Mitochondrial Dysfunction in Monogenic Developmental and Epileptic Encephalopathies

Before diagnostic whole exome sequencing, monogenic/chromosomal developmental and epileptic encephalopathies (DEEs) were frequently misdiagnosed as mitochondrial disorders (MDs) with epilepsy, due to overlapping clinical and biochemical features. Assessing muscle functional assays in patients with a genetic diagnosis and epilepsy offers a unique opportunity to explore mitochondrial dysfunction in monogenic/chromosomal DEEs, in comparison to the mitochondrial dysfunction observed in genetically confirmed MDs.

In this retrospective cohort study, clinical and biochemical data were extracted from patients suspected of MD with epilepsy who underwent muscle/fibroblast biopsy (2005-2015). Patients were classified into four groups based on the final diagnosis. Mitochondrial Disease Criteria scores were assigned. Statistical analyses were conducted using Fisher's exact, analysis of variance, and Kruskal-Wallis tests.

Of 27 included participants, eleven (40.7%) had DEEs, four (14.8%) had genetically confirmed MDs, eight (29.6%) were suspected MD cases without genetic confirmation, and four (14.8%) had nonmitochondrial metabolic diseases. Mitochondrial dysfunction was common across all groups; 85% of participants met probable/definite Mitochondrial Disease Criteria, over 70% had elevated plasma lactate (>2.5 mmol/L), and 92% exhibited impaired adenosine triphosphate production. Surprisingly, moderate to severe complex dysfunction was observed in all groups except genetically confirmed MDs.

Our findings indicate that mitochondrial dysfunction is prevalent in nonmitochondrial DEEs. Patients previously diagnosed with an MD based only on muscle/fibroblast biopsy may benefit from whole exome sequencing to identify genetic variants, for which targeted therapy may be available. Future research should explore whether treatment or prognosis of nonmitochondrial DEEs should be tailored to improve mitochondrial function.