Clinical heterogeneity associated with the mitochondrial DNA T8993C point mutation

Abstract

The mitochondrial DNA (mtDNA) point mutation T8993G has been associated with maternally inherited Leigh syndrome (MILS) when very abundant (>95%). MILS patients are usually severely affected and die in early infancy. In 1993, a novel T8993C point mutation was described in a juvenile form of Leigh syndrome (LS) characterized by a less aggressive clinical course. We describe four unrelated T8993C patients who had diverse, relatively mild, clinical manifestations. Polymerase chain reaction-restriction fragment length polymphorphism analysis showed that the heteroplasmic T8993C point mutation was very abundant in several tissues from all four patients (94.2 ± 1.5%) but was less copious in blood from 20 maternal relatives. ATP production in mitochondria isolated from skin fibroblasts in three patients was normal, whereas in one patient it was decreased to 20-35% of controls. These findings suggest that the T8993C mutation is less severe than the more common T8993G mutation.