard analysis revealed Kd and Bmax values which are comparable to the adult values. Three brains of aborted Down's syndrome fetuses were examined in parallel and exhibited comparable levels and similar distribution to normal non-Down fetuses except for a modest increase of receptor levels which was observed in the striatum.
Prog Clin Biol Res 373: 133-52 (1991)
Growth and development of the brain in Down syndrome
Becker L, Mito T, Takashima S, Onodera K
Department of Pathology, Neuropathology, University of Toronto, Ontario, Canada
The brain of a child with Down syndrome develops differently from a normal one, attaining a form reduced in size and altered in configuration. Directly related to the mental retardation are neuronal modifications manifest as alterations of cortical lamination, reduced dendritic ramifications, and diminished synaptic formation. However, selected cholinergic marker enzymes such as choline acetyl transferase and acetyl cholinesterase have shown no alterations in young children with Down syndrome. The pace of the neuronal transformations is related to stage of maturation. With early growth and development, the normal dendritic tree continuously expands. In Down syndrome, at 4 months of age, the neurons show a relatively expanded dendritic tree, but during the first year the dendrites stop growing and become atrophic relative to control neurons. Accompanying these neuronal irregularities are subtle alterations of other cell types: astrocyte, oligodendrogliocyte, microglia, and endothelial cell. In early infancy, one of the astrocytic markers, GFAP, is not altered, but there is greater expression of S-100 protein in the temporal lobe in Down syndrome. Oligodendrogliocyte dysfunction is reflected in delayed myelination in pathways of frontal and temporal lobes. Microglia appear more prominent in Down syndrome. A minority of children with Down syndrome have vascular dysplasias and focal calcification of basal ganglia. In young children, expression of beta-amyloid in Down syndrome is no different than in normal children but disappears after age two, only to reappear in adults. As some of these studies suggest, the identification of genes on chromosome 21 and the determination of the gene product allow the production of specific antibodies and, through immunohistochemical techniques, the identification of the expression of these proteins in both normal development and Down syndrome. Specifically, the localization and appearance in development of proteins such as the beta-subunit of S-100, beta-amyloid (A4 protein), superoxide dismutase, and OK-2 are providing the means for better understanding the morphogenesis of the cellular and eventually molecular basis for the mental retardation in Down syndrome.
Clin Neuropathol 9 (4): 181-90 (1990 Jul-Aug)
Brain growth in Down syndrome subjects 15 to 22 weeks of gestational age and birth to 60 months
Schmidt-Sidor B; Wisniewski KE; Shepard TH; Sersen EA
New York State Office of Mental Retardation and Developmental Disabilities, Department of Pathological Neurobiology, Staten Island 10314
We have found similarities of skull shape, brain growth and brain maturation in 17 DS and 10 non-DS (control) fetuses, ages 15-22 weeks of gestational age (Group A), and differences in 101 DS and 80 non-DS cases, from birth to 60 months (Group B). Postnatally, the gross neuropathological differences between DS and control brains are more distinct after 3-5 months of age. The anterior posterior diameter fronto-occipital length of the brain hemispheres is shortened and that is secondary to reduction of frontal lobe growth. Also flattening of occipital poles, narrowing of the superior temporal gyruses and generalized retardation of brain growth were common findings. Standard morphometric methods indicate changes from birth [Wisniewski et al. 1984, 1986, 1990]. The cerebral cortex of the DS cases had a 20-50% reduction of neurons since birth, mainly in the granular layers [Wisniewski et al. 1984, 1986, 1990]. Changes in brain weight with age were greater in the non-DS than in the DS cases, and greater in males than in females. CHD and GI malformations were associated with less brain weight in both DS and non-DS cases. We suggest that the prenatal retardation of neurogenesis begins after 22 weeks' gestational age. The postnatal retardation of brain growth is secondary to pre- and postnatal abnormalities in synaptogenesis.
Am J Med Genet (7): 274-281 (1990)
Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis
New York State Office of Mental Retardation and Developmental Disabilities, Staten Island 10314
All Down syndrome (DS) children have different degrees of developmental disabilities, developmental delay, and developmental brain abnormalities associated with CNS maturation delay and cortical dysgenesis. We have examined 780 occipitofrontal circumferences (OFC), mean and ± SD, of DS children from birth to age 5 years. Also, gross and microscopic neuropathological studies in the same age group were performed, with special attention to brain weight (BW), shape, myelin formation, cortical organization of 101 DS and 80 non-DS individuals; ultrastructural studies were also performed on selective cases (five DS and five non-DS). The OFC was plotted on Nellhause curves and showed microcranium after mid-infancy in most cases. Twenty percent of DS children had an OFC in the lower normal range. The brain shape in DS newborn infants was the same as in non-DS infants, but after 3-5 months of age in DS infants the antero-posterior diameter was found to be shorter than in non-DS infants. Narrowness of the superior temporal gyrus was noted in 34 of 101 (33%) of DS brains. Microscopic examination showed myelination delay in 22.5% DS and only in 6.8% non-DS children. Morphometric studies in DS cases from birth showed fewer neurons (20-50% less), lower neuronal densities, and neuronal distribution, especially of cortical layers II and IV. Ultrastructurally in DS, the synaptic density, synaptic length, and contact zones were found to be abnormal. The retardation of brain growth, maturation delay, and cortical dysgenesis present in DS children most likely are regulated by the extra chromosome 21, but the gene responsible for the abnormalities remains to be determined.
Int J Dev Biol 33 (1): 183-8 (1989)
On the etiopathogenesis and therapy of Down syndrome
Antila E, Westermarck T
Department of Anatomy, University of Helsinki, Finland
The etiopathogenesis of Down syndrome is reviewed concentrating on the possible consequences of over-expression of cytoplasmic superoxide dismutase gene located in chromosome 21. Increased superoxide dismutase activity may generate free radical stress through overproduction of hydrogen peroxide. The significance of inadequate adaptive responses, i.e. increase of the selenoenzyme glutathione peroxidase activity in the central nervous system and in the thyroid gland is discussed. Suggestions are made for prevention of the progress of Down syndrome and intervention studies with antioxidant supplementation are proposed.
Cell (CQ4) 54 (6): 823-9 (1988 Sep 9)
Down's syndrome: abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase
Avraham KB; Schickler M; Sapoznikov D; Yarom R; Groner Y
Department of Virology, Weizmann Institute of Science, Rehovot, Israel
To investigate the possible involvement of Cu/Zn-superoxide dismutase (CuZnSOD) gene dosage in the neuropathological symptoms of Down's syndrome, we analyzed the tongue muscle of transgenic mice that express elevated levels of human CuZnSOD. The tongue neuromuscular junctions (NMJ) in the transgenic animals exhibited significant pathological changes, namely, withdrawal and destruction of some terminal axons and the development of multiple small terminals. The ratio of terminal axon area to postsynaptic membrane decreased, and secondary folds were often complex and hyperplastic. The morphological changes in the transgenic NMJ were similar to those previously seen in muscles of aging mice and rats as well as in tongue muscle of patients with Down's syndrome. The findings suggest that CuZnSOD gene dosage is involved in the pathological abnormalities of tongue NMJ observed in Down's syndrome patients.
Clin Neuropathol 8 (2): 55-62 (1989 Mar-Apr)
Postnatal delay of myelin formation in brains from Down syndrome infants and children
Wisniewski KE; Schmidt-Sidor B
New York State Office of Mental Retardation and Developmental Disabilities, Institute for Basic Research in Developmental Disabilities, Staten Island 1031
fetuMyelination up to the age of 6 years was studied in two groups consisting of 129 Down syndrome (DS) 17/12ses and 112/129 postnatal) and 73 non-DS cases (10/73 fetuses and 63/73 postnatal). In both groups studied a similar number of congenital heart disease (CHD), gastrointestinal (GI) malformations and infections were diagnosed. Paraffin or celloidin brain sections were stained with Kluver-Barrera, Heidenhain or Loyez method. The myelination was found to be delayed in 29/129 (22.5%) DS and only in 5/73 (6.8%) non-DS cases. Myelination in fetuses and newborns in the DS and non-DS groups was not delayed. In DS the myelination was delayed between ages 2 months-6 years (17/29; 58.6%) up to 12 months, and 12/29 (41.4%) aged 2-6 years, while in non-DS aged 2-6 months only. The myelination delay affected tracts with late beginning and slow cycle of myelination, mainly the associated and intercortical fibers of the fronto-temporal lobes. In 3/7 of DS cases (ages 3, 4, 6 years) less advanced myelination of U fibers was noted. In both groups the myelination delay seemed also to depend on the systemic diseases which affected the subjects during the time of myelination. In DS where CHD was present the myelination delay was found in 14/29 (48.2%) in contrast to 3/5 (60%) non-DS. Also, in 28/129 (23%) DS cases dates regarding the developmental milestones were available and some correlation was found between developmental and myelination delay.
J Neurochem 52 (4): 1183-1187 (1989)
Down's syndrome individuals begin life with normal levels of brain cholinergic markers
Kish S, Karlinsky H, Becker L, Gilbert J, Rebbetoy M, Chang LJ, DiStefano L, Hornykiewicz O
Human Brain Laboratory, Clarke Institute of Psychiatry, Toronto, Ontario, Canada
We measured the activities of the cholinergic marker enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in autopsied brains of seven infants (age range 3 months to 1 year) with Down's syndrome (DS), a disorder in which virtually all individuals will develop by middle age the neuropathological changes of Alzheimer's disease accompanied by a marked brain cholinergic reduction. When compared with age-matched controls cholinergic enzyme activity was normal in all brain regions of the individuals with infant DS with the exception of above-normal activity in the putamen (ChAT) and the occipital cortex (AChE). Our neurochemical observations suggest that DS individuals begin life with a normal complement of brain cholinergic neurons. This opens the possibility of early therapeutic intervention to prevent the development of brain cholinergic changes in patients with DS.
J Neurol Sci (JBJ) 88 (1-3): 41-53 (1988 Dec)
Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: a model for tongue pathology in Down's syndrome
Yarom R; Sapoznikov D; Havivi Y; Avraham KB; Schickler M; Groner Y
Department of Pathology, Hebrew University, Hadassah Medical School, Jerusalem, Israel
We examined the tongue muscles in several strains of transgenic mice carrying the human Zn-Cu superoxide dismutase (CuZnSOD) gene. The presence of the extra gene was confirmed in mated progeny and the gene product activity was measured in the tongue and found to be much higher than in normal littermate controls. Using electron microscopic morphometry, the neuromuscular junctions of the transgenic mice showed significant changes resembling excessive aging, with atrophy, degeneration, withdrawal, and sometimes destruction of the terminal axons, as well as the development of multiple small terminals. The myofibers showed little change except for slight hypertrophy and an increased variability in size. They also had more megamitochondria, fat droplets and lipofuscin bodies. Excess CuZnSOD generates H2O2 and hydroxyl radicals which affect both NMJ membranes and plasticity, and which may produce premature aging. The findings resemble those observed in tongues of patients with Down's syndrome, in whom an extra CuZnSOD gene is present as part of the trisomy of chromosome 21.
J Clin Chem Clin Biochem 26(5): 255-8 (1988 May)
Glutathione peroxidase activity, lipid peroxides and selenium status in blood in patients with Down's syndrome
Gromadzinska J, Wasowicz W, Sklodowska M, Strozynski H.
Department of Biochemistry, Medical Academy, Lodz, Poland.
The concentrations of selenium and lipid peroxides and the catalytic activity of glutathione peroxidase were measured in the blood of 6 children (6-16 years of age) and 8 adults (17-27 years old) with Down's syndrome (trisomy 21). The values were compared with those for a control group of age-matched normal people. The selenium concentration in whole blood, erythrocytes and plasma was significantly lower in trisomy 21 patients than in normal subjects (p < 0.001) in both age groups. No statistically significant differences were observed in selenium concentration in whole blood, erythrocytes and plasma between children and adults in the Down's syndrome group. Glutathione peroxidase catalytic activity in erythrocytes was significantly higher in Down's syndrome children than in healthy children (p < 0.001). Plasma glutathione peroxidase catalytic activity in both investigated age groups was statistically considerably lower in the Down's syndrome patient group. The concentration of lipid peroxides, expressed as the malondialdehyde concentration, is lower in Down's syndrome patients. No correlation between selenium concentration, glutathione peroxidase catalytic activity and amount of lipid peroxides was found in the trisomy 21 patient group.
Hum Genet 75: 251-257 (1987)
Down syndrome with duplication of a region of chromosome 21 containing the CuZn superoxide dismutase gene without detectable karyotypic abnormality
Huret JL, Delabar JM, Marlhens F, Aurias A, Nicole A, Berthier M, Tanzer J, Sinet PM
We report the case of an 18-month-old boy with many typical Down syndrome features but a normal cytogenetic analysis. High-resolution banding techniques on lymphocytes and fibroblasts of the propositus and his parents did not show any detectable abnormality including that of trisomy 21 mosaicism. However, CuZn superoxide dismutase (CuZn SOD) in the patient's red cells was increased as in trisomy 21. DNA analysis (Southern blots) using a human CuZn SOD probe showed that the genotype of the propositus contained three CuZn SOD genes. In situ hybridization on metaphase chromosomes with the same probe confirmed the gene location in a segment enclosing the distal part of 21q21 and 21q22.1. There was no significant labeling on other chromosomes of the patient. These results indicate that the Down syndrome phenotype of this patient is due to microduplication of a chromosome 21 fragment containing the CuZn SOD gene.
Early Hum Dev 18(4): 237-46 (1989 Feb)
Neuronal maturation in the foetal brain in Down's syndrome
Brooksbank BW, Walker D, Balazs R, Jorgensen OS
Medical Research Council-Developmental Neurobiology Unit, London, U.K.
Biochemical indices of neuronal maturation have been examined in postmortem cerebral cortex tissue from Down's syndrome (DS) and control foetuses matched for age. No differences were found in the concentration of neural cell adhesion molecule (N-CAM), or in the proportion of the 'adult' form of N-CAM, in the total concentration or composition of gangliosides, or in the activity of choline acetyltransferase (ChAT). The concentration of major lipid classes was also examined, and the DS specimens differed only in having a small but significantly higher proportion of phosphatidylcholine. The findings suggest that, by the indices examined, there is no delay in neuronal maturation, nor a major abnormality in lipid composition although anomalies in the polyunsaturated fatty acid composition of phosphoglycerides do exist at this stage of brain development in DS (J. Neurochem., 44 (1985) 869-874). Furthermore, the normal activity of ChAT found in the DS foetal cerebral cortex suggests that the impaired cortical cholinergic innervation which is apparent later in life may not be due to initial defects in cholinergic differentiation
Psychological Reports 58(1): 207-217 (1986 Feb)
A report on phosphatidylcholine therapy in a Down syndrome child
Cantor, David S.; Thatcher, Robert W.; Ozand, Pinar; Kumin, Libby; Rothschild, J.
U Maryland School of Medicine, Applied Neuroscience Research Inst, Baltimore
Presents the case of a 2½-yr-old Downs syndrome (DS) boy who was given a phosphatidylcholine supplement (150 mg/kg, day) over a 7-mo period. Measures of the EEG indicate a normalization during the treatment period with minor reoccurrence of abnormalities during a placebo period. S showed a definitive increase in speech and language skills as well as general motor skills that exceeded same-aged DS peers experiencing like training programs. Data suggest that phosphatidylcholine therapy may be useful for improving neurophysiological and intellectual functioning of some DS children.
Brain Res 318(1): 37-44 (1984 Sep)
Superoxide dismutase, glutathione peroxidase and lipoperoxidation in Down's syndrome fetal brain
Brooksbank BW, Balazs R
Certain aspects of the metabolism of oxygen derivatives were investigated in the cerebral cortex from Down's syndrome (trisomy 21) fetuses. In comparison with controls of similar gestational age, the specific activity of the cytosolic Cu/Zn-dependent superoxide dismutase (SOD-I) was significantly elevated by 60 ± 5%. This is consistent with a gene dosage effect, as the gene coding for SOD-I is on chromosome 21. In order to determine whether the increase in SOD-I activity is associated with an adaptive rise in glutathione peroxidase (GSHPx), as has been observed in other tissues, the activity of this enzyme was also estimated but was found not to be altered in the Down's syndrome brain. In addition, in vitro lipoperoxidation, estimated by the formation of malondialdehyde (MDA) on incubation of homogenates fortified with ascorbate and Fe2+, was significantly elevated (36 ± 4%) in cerebral cortex of the Down's syndrome fetuses. The concentration of total combined polyunsaturated fatty acids (PUFA) was not significantly altered in the tissue, although there is evidence for differences in the composition of certain phospholipids. It is proposed that, on account of the evidence for a potential perturbation of oxygen free radical metabolism (notably an increased SOD-I activity not compensated by a rise in GSHPx) and for enhanced in vitro peroxidizability of PUFA, there may be increased lipoperoxidative damage in the Down's syndrome brain prenatally.