Developmental and Epileptic Encephalopathies (DEEs) comprise a heterogeneous group of severe neurological disorders with early onset refractory epilepsy and profound neurodevelopmental impairments. Despite the availability of more than thirty anti-seizure medications, most individuals with DEE remain refractory, experiencing persistent seizures that impose substantial burdens on patients, caregivers, and health care systems. DEEs are predominantly genetic, largely caused by de novo mutations, although non-genetic factors also contribute. Crucially, developmental deficits in DEE arise from both the underlying etiology and the disruptive effects of epileptic activity on the developing brain, distinguishing DEE from epilepsies without major neurodevelopmental involvement. Seizures during critical developmental windows exert acute and enduring effects on neurogenesis, synaptogenesis, circuit refinement, pruning, and brain maturation, which can greatly disrupt neurodevelopment. Mitochondria emerge as central regulators at the intersection of neurodevelopment and epilepsy. Mitochondrial dysfunction, whether from primary genetic mutations or seizure-induced injury, impairs bioenergetics, calcium homeostasis, redox states, and metabolic signaling, lowers seizure thresholds, and increases neuronal vulnerability. Moreover, mitochondrial metabolism directly interfaces with epigenetic regulation, linking energy state to long-term gene expression, altering developmental programming. This review synthesizes current knowledge on mitochondrial contributions to DEE pathogenesis, clinical diagnosis, and highlights emerging mitochondrial-targeted therapeutic strategies.

Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficient Disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy characterized by early-onset refractory epilepsy, severe neurodevelopmental impairment, and lifelong disability. Although more than thirty anti-seizure medications are available, most CDD patients remain pharmaco-resistant. Gene-based therapies are emerging, but therapeutic development is hindered by marked clinical heterogeneity, small patient populations, and the lack of robust, translatable brain-based biomarkers for clinical trials. Genetically engineered Cdkl5 mouse models recapitulate many cognitive, behavioral, and molecular features of CDD, yet their utility is limited by the absence of overt seizures, precluding seizure-based outcome measures. Here, we establish high-definition brain network (HDBN) biomarkers using advanced diffusion MRI tractography combined with graph-theoretical analysis to quantify whole-brain network organization in Cdkl5 knockout mice. Diffusion MRI enables non-invasive mapping of axonal connectivity by leveraging anisotropic water diffusion, while high-angular-resolution acquisition overcomes key limitations of conventional diffusion tensor imaging in regions with complex fiber architecture. We demonstrate that Cdkl5 knockout mice exhibit reproducible and region-specific disruptions in brain network organization, prominently affecting the somatosensory and somatomotor cortex, hippocampus, hypothalamus, amygdala, and superior colliculus—regions implicated in cognition, learning and memory, homeostasis, anxiety, and visual–motor function. In contrast, networks within the entorhinal cortex remain largely preserved. These findings identify HDBN metrics as sensitive, non-invasive biomarkers that capture clinically relevant circuit-level abnormalities in CDD. Because diffusion MRI–based network analyses are directly translatable across species, HDBN biomarkers provide a unified framework for therapeutic evaluation in mouse models, large animals, and human clinical trials, enabling longitudinal monitoring of disease progression and treatment response.

Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficient Disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy characterized by early-onset refractory epilepsy, severe neurodevelopmental impairment, and lifelong disability. Although more than thirty anti-seizure medications are available, most CDD patients remain pharmaco-resistant. Gene-based therapies are emerging, but therapeutic development is hindered by marked clinical heterogeneity, small patient populations, and the lack of robust, translatable brain-based biomarkers for clinical trials. Genetically engineered Cdkl5 mouse models recapitulate many cognitive, behavioral, and molecular features of CDD, yet their utility is limited by the absence of overt seizures, precluding seizure-based outcome measures. Here, we establish high-definition brain network (HDBN) biomarkers using advanced diffusion MRI tractography combined with graph-theoretical analysis to quantify whole-brain network organization in Cdkl5 knockout mice. Diffusion MRI enables non-invasive mapping of axonal connectivity by leveraging anisotropic water diffusion, while high-angular-resolution acquisition overcomes key limitations of conventional diffusion tensor imaging in regions with complex fiber architecture. We demonstrate that Cdkl5 knockout mice exhibit reproducible and region-specific disruptions in brain network organization, prominently affecting the somatosensory and somatomotor cortex, hippocampus, hypothalamus, amygdala, and superior colliculus—regions implicated in cognition, learning and memory, homeostasis, anxiety, and visual-motor function. In contrast, networks within the entorhinal cortex remain largely preserved. These findings identify HDBN metrics as sensitive, non-invasive biomarkers that capture clinically relevant circuit-level abnormalities in CDD. Because diffusion MRI–based network analyses are directly translatable across species, HDBN biomarkers provide a unified framework for therapeutic evaluation in mouse models, large animals, and human clinical trials, enabling longitudinal monitoring of disease progression and treatment response.