The cause of non-disjunction leading to trisomy 21 and the reason why triplication brings about this specific phenotype, are both unclear. Several etiological hypothe­ses have received considerable attention but there is no obvious reason to favor any of them. Similarly, there is no convincing evidence that any individual loci on chromo­some 21 are by themselves responsible for the Down’s syndrome (DS) phenotype. A newer hypothesis invokes mitochondrial DNA mutations in the etiology of DS and as an explanation of the phenotype. Evidence is presented in support of this hypothesis from animal studies, epidemi­ology, pedigree analysis and the investigation of donor mothers and affected individuals. In conclusion, there is more evidence in favor of the hypothesis than for any of the alternative explanations.

Key words: Down’s syndrome (DS); mitochondrial DNA (mtDNA); mutations; etiology; pathogenesis.