Heterogeneity in the phenotypic expression of the mutation in the mitochondrial tRNA^{Leu (UUR)} gene generally associated with the MELAS subset of mitochondrial encephalomyopathies

Background: Point mutations in the mitochondrial (mt) genome underlie a number of neurological disorders. Some are well defined including the myoclonus epilepsy ragged red fibre syndrome (MERRF) and the mitochondrial encephalopathy lactic acidosis stroke like episode syndrome (MELAS). However, other clinical phenotypes are less distinctive and mitochondrial studies are often included in the workup in complex neurological syndromes of uncertain aetiology. Aims: We investigated 27 consecutive patients with varied clinical phenotypes referred to our laboratory for mtDNA studies to determine the incidence of recognised point mutations in a patient group with a range of phenotypes including many where mt disease was possible but did not fall into a classical syndrome. Methods: The recognised point mutations were detected by amplification of the appropriate DNA fragment by PCR followed by restriction‐endonuclease digestion of the normal and mutant species. Results: The A‐G base substitution mutation at nucleotide (nt)3243 in the tRNA^Leu gene of mtDNA which is present in the majority of cases of MELAS syndrome, was detected in four cases, only one of whom had typical MELAS symptoms. Their clinical manifestations ranged from mild deafness to a mixture of chronic progressive external ophthalmoplegia symptoms (CPEO) and stroke like episodes. The nt3243 mutation was also identified in one of seven mtDNA deletion negative CPEO cases. Conclusions: The presentation of the mtDNA mutation at nt3243 appears therefore to be quite variable with some mild phenotypes as well as severe phenotypes observed. In general, the chance of finding a mitochondrial point mutation in a patient with an atypical clinical phenotype is small.