Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation

Two pathogenic mitochondrial DNA mutations, a T-to-G substitution (8993T > G) and a T-to-C substitution (8993T > C), at nucleotide 8993 have been repo rted. We describe 13 pedigrees with mitochondrial DNA mutations at nucleoti de 8993; 10 pedigrees with the 8993T > G mutation and three with the 8993T > C mutation. Prenatal diagnosis of the nucleotide 8993 mutations is techni cally possible. However, there are three major concerns: (i) that there is variation in mutant loads among tissues; (ii) that the mutant load in a tis sue may change over time; and (iii) that the genotype-phenotype correlation is not clearly understood. We have used the 13 pedigrees to determine spec ifically the extent of tissue- and age-related variation of the two mutatio ns at nucleotide 8993 in the mitochondrial DNA. The tissue variation was in vestigated by analysing two or more different tissues from a total of 18 in dividuals. The age-related variation of the mutation was investigated by co mparing the amount of both mutations in blood taken at birth and at a later age. No substantial tissue variation was found, nor was there any substant ial change in the proportion of either mutation over periods of 8-23 years in the four individuals studied. In addition, we noted that two features we re remarkably common in families with nucleotide 8993 mutations, namely (i) unexplained infant death (8 cases in 13 pedigrees), and (ii) de novo mutat ions (5 of the 10 8993T > G pedigrees).