Clinical heterogeneity associated with the mitochondrial DNA T8993C point mutation
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F M Santorelli1, S C Mak, M E Vazquez-Memije
1H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Department of Neurology, Columbia University, New York, New York 10032, USA.
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.
Insights
The T8993C mitochondrial DNA mutation causes a milder form of Leigh syndrome compared to the T8993G mutation. This finding offers new insights into Leigh syndrome genetics and patient outcomes.
Area of Science:
- Genetics
- Mitochondrial Biology
- Neurology
Background:
- Maternally inherited Leigh syndrome (MILS) is often caused by the T8993G mitochondrial DNA mutation, typically leading to severe early-infancy mortality.
- A less aggressive juvenile form of Leigh syndrome (LS) was previously linked to the T8993C mutation.
Observation:
- This study describes four unrelated patients with the T8993C mutation presenting with diverse, mild clinical symptoms.
- The T8993C mutation was highly abundant (>94%) in various tissues of affected patients.
- Maternal relatives showed lower levels of the T8993C mutation in their blood.
Findings:
- Mitochondrial ATP production was normal in three patients but reduced in one patient (20-35% of controls).
- The T8993C mutation appears to be less severe than the T8993G mutation in Leigh syndrome.
- Heteroplasmy levels of the T8993C mutation varied between patients and tissues.
Implications:
- The T8993C mutation represents a distinct genetic cause of Leigh syndrome with a more favorable prognosis.
- Understanding mutation-specific severity can improve diagnosis and patient management for Leigh syndrome.
- Further research into mitochondrial DNA mutation impacts on cellular energy production is warranted.
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