Mitochondrial DNA Maintenance Defects: Clinical, Imaging, and Genetic Spectrum of Four Patients from a Single...

Mitochondrial DNA maintenance defects (MDMD) are rare genetic disorders that typically present in infancy but can manifest later with multi-organ involvement. We describe four MDMD cases (age 19-25) with distinct clinical and genetic profiles and delayed diagnosis. Two patients with mitochondrial neurogastrointestinal encephalomyopathy (homozygous TYMP variants: c.454G>T, c.866A>C) exhibited cachexia, ptosis, neuropathy, and confluent white matter hyperintensities leukodystrophy. Two others with MPV17 (c.293C>T) presented with neuromyopathy and hepatosplenomegaly; one showed novel concentric ring lesions on magnetic resonance imaging (MRI). Despite severe white matter changes/leukodystrophy, cognition was preserved. Diagnoses were delayed due to atypical gastrointestinal or neuromuscular symptoms. This series highlights the diagnostic challenge of MDMD and underscores that it should be considered in adolescents or young adults with unexplained neuropathy, white matter hyperintensities/leukodystrophy, or cachexia, even without classic hepatic or encephalopathic features. Genetic testing is essential for diagnosis, as phenotypic variability often obscures underlying MDMD. Our findings underscore the need for increased awareness of this delayed-diagnosis presentation to enable timely intervention.