Leukoencephalopathy, developmental delay, and episodic neurological regression syndrome (LEUDEN)

We describe a clinical case of leukencephalopathy, developmental delay, and episodic neurologic regression (LEUDEN, OMIM 618877) associated with variants in the EIF2AK2 gene, with an emphasis on clinico-pathogenetic links and potential therapeutic targets. A 2-year-old boy presented with psychomotor delay, spastic tetraparesis, and fever-induced episodes of regression; brain MRI showed hypomyelination and white-matter atrophy. Whole-exome sequencing identified a de novo pathogenic EIF2AK2 variant, c.325G>T (p.Ala109Ser, NM_001135651.3). The synthesis of clinical, neuroimaging, and genetic data is consistent with chronic hyperactivation of the integrated stress response (ISR) via the PKR–eIF2α pathway, leading to sustained eIF2α phosphorylation, impaired synthesis of myelin proteins, activation of apoptosis, and synaptic dysfunction; external stressors (infections) act as triggers of transient deterioration manifesting as regression of skills. The phenotype may mimic cerebral palsy with episodes of regression, underscoring the need for early molecular genetic confirmation in pediatric hypomyelination. The pathogenetic involvement of the ISR highlights the promise of targeted modulation of this pathway (e.g., ISR inhibitors), although the clinical efficacy of such strategies in LEUDEN requires further evaluation in controlled studies; early diagnosis and patient stratification are key to developing personalized treatment approaches.

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