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Bi‐allelic alterations in the MDH2 gene have recently been reported in three unrelated toddlers with early‐onset severe encephalopathy. Here, we describe a new case of a child carrying novel variants in MDH2. This child presented with early‐onset encephalocardiopathy requiring heart transplant and showed cerebellar ataxia and drug‐responsive epilepsy; his family history was significant for multiple cancers, a feature often associated with monoallelic variants in MDH2. Functional studies in cultured skin fibroblasts from the proband showed reduced protein levels and impaired enzyme activity, further corroborating the genetic results. The relatively mild neurological presentation and severe cardiac manifestations requiring heart transplant distinguish this case from previous reports. This patient thus expands the spectrum of clinical features associated with MDH2 variants. [ABSTRACT FROM AUTHOR]

Background: Mitochondria adjust their shape in response to the different energetic and metabolic requirements of the cell, through extremely dynamic fusion and fission events. Several highly conserved dynamin-like GTPases are involved in these processes and, among those, the OPA1 protein is a key player in the fusion of inner mitochondrial membranes. Hundreds of monoallelic or biallelic pathogenic gene variants have been described in OPA1 , all associated with a plethora of clinical phenotypes without a straightforward genotype-phenotype correlation., Methods: Here we report two patients harboring novel de novo variants in OPA1 . DNA of two patients was analyzed using NGS technology and the pathogenicity has been evaluated through biochemical and morphological studies in patient's derived fibroblasts and in yeast model., Results: The two patients here reported manifest with neurological signs resembling Leigh syndrome, thus further expanding the clinical spectrum associated with variants in OPA1 . In cultured skin fibroblasts we observed a reduced amount of mitochondrial DNA (mtDNA) and altered mitochondrial network characterized by more fragmented mitochondria. Modeling in yeast allowed to define the deleterious mechanism and the pathogenicity of the identified gene mutations., Conclusion: We have described two novel-single OPA1 mutations in two patients characterized by early-onset neurological signs, never documented, thus expanding the clinical spectrum of this complex syndrome. Moreover, both yeast model and patients derived fibroblasts showed mitochondrial defects, including decreased mtDNA maintenance, correlating with patients' clinical phenotypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors (EBa, DM, EBe, FMS and RC) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Di Nottia, Rizza, Baruffini, Nesti, Torraco, Diodato, Martinelli, Dal Canto, Gilea, Zoccola, Siri, Dionisi-Vici, Bertini, Santorelli, Goffrini and Carrozzo.)