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 Downs Syndrome

Kip Karges
Mini Review 2 - Biochem 5853, 1998
Oklahoma State University 		  Printed with the permission of Franklin R. Leach

Introduction
     Down syndrome also known as trisomy 21, is a genetic defect affecting 1 in 600 to 1 in 1000 births. Approximately 95% of Down syndrome cases have the extra chromosome 21, making the chromosome count 47 instead if the normal 46. The other 5% are accounted for by other chromosomal abnormalities such as translocation and partial trisomy. Esquirol provided the first description of a child who presumably had Down syndrome in 1838. However, it was not until 1959, Lejune and Jacobs independently determined that Down syndrome was caused by trisomy 21. Many medical advances, special educational programs, and increasing social acceptance of disabled people in the community have resulted in current trends of normalization and deinstitutionalization of these patients with Down syndrome (1). The frequency of Down syndrome is directly correlated to maternal age with the incidence of occurrence increasing as age increases. For example, a maternal age of 45 results with a risk of 1 in 30 as compared to a risk of 1 in 1500 with a maternal age of 20 (2). This mini-review will attempt to focus its discussion on factors dealing with Down syndrome from the standpoint of metabolism.

Factors affecting Down syndrome metabolically
     Just recently data has come out suggesting a common disease mechanism between Alzheimer's disease and Down syndrome. These mechanisms are not only through clinical and neuropathological similarities but also from a genetic and biochemical data. For example, Peeters et al.,(3) found a highly significant decrease in mitotic index in the presence of exogenous glutamine. This was observed for patients with an Alzheimer type dementia with or without an associated Down syndrome. These findings suggest that glutamine sensitivity or some dysregulation of the glutamine/glutamate pathway (Fig. 1) may play a key role in the pathogenesis of Alzheimer's disease. These findings could have important implications in the development of preventive strategies for people at risk for Alzheimer's disease.

Figure 1.
Glutamine/Glutamate Pathway
     In another study (4) amyloid precursor protein (APP) content in peripheral lymphocytes was looked at to see if there is any correlation between Down syndrome (DS) and Alzheimer's disease (AD). Results indicated that patients with DS had a significantly higher, 1.5 fold increase in lymphocyte APP signal compared to normal aged-matched subjects. In contrast, both AD patients and elderly control groups had significantly increased lymphocyte APP as compared to young controls. APP immunoreactivity more than doubles from the age of 20 to 80 for non-DS subjects. This study suggest that with increased cellular APP content in DS as well as aging that it may correspond to generalized alterations in expression or processing of this molecule and possibly could be used as timing determinant of AD onset.
     Researchers have also found that DS subjects are at a greater risk for developing neuropathological features of senile dementia of the Alzheimer's disease (SDAD) by middle age. Recent evidence suggest that gastoinstestinal aluminum is increased with subjects having SDAD and that aluminum may contribute to associated neuropathological changes. Although the mechanism of enhanced absorption are unknown at this time, the data indicate that similar abnormalities in the gastrointestinal handling of aluminum occurs in both SDAT and DS subjects (5).
     Purines have been shown to be critical for energy metabolism, cell signaling and cell reproduction. Nevertheless, little is known about the regulation of this essential pathway during development. Purine biosynthesis is catalyzed by a trifunctional protein with glycinamide ribonucleotide synthetase (GARS), aminoimidazole ribonucleotide synthetase (AIRS) and glycinamide ribonucleotide formyltransferase (GART) enzymatic activities. The gene encoding this trifunctional protein is located on chromosome 21 (6). These results tie back into Down syndrome in that all three proteins are expressed at high levels during normal prenatal cerebellum development but become undetectable shortly after birth. In contrast, these proteins continued to be expressed during postnatal development of the cerebellum in individuals with Down syndrome. Furthermore, the premature aging seen in Down syndrome could possibly be contributed to an altered ratio between two enzymes in their organs, CU/Zn-superoxide dismutase (SOD) and glutathione peroxidase (GPX)(7). This is based on the observation that an altered Cu/Zn-SOD and GPX ratio exists in the brain of aging mice and that this correlates with increased lipid damage. Normally these enzymes serve to neutralize harmful reactive oxygen species produced during oxidative metabolism (Fig. 2) however, with an altered ratio it is postulated that this could affect the aging process in Down syndrome.

Figure 2.

Superoxide Dismutase (SOD)
202+ 2H H2O2 + O2Glutathione peroxidase (GPX)
2GSH + R-O-O-H GSSG + ROH +H2O
Conclusion
     It appears that much research has been performed on how to deal/cope with the wide array of medical, educational systems and social problems of people with Down syndrome. In contrary, it appears that not much is known about how the metabolic processes affects and functions in Down syndrome people. In my opinion this research is very much in the infant stages and much will be learned about metabolism and its influence on this genetic disorder as well as others in the future.

References

  1. Desai, S.S., (1997) Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. Sep;84(3), 279-285
  2. Dick, P.T., (1996) Can. Med. Assoc. J. Feb;154(4), 465-479
  3. Peeters, M.A., Salabelle, A., Attal, N., Rethoe, M.O., Mircher, C., Laplane, D., and Lejeune, J. (1995) J. Neurol. Sci. Nov;133(1-2), 31-41
  4. Pallister, C., Jung, S.S., Shaw, I., Nalbantoglu, J., Gauthier, S., and Cashman, N.R. (1997) Neurobiol. Aging Jan-Feb;18(1), 97-103
  5. Moore, P.B., Edwardson, J.A., Ferrier, I.N., Taylor, G.A., Lett, D., Tyrer, S.P., Day, J.P., King, S.J., and Lilley J.S. (1997) Biol. Psychiatry Feb;41(4), 488-492
  6. Brodsky, G., Barnes, T., Bleskan, J. Becker, L., Cox, M., and Patterson, D. (1997) Hum. Mol. Genet. Nov;6(12), 2043-2050
  7. De Haan, J.B., Cristiano, F., Iannello, R.C., and Kola, I. (1995) Biochem. Mol. Biol. Int. May;35(6), 1281-1297
Revised: July 17, 2001.