Year-end Sale % OFF 
Abstract
Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs.
Highlights
Porphyrias are a group of congenital and acquired diseases characterized by an impairment of the heme biosynthetic pathway [1]
Central nervous system (CNS) disturbances may develop throughout the entire course of acute porphyric attacks (APAs), the most dramatic being encephalopathy of varying severity, seizures, and hyponatremia due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH); psychiatric symptoms may complete the picture, ranging from depression, irritability, hallucination, to overt psychosis or catatonia
Similar results were obtained by intraperitoneal injections of aminolevulinic acid (ALA), which caused an increase in total non-heme iron and ferritin in the cortex, in ferritin content in the striatum, in CuZnSOD activity in brain homogenates, lipid peroxidation and protein carbonylation in synaptic membrane preparations of total brain tissue, and in calcium uptake by cortical synaptosomes [80]
Summary
Porphyrias are a group of congenital and acquired diseases characterized by an impairment of the heme biosynthetic pathway [1]. In vivo studies have shown that the influx-rate constant for ALA movement from bloodstream to the brain is, quite low and decreases with age It seems to be a result of passive diffusion, except at the CSF-blood and choroid plexus-blood barriers, where the active transport of ALA has been described [40]. It is interesting the case report of an 82-year-old man who developed a clinical and biochemical picture suggestive of variegate porphyria, immediately following an oral loading of ALA, administered as a prodrug in the context of a photodynamic therapy for Barrett’s esophagitis is interesting [58] In this case, even allowing for a genetic predisposition of the patient, which may have precipitated a full porphyric syndrome, an -at least initial- direct neurotoxic effect of ALA is too compelling a hypothesis to be discarded. Trypanosoma cruzi is a parasite that constitutively lacks some cytosolic enzymes of the heme biosynthetic pathway [60] and relies on host heme to survive; it is the causative agent of Chagas disease, whose manifestations include, intriguingly, neuropathy and autonomic dysfunction [61,62,63]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
