Animal Studies. The Dip 1 mutation in mice, which produces a high incidence of ovulated diploid oocytes, is carried by the mitochondria [15].

Epidemiology. There is a congruity between the sa­lient facts of mtDNA mutation and the epidemiology of DS. The number of mtDNA mutations increases with age in different cells, particularly in oocytes [16], and mtDNA is almost entirely of maternal origin [17]. There are proven associations between mtDNA mutations and AD, diabetes and hypothyroidism [18].

Pedigree Studies: Changing Partners. Studies of families with either two DS cases or one DS and another aneuploidy in which there were different reproductive partners in the parental or grand-parental generation, sug­gest the inheritance of a cytoplasmic factor. Seven pedi­grees were analyzed from such families, referred to two regional genetics centers, and in every pedigree the recur­rence was on the maternal side [2]. In the literature there are six case reports of recurrence involving maternal re­marriage, and only one report of affected half-siblings to the same father and different mothers, but this was in a highly inbred population (see citations in [2]).

Pedigree Studies: Multiple Generations. There are three reports of familial DS where the origin of the addi­tional chromosome 21 can be traced between generations, and they too suggest inheritance of a cytoplasmic factor. In one family, the father of a child with DS had twin sib­lings with DS [19]. He was the source (meiosis II) of the extra chromosome in his child and it was identical to that in his mother, which was duplicated (meiosis I) in the twins. In a similar study, the mother of the child with DS had a sister with DS, and the extra chromosome 21 (meio­sis I) that she passed to her child was identical to that in her mother which was duplicated in her affected sister [20]. In the third family, a brother and sister both had children with DS, they were each the origin of the extra chromosome (paternal meiosis II and maternal meiosis I) which they had inherited it from their mother [19].

Donor Mothers. Impaired function of the oxidant-antioxidant system has been found in mothers of infants with DS, and entire mtDNA sequencing in one donor of the extra chromosome 21 identified four mutations, not previously described, all causing amino acid changes [12].

Affected Individuals. The entire mtDNA sequence of three individuals with DS with a high incidence of mtDNA mutations has been reported, including those not previously described [21]. In a study of DS astrocytes there was impaired mitochondrial function, as demon­strated by reduced mitochondrial redox activity and mem­brane potential. It was also shown that a defect in APP processing related to the mitochondrial dysfunction [22].

Haplotype analysis of the mtDNA sequence in eight individuals with Klinefelter’s syndrome was found to be identical, unique and specific, as it was not found in the normal population, indicating that possible interaction of chromosomes and the mtDNA exists [23].