GENETICS AND METABOLISM OF DOWN SYNDROME

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Down Syndrome is a congenital developmental disorder that occurs with an incidence of approximately 1:600 births worldwide. John Langdon H. Down described the disease in 1866 based on his observations in purely symptomatic terms. In 1959, Jérôme Lejeune was able to show that the cause of the disease lies in an extra copy of chromosome 21, which is why it is also referred to as trisomy 21. 

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​The sequence of chromosome 21 was published in 2000 and the approx. 225 genes described on it 1. It is now known that the effects of the extra chromosome 21 are not limited to this, but rather extend genome-wide 2,3,4. There are two ways of how the biochemistry of a person with Down syndrome is be influenced: On the one hand, it is assumed that a gene dosage effect is present (in trisomy 21, all genes on chromosome 21 are not present in duplicate, but in triplicate; this means that the synthesis rate for a gene product can reach 150% instead of 100%). On the other hand, there are a variety of epigenetic changes 5,6,7. These represent reversible changes in gene expression that are not based on an altered DNA sequence, but rather involve mechanisms such as DNA methylation and histone modifications. The human epigenome is theoretically flexible throughout our life using methylation of DNA, e.g. through environmental influences, medication and diet, but also through targeted interventions with nutritional supplements, so-called Nutraceuticals.

 

A treatment option for Down Syndrome is the so-called Targeted Nutritional Intervention (TNI), which attempts to balance the metabolic pathways that are altered by the extra genetic material. This applies, among other things, to the problem of systemic oxidative stress, folic acid metabolism and the methylation, collagen metabolism, the altered balance of neurotransmitters, as well as the premature development of the Alzheimer's dementia. All changes in biochemistry and metabolism ultimately lead to what we know as Down Syndrome. TNI treatment does not represent a cure and does not attempt to change the personality of the person affected with Down Syndrome, but rather to supplement the individual biochemical needs and thus reduce or stop the known secondary diseases. Given the neurodegenerative character of Down Syndrome, it makes sense that any treatment should be started as early as possible - but in principle treatment is possible at any time (prenatal, first years of life, adolescence).

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CLINICAL RESEARCH ON DOWN SYNDROME

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The common objection often heard against TNI is that there are not enough double-blind, randomized clinical studies as well as long-term studies on the treatment of Down Syndrome. However, some studies on this topic have been published 8,9,10,11,12,13,14, and in addition there are countless published peer-reviewed, mechanistic studies, as well as preclinical and translational studies that have shown positive effects of treatment and explain why a treatment for Down Syndrome is possible and important. The genetic and epigenetic complexity of Down Syndrome and the associated high individual variability make it clear that meaningful clinical studies in this area are difficult to carry out. Short-term studies with individual inhibitors or antioxidants are not enough to demonstrate significant positive effects, at least not as measurable changes in “intelligence” or “developmental milestones.” There are currently no clinical studies on today's extensive TNI protocol.

 

The best possible window for effective treatment is a prenatal development, as this is where early correction of the genetic imbalance can have the greatest impact 15. Treatment of trisomy 21 at a later point in time would require as many of the as possible critical genes of chromosome 21 and not just individual biochemical pathways. In addition, underlying diseases such as hypothyroidism would also have to be included in clinical studies, as these are often associated with trisomy 21 and have an intensive influence on child development 16,17.

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RISKS OF TARGETED NUTRITIONAL INTERVENTION

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Every medical and naturopathic treatment has its risks, but these should always be compared with the risks that may arise without treating the condition. The risks of TNI treatment are low compared to the known long-term damage of an extra 21st chromosome, especially if the blood is regularly checked to ensure that all important parameters are within the reference values, as I generally do in my practice. A 20-year follow-up study showed that over 97% of study participants with Down Syndrome develop dementia at an average age of diagnosis of 55 years 18. More recent studies show symptomatic Alzheimer's disease with a prevalence of 90-100% from the age of 60 onwards 19. The corresponding biomarkers of neuropathologies (Alzheimer's plaques and neurofibrils), however, can sometimes be detected in the brain much earlier (from the age of 20) 19 -  the premature aging and neurodegeneration, which occur in Down Syndrome, have been described in detail 20,21,22,23. However, individuals with Down Syndrome now have a significantly longer life expectancy due to better prenatal and perinatal care: in Europe it rose from an average of nine years (1929) to around 60 years (2004) and many people with Down Syndrome are now reaching the age of 70. The early development of Alzheimer's therefore represents a serious problem 24. Only through effective treatment or prevention of Alzheimer's disease could the life expectancy of people with Down Syndrome be further increased. 25 A number of studies have now shown that the cause of this is, at least in part, the increased rates oxidative stress 25,26,27, which occurs in individuals with Down Syndrome and which can be effectively reduced to normal levels by TNI 28.

 

It is critical to question whether comprehensive biochemical and metabolic treatment of trisomy 21 should be fundamentally rejected due to limited clinical trials, although the increasing number of pharmacological studies have so far had very little success in finding effective treatments to improve the quality of life of people with trisomy 21 29. The Functional medicine that I use in my practice can help to identify individual weak points in biochemistry and treatment with TNI can successfully compensate for these in order to prevent long-term damage. Treatment with TNI must always be individualized and appropriate blood tests should be carried out regularly. The necessary tests can all be carried out in my practice. In this way, the individual developmental potential can be maintained and the quality of life of families can be significantly increased.