Why it is necessary to study the role of mitochondrial genome in Trisomy 21 Pathogenesis

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Abstract
An analysis of 190 pedigrees with Trisomy 21 suggests a cytoplasmic predisposition for the inheritance of Down syndrome and an association with other aneuploidies, non-chromosomal syndromes, autoimmune, neurodegenerative and oncological diseases.The extra chromosome seems to be responsible for the increase in free-radical intensity and the decrease of SOD-1 activity with age. The disturbance of the oxidant-antioxidant system could be the direct cause of this chromosomal nondisjunction. These data as well as the predominant maternal origin of the extra chromosome and the age-dependent incidence was the basis for the mtDNA sequencing in a donor of extra chromosome 21. Three new point, non-polymorphic mutations, not described before, were found in the following genes:- ATP-ase, G8764A and ND-5 G13243A with the same amino-acid substitutions Ala/Thr and in ND-1 G3337A-Val/Met. The mtDNA mutations detected in cases of Alzheimer's disease, insulin-independent diabetes, some cancers, and in somatically healthy people of 40 years and older could explain the connection of Down syndrome with these diseases and aging. Moreover, mtDNA analysis in patients with trisomy 21 might help to elucidate the nature of free-radical damage. This phenomenon is directly related to the manifestation of the syndrome and cannot be explained solely by the secondary SOD-1 gene dosage effect.

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