Long Survival in Patients With Leigh Syndrome and the m.10191T>C Mutation in MT-ND3

Abstract

We report an unusual case history of Leigh syndrome due to the m.10191T>C mutation in the complex I gene MT-ND3. This mutation has been associated with a spectrum of clinical phenotypes ranging from infant lethality to adult onset. Despite infantile onset and severe symptoms, our patient has survived to early adulthood due to a strict dietary regimen and parental care. This patient is an extreme example of the frequently prolonged course of Leigh syndrome due to this particular mutation.

Adult-onset Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke (MELAS)-like Encephalopathy Diagnosed Based on the Complete Sequencing of Mitochondrial DNA Extracted from Biopsied Muscle without any Myopathic Changes

“…A higher proportion of heteroplasmic mitochondrial DNA mutation was reported to be associated with RRFs, based on an analysis of patients with different large mitochondrial DNA deletions and MELAS patients with the m.3243A>G point mutation ( 9 ). In addition to the m.10158T>C mutation, the m.10191T>C as well as m.10197G>A mutations are located in the matrix-loop domain of the ND3 subunit protein and are known to cause Leigh syndrome or Leigh-like syndrome with dystonia, respectively ( 6 , 10 - 12 ). Patients aged 16, 25, and 52 years harboring 73%, 70%, and 77% m.10191T>C mutation in muscle ( 6 , 10 , 11 ) and 9-month-old and 37-year-old patients harboring 100% and 97% m.10197G>A mutation ( 12 ) were found to have no RRFs, although all of these patients who underwent an analysis of mitochondrial respiratory chain activities in muscle showed a specific defect in the activity of complex I.…”

Ischemic A/D transition of mitochondrial complex I and its role in ROS generation

“…This loop is an important hot spot for mutations in complex I deficiencies. Single amino acid changes in this domain of ND3 lead to various mitochondrial encephalopathies as well as Leigh syndrome, indicating the significance of this loop in complex I function or regulation [33] , [34] , [35] , [36] , [37] . Although Cys-39 of ND3 is highly conserved among the eukaryotes (99% conserved over 108 sequences), its presence does not correlate with the apparent ability of complex I to undergo the A/D transition [38] .…”

Targeted Reduction of Pathogenic Heteroplasmy Through Binding of G-Quadruplex DNA

“…Although exact incidence figures are not available for this mutation, it is viewed as a relatively common cause of complex I-deficient Leigh syndrome (LS) (26). All known patients with this mutation are heteroplasmic (26)(27)(28). The heavy-strand region proximal to mt.10191 has a high potential for GQ formation and the mt.10191C variant was predicted to increase both the number of potential GQs and their stability by extending a stretch of five guanines that is present in wild type mtDNA.…”