Balkan Journal of Medical Genetics

Despite a vast amount of epidemiological and genetic research into Down’s syndrome (DS), the cause of the non-disjunction leading to trisomy 21 and the reason why triplication brings about this specific phenotype, are both unclear. Down’s syndrome is the most common cause of mental retardation, with a prevalence, in the absence of prenatal diagnosis, of 1-2 per 1,000 births. In addition to severe learning difficulties, typical appearance, and cardiac and digestive tract abnormalities, DS is associated with a general acceleration in the ageing process.

In particular, affected individuals develop changes in the brain by about age 30 similar to Alzheimer’s disease (AD), and there is a substantial early onset of auto-immune diseases and cataracts.

Advanced maternal age is by far the strongest epidemiological variable with birth prevalence increasing from 0.06% at age 15 to 4.1% by age 45 [1]. There is familial aggregation: having had a previous DS pregnancy confers a 0.54% higher risk than the age-specific prevalence, other types of aneuploidy are also more frequent and there is an excess of double aneuploidies including trisomy 21 [2]. Other risk factors, such as a family history of AD, diabetes or hypothyroidism are much weaker [3,4].

Chromosome 21 has now been completely sequenced and it includes a number of important genes, such as those for Cu,Zn-superoxide dismutase (SOD-1) and the amyloid precursor protein (AbPP). Genetic mapping shows that in about 90% of trisomy 21 the extra chromosome is maternal in origin, and that certain types of crossovers at maternal meiosis I confer a substantial susceptibility [5]. Parental DNA studies have reported an altered distribution of polymorphisms in the genes for apolipoprotein E, presenilin-1 and those involved in folate metabolism, but the effects are not great and the results inconsistent between studies (see citations in [6]).

Several etiological hypotheses have received considerable attention but there is no obvious reason to favor any of these [7]. Similarly, there is no convincing evidence that any individual loci on chromosome 21 are by themselves responsible for the DS phenotype [8]. Less attention has been paid to a newer hypothesis, namely that mitochondrial DNA (mtDNA) mutations are involved in DS etiology [9-11], and that they could also explain the DS phenotype [10,12].

Mutations in mtDNA bring about an increase in the generation of free-radicals and reduce ATP levels. The enzymes participating in recombination and DNA repair are ATP-dependent [13,14], and reduced availability could affect the synaptonemal complex, chromosome segregation and division spindle, alter recombination and lead to aneuploidy. Both point mutations and micro-deletions could be expected to induce non-disjunction, but it is more likely that it would probably take the accumulation of several mutations to decrease mitochondrial function sufficiently to affect meiosis.

The mitochondrial respiratory system is the most important intracellular source of reactive oxygen species (ROS) and free radicals, and mitochondria have a central role in apoptosis. The accumulation of mtDNA mutations is a major contributor to degenerative diseases and ageing. Down’s syndrome individuals are subject to oxidative stress, as measured by increased lipid peroxidation, and there is general agreement that a disturbance in the balance of ROS may be a key point in the pathogenesis. Moreover, mtDNA mutations can be inherited and can be caused by both endogenous and exogenous factors. In DS, the inheritance of such mutations could account for both the familial aggregation and some of the phenotypic features of the disorder that are present in both families and affected individuals.