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| Médium: | Recurso digital |
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Zenodo
2026
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| Témata: | |
| On-line přístup: | https://doi.org/10.5281/zenodo.18942603 |
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- <p>Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by mutations in the enzyme porphobilinogen deaminase (HMBS), a crucial catalyst in the heme biosynthetic pathway. This disorder is characterized by variable phenotypic expressivity and penetrance that depends on genetic, metabolic, and environmental factors. Biochemically, PAI occurs as a threshold-dependent continuum, in which the accumulation of the soluble precursor with high ROS potential (δ-aminolevulinic acid (ALA)) must exceed the body's antioxidant detoxification capacity to trigger the cascade of biochemical events that lead to acute symptoms. Chronic excess of this precursor results in the production of reactive oxygen species (ROS), which cause oxidative damage at the cellular and tissue levels, resulting in structural and functional alterations in highly metabolic tissues, such as the peripheral nervous system, kidneys, heart, and liver.</p> <p>Genetic factors that influence the clinical severity of PAI include variants in genes involved in oxidative detoxification systems, including cytochrome P450s and cellular redox systems. These mutations contribute to the body's difficulty managing the oxidative load resulting from the accumulation of biosynthetic precursors, leading to metabolic memory which persists even during periods of clinical quiescence. The inadequate response to metabolic stress, especially in the presence of genetic polymorphisms in epigenetic modulators, impairs the body's ability to efficiently respond to ALA and PBG overload, explaining the phenotypic variability of the disease.</p> <p>Beyond acute symptoms, the biochemistry of oxidative damage generated by ROS has significant implications not only for the recurrence of exacerbations and long-term damage, but also for subacute or subclinical manifestations of the "deficient" phenotype. These manifestations, although not acute, are linked to persistent biochemical damage at the level of cell membranes, mitochondria, and structural proteins and can significantly contribute to disease progression. Long-term damage is observed in highly vascularized and metabolically active organs, such as the kidneys, enteric and peripheral nervous system, heart, and liver.</p> <p>In conclusion, HMBS deficiency (and acute intermittent porphyria) must be understood as a disorder dynamic metabolic, not exclusively intermittent, in which the interaction between genotype, oxidative damage and epigenetic regulation defines latency and progression, with a biodiagnostic panel useful for adequate metabolic follow-up.</p>