​​ GENETICS AND METABOLISM OF DOWN SYNDROME

​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 purely symptomatically in 1866 based on his observations. 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 known as trisomy 21.

The sequence of chromosome 21 was published in 2000 and the approximately 225 genes on it were described 1 . It is now known that the effects of the extra chromosome 21 are not limited to it, but extend genome-wide 2,3,4. There are two ways in which the biochemistry of a person with Down syndrome can be influenced: On the one hand, it is assumed that there is a gene dose effect (in trisomy 21, all genes on chromosome 21 are not duplicated, but duplicated; thus the synthesis rate for a gene product can reach 150% instead of 100%). On the other hand, diverse epigenetic changes take place 5,6,7. These represent reversible changes in gene expression that are not based on an altered DNA sequence but affect mechanisms such as DNA methylation and histone modifications. Due to the possibility of methylation, the human epigenome can theoretically be flexibly changed throughout life, e.g. through environmental influences, medication and nutrition, but also through targeted intervention with dietary supplements, so-called nutraceuticals.

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One treatment for Down syndrome is the so-called Targeted Nutritional Intervention (TNI), which tries to balance the metabolic pathways that are altered by the extra genetic material. This affects, among other things, systemic oxidative stress, folic acid metabolism and methylation, collagen metabolism, the balance of various neurotransmitters, and the premature development of Alzheimer's dementia. All changes in biochemistry and metabolism eventually lead to what we know as Down syndrome. A TNI treatment does not represent a cure and does not try to change the personality of the person affected with Down syndrome, but to supplement the individual biochemical needs and thus reduce or stop the known secondary diseases. As a neurodegenerative disease, it makes sense to start treatment as early as possible - in principle, however, this is possible at any time (prenatal, early years of life, adolescence).

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CLINICAL RESEARCH ON DOWN SYNDROME

A common objection to TNI is that there are not enough double-blind, randomized clinical trials and 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, which could show and explain positive effects of a treatment as well as why treatment of 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 conduct. Short-term studies of individual inhibitors or antioxidants are unlikely to show significant beneficial effects, at least not as measurable changes in "intelligence" or "developmental milestones." To date, there have been no clinical studies on today's extensive TNI protocol.

The best possible window for an effective treatment is during prenatal development, since an early compensation of the genetic imbalance can have the greatest effects 15. Treatment of trisomy 21 at a later point in time would have to encompass as many of the critical genes of chromosome 21 as possible and not only single biochemical pathways. In addition, underlying diseases such as hypothyroidism should also be included in the 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

All medical and naturopathic treatments have their risks, but these should always be weighed against the risks of not 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 checked regularly to ensure that all important parameters are within the reference values, as I generally do in my practice. A 20-year follow-up study was able to show that more than 97% of study participants with Down syndrome already 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 that date Age 60 19. The corresponding biomarkers of the neuropathologies (Alzheimer's plaques and neurofibrillary tangles) can, however, in part be detected much earlier in the brain (from the age of 20) 19 - the premature aging and neurodegeneration that occur in Down syndrome are detailed described 20,21,22,23. However, people with Down syndrome have a significantly higher life expectancy today thanks to better prenatal and perinatal care: in Europe it has increased from an average of nine years (1929) to around 60 years (2004) and a number of people with Down syndrome are now reaching their 70th birthday . Age. The early development of Alzheimer's is therefore a serious problem 24. The life expectancy of people with Down's syndrome could only be further increased through effective treatment or prevention of Alzheimer's disease. 25 Several studies have now shown that this is at least partly due to the increased oxidative stress 25,26,27 that occurs in the body of people with Down syndrome and which can be reduced to normal levels by TNI 28.

It is critical to question whether a comprehensive biochemical and metabolic treatment of trisomy 21 should be fundamentally rejected due to limited clinical studies, although the increasing number of pharmacological studies have so far had very little success, effective treatments to improve the quality of life of people with trisomy 21 to identify 29. The principle of Functional Medicine I use in my practice can help identify individual weak points in biochemistry and treatment with TNI can successfully balance these to prevent long-term damage. Treatment with TNI must always be individualized and blood tests should be carried out regularly. The necessary tests can all be carried out in my practice. The individual development potential can thus be preserved and the quality of life of the family can be significantly increased.