Background <p>Mitochondrial diseases comprise a genetically and clinically heterogeneous group of disorders primarily resulting from defects in oxidative phosphorylation, leading to impaired ATP synthesis and cellular energy deficiency. The functional competence of mitochondria critically depends on the ultrastructural integrity of the inner mitochondrial membrane, notably the cristae, which serve as the platform for respiratory chain complexes. The mitochondrial contact site and cristae organizing system complex (MICOS) is essential for maintaining cristae junction architecture and inner membrane morphology. Disruption of this complex, especially mutations affecting the MIC13 subunit, compromises cristae junction integrity, leading to severe multisystem mitochondrial cytopathies with prominent neurological and hepatic manifestations.</p> Methods and results <p>We report here a consanguineous family with a patient presenting with cholestatic hepatopathy, profound developmental delay, optic atrophy, sensorineural hearing loss, microcephaly, and cerebellar atrophy. Whole-exome sequencing performed in the patient identified a homozygous pathogenic novel c.209dupT (p. A73Rfs*32) variant in the <i>MICOS13</i> gene inherited from his heterozygous parents. The variant introduces a premature termination codon, leading to a truncated protein that lacks the second RDSWN motif, which is critical for MIC13 function. Protein modelling and molecular dynamics simulation support the hypothesis that the mutation induces structural destabilization, impairing protein folding and function, which may contribute to mitochondrial dysfunction. Additionally, analysis of mitochondrial DNA copy number revealed a mitochondrial depletion in the patient.</p> Conclusions <p>This case expands the clinical and molecular spectrum of <i>MICOS13</i> deficiency, causing mitochondrial hepatoencephalopathy.</p>