BEYOND THE GENETIC CODE: SYSTEMIC REGULATORY MELTDOWN AS A FRAMEWORK FOR PRIMARY EPIGENETIC DISEASES.

BACKGROUND: Modern medicine is increasingly encountering multisystemic disorders that do not fit into traditional genetic or organ-specific nosologies. This study proposes and validates the concept of "primary epigenetic disease" (PED) as a distinct clinical entity. OBJECTIVE: to define the molecular mechanisms, genetic foundations, and clinical manifestations of PED, and to establish a standardized diagnostic framework using autism spectrum disorder (ASD) and chronic fatigue syndrome (CFS) as primary models. MATERIALS AND METHODS: A narrative review was conducted using PubMed and Scopus databases (predominantly 2021-2026). Evidence was synthesized from meta-analyses, randomized controlled trials, and large-scale genomic studies focusing on DNA methylation, histone modifications, and microRNA networks. RESULTS: We identified that PED emerges from a synergistic failure of the epigenetic machinery, often driven by a high load of common single nucleotide polymorphisms (SNPs) in genes such as MTHFR, DNMTs, and HDACs. We established a 30-point diagnostic matrix comprising 15 clinical criteria (e.g., developmental delays, connective tissue dysplasia, and paradoxical drug sensitivity) and 15 laboratory criteria (e.g., SAM/SAH imbalance, mitochondrial dysfunction markers, and global DNA hypomethylation). The application of this matrix to ASD and CFS demonstrates a shared pathogenic core: systemic biological desynchronization, barrier failure, and persistent low-grade inflammation. CONCLUSION: Primary Epigenetic Disease represents a "regulatory meltdown" of the genome. Effective management requires a paradigm shift from symptomatic treatment to "epigenetic rehabilitation," which combines systemic genomic modulation with precision biochemical correction of identified bottlenecks. This framework provides a robust toolkit for the identification and management of multisystemic patients in the era of systems medicine.