Materiały źródłowe

• #1 Overview of Porphyrias – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/the-porphyrias/overview-of-porphyrias

  Porphyrias are rare disorders in which there are defects in the pathway of heme synthesis, in all but one type (X-linked protoporphyria), due to genetic or acquired deficiencies of enzymes of the heme biosynthetic pathway. These deficiencies, coupled with other factors, especially up-regulation of the first and normally rate-controlling step in the pathway, allow heme precursors to accumulate, causing toxicity. […] Porphyrias result from a deficiency of any of the last 7 enzymes of the heme biosynthetic pathway or from increased activity of the erythroid form of the first enzyme in the pathway, ALA synthase-2 (ALAS 2). […] When an enzyme of heme synthesis is deficient or defective, its substrate and any other heme precursors normally modified by that enzyme may accumulate in bone marrow, liver, skin, or other tissues and have toxic effects.

• #2 Acute Porphyria – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537352/

  Acute porphyria refers to a group of rare disorders characterized by an enzymatic defect in the heme biosynthetic pathway. […] Acute porphyrias are genetic conditions; however, environmental, e.g., drugs and physiological factors, are crucial for clinical manifestation. Porphyria is a genetic disorder. […] More than 100 mutations have been identified. Clinical manifestation is associated with a 50% or more reduction in enzyme function. […] The pathogenesis of neurovisceral symptoms in acute porphyria has not been fully elucidated. One hypothesis is that the deficiency of heme affects neuronal function; the other hypothesis is that the precursors aminolevulinic acid (ALA) and porphobilinogen PBG may have direct neurotoxic effects. […] The liver is the source of the four acute porphyrias and also to one of the cutaneous porphyrias (PCT). The most common acute porphyria is acute intermittent porphyria (AIP). AIP is an autosomal dominant acute hepatic porphyria. […] Porphyrias fall into two classes: either erythropoietic or hepatic forms depending on the site of the major enzyme deficiency. The enzyme deficiencies are inherited as either autosomal dominant (AD), autosomal recessive (AR), or less commonly as X-linked.

• #3 Acute Porphyria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/957604-overview

  The porphyrias are caused by enzyme deficiencies in the heme production pathway. Such deficiencies may be due to inborn errors of metabolism or exposure to environmental toxins or infectious agents. Because of the ubiquitous use of heme in the human body, severe enzyme deficiencies are lethal. […] Heme is an essential physiologic compound. It is critical for oxygen binding and transport, for the cytochrome P-450 pathway, for activation and decomposition of hydrogen peroxide, for oxidation of tryptophan and prostaglandins, and for the production of cyclic guanine monophosphate (cGMP). The liver produces approximately 15% of the body’s heme; bone marrow produces the remainder. Heme produced in the liver is primarily used for cytochromes and peroxisomes, whereas heme produced in the bone marrow is used primarily for oxygen transport. Biosynthesis of 1 heme molecule requires 8 molecules of glycine and succinyl-coenzyme A (CoA).

• #4 Porphyria | PM&R KnowledgeNow

  https://now.aapmr.org/porphyria/

  Porphyria refers to a group of nine hereditary metabolic disorders caused by defects in the heme biosynthesis pathway. They result from reduced activity of specific enzymes in the pathway causing accumulation of toxic metabolites of heme. […] A deficiency any of the last seven enzymes in the heme biosynthesis will cause a specific type of porphyria. Mutations of the first enzyme in the pathway, Aminolevulinic acid synthase-2 (ALA) will cause sideroblastic anemia rather than porphyria. Clinical manifestations occur due to the accumulation of toxic metabolites that are not processed. […] Hepatotoxicity may be precipitated by deposition of protoporphyrin crystals in hepatocytes and bile canaliculi, promoting interference with redox mechanisms in the liver which promotes the production of cytotoxic bile.

• #5 Porphyria – Wikipedia

  https://en.wikipedia.org/wiki/Porphyria

  In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes. […] The body requires porphyrins to produce heme, which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. […] Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or in the bone marrow and red blood cells. […] Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. Heme function plays a central role in cellular metabolism. This is not the main problem in the porphyrias; most heme synthesis enzymes even dysfunctional enzymes have enough residual activity to assist in heme biosynthesis.

• #6 Porphyria – Wikipedia

  https://en.wikipedia.org/wiki/Porphyria

  The principal problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. […] The chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted (in the urine or feces). […] The hepatic porphyrias are characterized by acute neurological attacks (seizures, psychosis, extreme back and abdominal pain, and an acute polyneuropathy), while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth. […] Variegate porphyria (also porphyria variegata or mixed porphyria), which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. […] Hereditary coproporphyria, which is characterized by a deficiency in coproporphyrinogen oxidase, coded for by the CPOX gene, may also present with both acute neurologic attacks and cutaneous lesions. All other porphyrias are either skin- or nerve-predominant.

• #7 Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

  https://www.mdpi.com/2075-1729/12/11/1858

  The two main hypotheses proposed for the physiological origin of acute attacks are the potential neurotoxicity of ALA/PBG accumulation, or heme deficiency leading to decreased hemoprotein function and energy production in the mitochondria. […] The first is the most widely accepted hypothesis, as the onset of acute attacks has always been associated with the accumulation of porphyrin precursors. […] Despite all of this, the relationship between porphyrin precursor levels and prodrome symptoms is still unclear. […] Current treatments are based on down-regulation of hepatic ALAS1 expression using carbohydrate loading, intravenous (iv) hemin therapy, or the subcutaneous (sc) administration of a small interfering RNA (siRNA) targeting ALAS1 mRNA. […] Givosiran therapy is based on the fact that the accumulation of ALA and PBG precursors is the sole cause of the pathophysiology of the disease.

• #8 Acute Porphyria: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/957604-overview

  ALA, PBG, and their derivatives are neurotoxic to central and peripheral nerves. Disturbed heme synthesis in neural tissue results in depletion of essential cofactors and substrates. For example, Schwann cells may be sensitive to damage because they synthesize and use cytochrome P-450. Any disturbance in cytochrome production and function may lead to cell dysfunction and demyelination. […] Chronic renal failure may be caused by a combination of sustained hypertension, analgesic nephropathy, and intermediates in the nephrotoxic porphyrin pathway. […] ALA may cause dose-dependent damage to nuclear and mitochondrial DNA.

• #9 Acute intermittent porphyria – Wikipedia

  https://en.wikipedia.org/wiki/Acute_intermittent_porphyria

  Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting the production of heme resulting from a deficiency of the enzyme porphobilinogen deaminase. […] In AIP, over 100 mutations have been identified on the long arm of chromosome 11 at the HMBS gene, which codes for the cytoplasmic enzyme porphobilinogen deaminase. This deficiency prevents heme synthesis, which can not be completed and the metabolite porphobilinogen accumulates in the cytoplasm. […] The exact mechanism of acute attacks is not clear. The most favored hypothesis is that porpholobilinogen buildup causes a toxic effects on neurons. The autonomic and peripheral nervous system are more vulnerable than the central nervous system because they are not protected by the blood-brain barrier. This explains findings such as abdominal pain and tachycardia. Some individuals may be more likely to develop paresis based on increased susceptibility of neurons to toxins.

• #10 Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

  https://www.mdpi.com/1422-0067/22/2/675

  For a patient with AIP, in situations with increased demand for haem, a deficient HMBS enzyme becomes rate-limiting in the haem biosynthesis in the liver. […] The increased flux through this step causes accumulation of the haem precursors such as ALA and PBG. […] ALA is most likely the metabolite causing the neuropathic symptoms in AIP. […] The toxic effects of ALA have been reported to be concentration-dependent and associated with ROS. […] DNA damage because of ALA-induced ROS has also been implicated in the development of primary liver cancer in AIP. […] In addition to factors influencing ALAS1 activity, conditions affecting ALAD activity, e.g., by changing its quaternary structure, may be likely to also modulate ALA concentration. […] There are several reports describing a variation in the penetrance of selected mutations.

• #11 Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

  https://www.mdpi.com/1422-0067/22/2/675

  Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. […] In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. […] AIP is characterised by the overproduction of toxic haem precursors in the liver, resulting in so-called acute attacks, presenting with severe abdominal pain and a wide array of neurological and psychiatric symptoms. […] Long-term complications of AIP include hypertension, kidney failure and primary liver cancer. […] The haem biosynthesis pathway starts in the mitochondria with the condensation of glycine and succinyl CoA to ALA by ALA synthase (ALAS), followed by four enzymatic steps in the cytoplasm, and then back into the mitochondria, with three final steps resulting in the haem molecule.

• #12 AI Porphyria Precipitating Factors │ Healthcare Professionals

  https://isitaip.com/hcp/precipitating-factors/

  AIP is caused by a deficiency of the enzyme porphobilinogen (PBG) deaminase in the heme biosynthetic pathway. This enzyme deficiency predisposes patients to the effects of precipitating factors that can increase the demand for hepatic heme and lead to a chemical buildup that may cause symptoms to develop. […] Specialists in the treatment of AIP, Manisha Balwani, MS, MD, Associate Professor and Robert Desnick, Ph.D, MD, Dean for Genetics and Genomic Medicine from the Icahn School of Medicine at Mount Sinai describe the pathogenesis of AIP. […] Many drugs that are commonly prescribed to treat signs and symptoms of AIP actually increase the demand for hepatic heme and induce ALA synthase. These drugs may therefore exacerbate attacks and should be avoided.

• #13 Porphyria, Acute Intermittent – Hematology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.7.7.

  Acute intermittent porphyria (AIP) is a hereditary autosomal dominant disorder of heme synthesis. Potential disease-causing mutations occur in ~1 in 1700 Europeans. It is a result of deficiency of hepatic porphobilinogen (PBG) deaminase, which leads to the accumulation of porphyrin precursors PBG and delta-aminolevulinic acid (ALA) in situations associated with increased heme synthesis. This is a probable cause of intermittent peripheral neuropathy and sympathetic overactivity. […] An acute attack of porphyria is often triggered by factors that increase the synthesis of porphyrins, such as hepatocyte cytochrome P450 inducers (most commonly alcohol, steroid sex hormones [eg, progesterone], barbiturates, sulfonamides, carbamazepine, valproic acid, griseofulvin, and ergot derivatives), fasting (including weight-loss diets with a significantly reduced calorie and carbohydrate intake), tobacco and marijuana smoking, infection, stress, and surgery.

• #14 Drug-associated porphyria: a pharmacovigilance study | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03294-8

  The potentially fatal attacks experienced by porphyria carriers are triggered by various porphyrinogenic drugs. […] Porphyria is a group of rare metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis. […] Porphyrinogenic drugs induce the hepatic expression of ALAS1 or enhance utilization and depletion of hepatic regulatory heme, producing more neurotoxic porphyrin precursors, ALA, and porphobilinogen (PBG). […] It is, therefore, important for medical providers to accurately determine the safety of drugs for use in carriers of porphyria genetic mutations. […] This study suggests that immunomodulating agent drugs, like Leflunomide, are associated with porphyria attacks. […] Patients who experience drug-induced porphyria generally have bad outcomes. Hence, considerable care must be taken to ensure that carriers of acute porphyria genetic mutations are not prescribed porphyrinogenic drugs.

• #15 About Acute Hepatic Porphyria | Thinkporphyria.eu

  https://www.thinkporphyria.eu/about-ahp

  Each type of porphyria involves a genetic defect in a heme biosynthesis pathway enzyme. […] The pathophysiology of porphyria comprises 8 genetic metabolic disorders of the heme biosynthesis pathway. AHP, a subset of porphyria, often presents as a sudden acute attack requiring hospitalization and is triggered by excess ALA and PBG. […] Acute hepatic porphyria is caused by a build-up of neurotoxic intermediates, ALA PBG, in the liver. AHP is caused by enzymatic defects that result in accumulation in the liver of toxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG). Upregulation of ALAS1 (aminolevulinate acid synthase 1) is a central pathophysiologic mechanism underlying AHP, and leads to this toxic accumulation. ALA and PBG then enter the circulatory system and are thought to cause neurologic lesions leading to dysfunction across the autonomic, central, and peripheral nervous systems. Dysfunction in these systems can cause patients to have severe, diffuse abdominal pain plus one or more of the following symptoms: anxiety, confusion, nausea, vomiting, limb weakness and pain. This can potentially result in irreversible neuropathies and long-term disease complications such as kidney disease and hepatocellular carcinoma. Elevated PBG is important as a highly specific diagnostic marker. ALA is believed to be the primary toxic intermediate responsible for causing acute attacks, ongoing symptoms between attacks, and prolonged or potentially permanent neuropathy in AHP. […] Upregulation of ALAS1 leads to neurotoxic accumulation of ALA and PBG.

• #16 What Hematologists Need to Know About Acute Hepatic Porphyria – Hematology & Oncology

  https://www.hematologyandoncology.net/archives/november-2016/what-hematologists-need-to-know-about-acute-hepatic-porphyria/

  MB A genetic change leads to a deficiency in one of the enzymes in the heme biosynthetic pathway. […] The presence of certain precipitating factors, however, can lead to symptomatic disease. […] The marked overexpression of ALAS1 results in the increased production and subsequent accumulation of the neurotoxic porphyrin precursors, aminolevulinic acid (ALA) and urine porphobilinogen (PBG). […] One of the recent studies from our center that has greatly helped us understand the pathophysiology of acute intermittent porphyria was conducted on the explanted liver of a patient who had a liver transplant for this disease. The biochemical and other results from this study allowed us to confirm that ALAS1 mRNA is significantly increased in patients with acute attacks, and that ALA and PBG are the primary mediators of acute attacks. […] We also have seen results from several studies addressing an experimental therapy for acute porphyrias called ALN-AS1, which is currently in phase 1 clinical trials. ALN-AS1 is a small interfering RNA therapy that decreases the upregulation of ALAS1 mRNA.

• #17

  https://www.jci.org/articles/view/107131

  Porphyria cutanea tarda (PCT) is characterized biochemically by excessive hepatic synthesis and urinary excretion of uroporphyrin I. Clinical evidence has implicated iron in the pathogenesis of PCT. […] Thus, inactivation of COSYN results in accelerated synthesis of uroporphyrin I. This effect of ferrous ion provides a possible biochemical explanation for the excess production and excretion of uroporphyrin I in patients with PCT and the reversal of this defect by phlebotomy.

• #18 Porphyria Cutanea Tarda (PCT) | International Porphyria Network

  https://new.porphyrianet.org/en/content/porphyria-cutanea-tarda-pct-0

  PCT occurs due to reduced activity of hepatic uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the haem biosynthesis pathway. This is a consequence of an iron catalyzed reaction which produces porphomethene, a UROD inhibitor. The reduced activity of UROD leads to increased production of porphyrin intermediates in the liver, which are released into the systemic circulation and accumulate in the skin, causing cutaneous fragility and blistering to photoexposed sites. Clinically significant PCT symptoms occur when hepatic UROD activity is 20%. […] Both familial and sporadic PCT result from conditions that induce progressive inhibition of UROD in the liver, resulting in the accumulation of uroporphyrinogen, and its partially decarboxylated intermediates. The porphyrinogens undergo oxidation to their equivalent porphyrins, which act as chromophores in the skin and absorb light at wavelengths of 405 nm (the Soret band), which is able to penetrate into the dermis and basement membrane. Porphyrins circulating through dermal blood vessels are photosensitised on exposure to longer wavelength UVA and visible light and emit free radicals that result in the formation of reactive oxygen species (ROS) which damage the dermo-epidermal junction, leading to the formation of subepidermal bullae.

• #19

  https://scispace.com/papers/porphyria-cutanea-tarda-in-a-patient-with-hereditary-7nccz9cddkxi

  In aggregate, clinically ascertained cases who are homozygous for the C282Y mutation are associated with a 411-fold risk of liver disease, whereas all 5 hemochromatosis genotypes are associated with a 248 fold risk of porphyria cutanea tarda. […] The mechanism underlying clinical expression of the PCT phenotype is defined, namely oxidation of uroporphyrinogen to Uroporphomethene, a competitive inhibitor of URO-D, which is iron-dependent.

• #20 Skin Disease in Porphyria | Porphyria for Professionals

  https://porphyria.uct.ac.za/porphyria-professionals/skin-disease/skin-disease-porphyria

  Porphyric skin disease has a characteristic appearance. Lesions are found only in sun-exposed areas: typically the backs of the hands, the forearms and to a lesser extent, the back of the neck and the feet in people who wear open shoes or sandals. […] Porphyrin molecules exhibit the property of fluorescence. Light is absorbed at ultraviolet wavelengths centred around 406 nm. The trapped energy promotes electrons to a higher-energy state. As the electrons subsequently relax to the low-energy state, they re-radiate the additional energy at red wavelengths-typically about 630 nm. It is believed that these energy fluxes, occurring within the skin, underlie the photodermatitis characteristic of the porphyrias. There are thus two factors necessary for the pathogenesis of the skin lesions: excess porphyrins within the skin, and exposure to light. Frequently a third factortraumais present: it is often noted that the skin breaks easily after minor trauma such as knocks and scrapes, and then heals unusually slowly.

• #21 Skin Disease in Porphyria | Porphyria for Professionals

  https://porphyria.uct.ac.za/porphyria-professionals/skin-disease/skin-disease-porphyria

  Not all wavelengths of light have the same damaging effect on the skin. It is principally the long-wavelength ultraviolet light (UVA), of wavelength approaching 400 nm, that is most damaging. Note that these wavelengths are considerably longer than those which cause sunburnUVB. Even longer wavelengths, in the visible spectrum, can be damaging in porphyria. This has important consequences for the prevention of porphyrin skin disease: conventional sunblocks, which screen out UVB rather than UVA, are unhelpful in preventing porphyric skin damage.

• #22 About Acute Hepatic Porphyria | Porphyria Diagnosis™

  https://www.porphyria.com/hcp/about-ahp

  Chronically elevated levels of ALA and/or PBG may present a higher risk of long-term complications such as chronic kidney disease, hepatocellular carcinoma, and hypertension. […] Multiple studies have shown that symptomatic patients had 30 to 100 times higher risk of primary liver cancer vs reference controls. […] Upregulation of ALAS1 leads to toxic accumulation of aminolevulinic acid (ALA) and porphobilinogen (PBG).

• #23 Porphyria | PM&R KnowledgeNow

  https://now.aapmr.org/porphyria/

  Metabolic and hormonal derangements such as hyponatremia, thyrotoxicosis, and exaggerated estrogen response may be seen in the acute phases of illness. […] Gene panels, which are increasingly available, and enzyme activity level analysis of the heme biosynthetic enzymes are definitive and specific laboratory studies. […] Early detection and treatment of porphyria is important as both the acute phases of illness and long-term sequelae may be fatal or profoundly debilitating. Full recovery from acute episodes is possible. […] Prevention techniques are commonly employed to minimize the frequency and severity of disease exacerbations; however, the efficacy of these techniques is not well established in the literature.

• #24 Management of hyponatremia associated with acute porphyria—proposal for the use of tolvaptan

  https://atm.amegroups.org/article/view/50671/html

  Acute porphyria attacks are characterized by intense abdominal pain often accompanied by nausea, vomiting, hyponatremia, constipation, hypertension, tachycardia, insomnia and anxiety. Severe attacks can lead to neuropsychiatric disorders, seizures, sensory loss or motor neuropathy. The current goal of treatment for acute attacks is to reduce the activity of hepatic ALAS1, thus resulting in decreased production of early porphyrin precursors. The administration of intravenous human hemin down-regulates hepatic ALAS1 transcription, inhibits ALAS1 mRNA translation and the translocation of the ALAS1 protein precursor into the mitochondria. […] Mild to severe hyponatremia is a rather common phenomenon during an acute attack, as well as a marker of the severity of the crisis. Major motor seizure occurs in up to 20% of acute attacks and is often associated with severe hyponatremia. Although undoubtedly the etiology of the acute attack in hepatic porphyrias is the rise in plasma ALA and PBG levels, hyponatremia, as well as the development of a syndrome of inappropriate antidiuretic hormone secretion (SIADH), play a central role in the prognosis of the patient. Although intestinal losses of Na+ during the crisis, or renal losses secondary to a salt-wasting ALA-dependent syndrome may play a role, hyponatremia in AHPs is more likely to be caused by SIADH. In fact, elevated plasma levels of ADH in euvolemic conditions have been observed during acute attacks.

• #25 Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

  https://www.mdpi.com/2075-1729/12/11/1858

  Current approved treatments for acute porphyria do not provide an etiological solution to the disease. […] The current prevalent R&D trends related to AIP therapy focus on increasing hepatic PBGD activity and restoring the physiological regulation of the heme synthesis pathway. […] Based on the PoC obtained in animal models, increasing PBGD levels appears to be a promising strategy for the etiological treatment of AIP, regardless of whether it is achieved by the administration of a recombinant rApoAI-PBGD protein, an rAAV-mediated GT, or mRNA encapsulated in LNPs.

• #26 Acute Porphyrias – Endocrine and Metabolic Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/the-porphyrias/acute-porphyrias

  All components of the peripheral nervous system and the central nervous system may be involved. […] Chronic kidney disease in acute porphyria is multifactorial; acute hypertension (possibly leading to chronic hypertension) is likely a main precipitating factor. […] Givosiran can be used to treat adults with acute hepatic porphyria to prevent recurrent acute attacks. It is a small interfering RNA (siRNA) that selectively targets and markedly down-regulates hepatic ALA synthase-1. […] Treatment of the acute attack is identical for all acute porphyrias. […] Liver transplantation remains an option. Successful liver transplantation leads to permanent cure of acute intermittent porphyria. […] The incidence of hepatocellular cancer is high among carriers of acute porphyria, especially in patients with active disease.

• #27

  https://www.xiahepublishing.com/2572-5505/JERP-2016-00022

  When other means of treatment are unsuccessful in reducing attacks and improving quality of life in AIP patients, liver transplantation can be considered, if the risks outweigh the benefits and the patient is deemed a suitable candidate for liver transplantation. […] Liver transplantation corrects the genetic deficiency of PBG deaminase, which leads to normalization of PBG and ALA levels. This results in resolution of symptoms for AIP and corrects the liver disease caused by variegate and erythropoietic porphyria. […] The literature on AIP and liver transplantation notes that liver transplant does not result in improvement or cure of AIP among patients with longstanding neurological deficits and patients with severe neuromuscular or respiratory dysfunction. These types of patients have poorer outcomes, up to and including death. […] Therefore, liver transplantation should be considered as a viable option to cure patients with AIP.

• #28 Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

  https://www.mdpi.com/1422-0067/22/2/675

  The complete picture is not yet understood, particularly considering HMBS mutation carriers who have high concentrations of ALA without ever experiencing symptomatic disease. […] The instability associated with catalysis may explain the increased in vivo degradation of intrinsically active but unstable HMBS mutants. […] The pharmacological chaperone therapeutic concept can be applied to, among others, prolonging the half-life of unstable mutants in vivo, to allosteric activate enzymes and to achieving functional cellular localization. […] In the case of inborn errors of metabolism, the pharmacological chaperone therapeutic concept can be applied to, among others, prolonging the half-life of unstable mutants in vivo, to allosteric activate enzymes and to achieving functional cellular localization. […] The effectiveness of high-resolution mass spectrometry to separate and identify the intermediates, and its adaptability to high-throughput screening, readily encourages the search for these kind of pharmacological chaperones for specific AIP mutants.

• #29 Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment – Archive ouverte HAL

  https://hal.science/hal-04060248/

  Recent insights into the pathogenesis of acute attacks and provides an update on emerging treatments aimed at increasing the activity of the deficient enzyme in the liver and restoring the physiological regulation of the pathway. […] AIP is characterized by haploinsufficiency in the third enzyme of the heme biosynthesis pathway. […] Identification of the liver as the target organ and a detailed molecular characterization have enabled the development and approval of several therapies to manage this disease, such as glucose infusions, heme replenishment, and, more recently, an siRNA strategy that aims to down-regulate the key limiting enzyme of heme synthesis. […] Given the involvement of hepatic hemoproteins in essential metabolic functions, important questions regarding energy supply, antioxidant and detoxifying responses, and glucose homeostasis remain to be elucidated.

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