TSPO-PET highlights an atypical mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype.

BACKGROUND

The m.10158T > C mutation in the mitochondrial gene (MT-ND3) is a rare cause of adult-onset mitochondrial encephalopathy, typically presenting as MITOCHONDRIAL ENCEPHALOMYOPATHY WITH LACTIC ACIDOSIS AND STROKE-LIKE EPISODES (MELAS) with predominant cortical involvement. Early cerebellar onset and progressive atrophy are atypical. To investigate the underlying pathophysiology, we innovatively applied TSPO-PET to visualize neuroinflammation and MITOCHONDRIAL PATHOLOGY linked to mitochondrial encephalopathies. CASE PRESENTATION: A 32-year-old woman had a 20-year progressive disorder starting with migraines at age 12. Left cerebellar atrophy was found incidentally at 15, followed by episodic ataxia, dysarthria, and generalized seizures at 24. She later developed refractory status epilepticus, right side sensory ataxic symptoms, and neurocognitive decline. MRI showed progressive bilateral cerebellar atrophy and multifocal cortical lesions. Genetic testing identified the m.10158T > C mutation. TSPO-PET revealed increased uptake, indicating neuroinflammation, in the left thalamus, temporoparietal-occipital lobe, bilateral cerebellum, corresponding FDG-PET showed hypometabolism. Of note, the MRI-normal regions, including the right thalamus, hippocampus and brainstem, exhibited elevated TSPO uptake with or without subtle FDG changes.

CONCLUSION

Our study defined an atypical MELAS phenotype associated with m.10158T > C mutation, characterized by cerebellar early involvement, subsequent progressive atrophy, and repeated stroke-like episodes. In addition, TSPO-PET uptake extends well beyond the boundaries of detectable structural damage, demonstrating that molecular pathology exceeds visible damage. To our knowledge, our study represents the first preliminary exploration of in vivo histopathological changes using a second-generation TSPO radioligand (¹⁸F-DPA-714) in a patient with MELAS, advancing our understanding of the relationship between neuroinflammation and primary mitochondrial diseases.