Heteroplasmic pathogenic m.12315G>A variant in MT-TL2 presenting with MELAS syndrome and depletion of nitric oxide donors

by Selleckchem | Dec 25 2023

The MT-TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5-year-old child with heteroplasmy for this variant who developed neurological regression and stroke-like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z-scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke-like episodes. The use of intravenous arginine during stroke-like episodes and daily enteral L-citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1-methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N-acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A to include neurological regression and a MELAS-like phenotype. Individuals with this variant should undergo in-depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment.

Comments:

It sounds like a complex case involving a 5-year-old child with a specific mitochondrial variant (MT-TL2 m.12315G>A) that resulted in neurological regression and stroke-like episodes reminiscent of a condition known as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The report emphasizes the importance of detailed biochemical evaluations in understanding and managing such cases.

The depletion of arginine and low citrulline z-scores indicated a potential link to decreased nitric oxide availability, likely contributing to the stroke-like episodes. Treatment involving intravenous arginine during episodes and daily enteral L-citrulline supplementation helped normalize the biochemical values of arginine and citrulline.

Additionally, the absence of nicotinamide, 1-methylnicotinamide, and low plasma total glutathione levels prompted the initiation of nicotinamide riboside and N-acetylcysteine therapies. These treatments were likely aimed at addressing deficiencies and optimizing metabolic pathways affected by the mitochondrial variant.

The report suggests that individuals with this specific mitochondrial variant should undergo thorough biochemical analysis, including untargeted plasma metabolomics, plasma amino acids, and glutathione levels, to tailor a targeted approach to treatment.

This case expands the known phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A, indicating the importance of ongoing research and comprehensive evaluations to better understand and manage mitochondrial disorders.