The study has now concluded and results are awaited.

Centre for International Child Health, Institute of Child Health,

University College London, 30 Guilford Street, London WC1N IEH

^** Biochemistry Unit, Institute of Child Health, University College London,

^*** Neurodegenerative Diseases Research Centre, Kings College, University of London,

This protocol was prepared at the suggestion of and in collaboration with

The Down’s Syndrome Research Foundation

Introduction

Down’s syndrome (DS) results from having an extra chromosome 21. The pathological features of the syndrome are thought to result from having these extra genes. One of the genes codes for the enzyme copper-zinc superoxide dismutase (SOD1) which dismutates (helps to convert) superoxide radicals to hydrogen peroxide. Because there is 50% extra SOD1 there is extra production of hydrogen peroxide and no corresponding mechanism to dispose of this excess. Excess hydrogen peroxide may then react with transition metals to form hydroxyl radical. The latter is the most reactive oxygen radical known and for example readily initiates damage to lipid components of cell membranes in organs like the brain.

There is increasingly good evidence from animal studies and in vitro and in vivo human studies associating DS with increased oxidative damage to neurons, phagocytic cells, and DNA which suggests that this mechanism might contribute to poor cognitive development and the high incidence of Alzheimer's, depressed immunity and increased morbidity, poor growth and increased susceptibility to cancer typically seen in DS.

We therefore hypothesize that supplementation with optimum levels of antioxidant nutrients may counteract this oxidative damage and thus improve the mental development and growth and reduce the morbidity of DS children. If the hypothesis is proven then the quality of life of DS children could be markedly improved.

Evidence for increased oxidative stress in DS

The first evidence is the increase in SOD1. The presence of an extra chromosome 21 in DS results in 50% or more increase in SOD (e.g. Brooksbank and Balazs 1984). S0D converts superoxide radicals to hydrogen peroxide (Halliwell and Gutteridge 1989) which is further converted to water by glutathione peroxidase (GSH-Px) or catalase (Halliwell and Gutteridge1989). In DS, this increase in SOD is not matched by a proportionate increase in GSH-Px or catalase. The resulting SOD/GSH-Px imbalance may lead to accumulation of unmetabolised hydrogen peroxide which can decompose (via Fenton reaction) to form the hydroxyl radical (Sinet 1982). The latter is the most dangerous oxygen radical known (Sinet 1982, Lohr 1991) and for example can readily damage lipids in cell membranes in organs like the brain {Sinet 1979). The second evidence is a consistent association shown between increased SOD and increased oxidative lipid damage in the brain of transgenic mice (e.g. Ceballos-Picot et al 1992). In addition Busciglio and Yankner (1995) showed with in-vitro human studies that cortical neurons from DS foetuses have 4 times more free radicals and were more likely to degenerate compared with normal neurons. This degeneration was also prevented by the addition of antioxidants. The other evidence is the upregulation of GSH-Px in DS which is in apparent physiological / adaptive response to increased oxidative stress (Sinet 1982). Slnet et al (1979) found a positive correlation between GSH-Px and IQ in 22 DS subjects and concluded that GSH-Px may be important in preserving the cerebral status of DS subjects. Since GSH-Px is an endogenous antioxidant we can hypothesize that supplementing DS subjects with exogenous antioxidants may offer similar protection to their cerebral status. Finally de Haan et al (l 997) have shown that elevated SOD/GSH-Px ratio results in normal aging so that a more profound imbalance as in DS could result in premature aging as seen in DS.

Literature Review

A systematic review of over 126 published papers has been done at the Institute of Child Health in London. Most of these are included in the protocol document. Several previous studies of nutritional supplementation have been conducted in DS but most suffered from serious design problems including small sample size (hence limited power), short duration, and targeting older children and adults who may be too old to benefit. No previous study specifically evaluated the effect of antioxidants on people with DS. We intend to correct these errors and conduct a randomized controlled double blind treatment trial with large enough samples to provide adequate statistical power, beginning as early in life as possible and continuing for two years in the first instance and using optimum levels of antioxidants.

Potential importance to health

About 600 DS babies are born each year in UK. They will all develop some degree of mental impairment most likely due to peroxidation of the lipids, which make up most of the brain. The damage to the brain can be seen as plaque formations from a very early age. Due to this brain injury they will develop dementia much sooner than normal and 40% will get Azheimer's by age 60. Their immune system is not as robust as it should be and most will have a much higher incidence of illness. Upper respiratory infections are common and can be life threatening, leukemia and celiac disease has 20x-30x higher incidence.

A successful outcome for this project has the potential to improve mental function and health of DS subjects. It could result in better growth and development. Although the greatest opportunity is to help newborns to develop more normally the same therapy could be effective at all stages of life because it could ameliorate the pathology of Down's syndrome by helping to reduce the oxidative stress that is an important part of the disease process in this medical condition. 50,000 people in the UK and over 300,000 in the EC have DS. So the health impact can be very significant.

Plan of Investigation

The target start date for the project is July 1 2000. The specific objectives of the study are:

1) To assess the effect of antioxidant supplementation of DS infants on the incidence and duration of episodes of infections, growth in head circumference length and weight, mental and psychomotor development, and behavior.

2) To compare the concentrations of products of oxidative damage to lipids and DNA as well as the activities of glutathione peroxidase and CuZnSOD, in erythrocytes and serum of treated and untreated DS infants.

3) To compare the serum profile of antioxidants, micronutrients and parameters of lipid peroxidation in untreated DS infants and normal infants.

The project will be coordinated by the Institute of Child Health, University College London in collaboration with The Downs Syndrome Research Foundation and Kings College, University of London. A sample of 200 DS infant's age one to six months will be recruited in the first year from DS infants in greater London, Birmingham and Manchester regions. All infants cytogenetically confirmed to have Trisomy 21 of the non-disjunction type would be eligible except if they have congenital abnormalities deemed unlikely to respond to usual treatments. Eligible infants will be identified from advertisements and from those who become members of parental support organizations. They will also be identified from maternity units and cytogenetic laboratories in London, Birmingham and Manchester, and parents will be approached about 2 weeks after diagnosis. After obtaining consent, the children will be randomly assigned to treatment or placebo group. The supplement will contain vitamins A, C, and E, and Beta-Carotene, Selenium, Zinc and Folic acid. All ingredients will be well within safe levels. Subsequently, parents will be contacted by telephone weekly to check for occurrence of illnesses and visited bimonthly to check for compliance and to record growth. The children will have developmental tests at 18 months while blood tests will be conducted once at age 12 months. Each participant will be in the study until age 18 months. Additional funding will be sought during this period to extend the trial for an additional year and to fund the cost to investigate and document the progress of these children up to age 8 years.

With the increasing age of maternity there is potential for increased incidence of DS births. This project is the first of a series of new initiatives to better understand the health and development issues of Down's syndrome and it will test the effectiveness of an antioxidant therapy to ameliorate the pathology. Improved health care is an expected outcome for all those who participate in the study and for new NHS DS patients throughout the UK. Collaboration is needed between organizations within the West Midlands, the North West and London Regions in order to recruit the number of babies required. The project will contribute to capability building within the regions as NHS staff from a variety of disciplines would be involved in a unique high quality, large, multi-centre study, supported by the experienced professionals at the Institute of Child Health in Birmingham and in London.

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Links of interest:

Review of Research "Nutritional supplementation in Down syndrome: theoretical considerations and current status"