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Acute Intermittent Porphyria

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Acute Intermittent Porphyria. Core disease mechanisms, molecular and cellu...

2026-04-22
Asta MONDO:0008294 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Acute Intermittent Porphyria. Core disease mechanisms, molecular and cellu...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Porphyrias in the Age of Targeted Therapies

  • Authors: Angelika L Erwin, M. Balwani
  • Year: 2021
  • Venue: Diagnostics
  • URL: https://www.semanticscholar.org/paper/ca5b48195af03a4b8fc46cc7eb530d0a711e62a4
  • DOI: 10.3390/diagnostics11101795
  • PMID: 34679493
  • PMCID: 8534485
  • Citations: 12
  • Influential citations: 1
  • Summary: The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins, which can result in severe clinical manifestations, long-term complications and a significantly diminished quality of life.
  • Evidence snippets:
  • Snippet 1 (score: 0.550) > The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins. Depending on the tissue site as well as the chemical characteristics of the accumulating substances, the clinical features of different porphyrias vary substantially. Heme precursors are neurotoxic, and their accumulation results in acute hepatic porphyria, while porphyrins are photoactive, and excess amounts cause cutaneous porphyrias, which present with photosensitivity. These disorders are clinically heterogeneous but can result in severe clinical manifestations, long-term complications and a significantly diminished quality of life. Medical management consists mostly of the avoidance of triggering factors and symptomatic treatment. With an improved understanding of the underlying pathophysiology and disease mechanisms, new treatment approaches have become available, which address the underlying defects at a molecular or cellular level, and promise significant improvement, symptom prevention and more effective treatment of acute and chronic disease manifestations.

[2] European porphyria initiative (EPI): a platform to develop a common approach to the management of porphyrias and to promote research in the field.

  • Authors: J. Deybach, M. Badminton, H. Puy, Sverre Sandberg, J. Frank et al.
  • Year: 2006
  • Venue: Physiological research
  • URL: https://www.semanticscholar.org/paper/4fc661b027e2d7ee6630dd73b664908fd6218aa7
  • DOI: 10.33549/physiolres.930000.55.s2.67
  • PMID: 17298223
  • Citations: 22
  • Influential citations: 1
  • Summary: The European Porphyria Initiative (EPI) network will set a pattern for establishing, and subsequently harmonising, between countries best clinical practice for a rare but important group of diseases, and will help to develop the optimal therapy and ensure its cost effectiveness.
  • Evidence snippets:
  • Snippet 1 (score: 0.540) > The porphyrias are uncommon inherited metabolic disorders of haem biosynthesis in which specific patterns of overproduction of haem precursors are associated with characteristic clinical features. Each type of porphyria is the result of a specific decrease in the activity of one of the enzymes of haem biosynthesis. > The porphyrias are inherited by a dominant autosomal mechanism, except in the cases of congenital erythropoietic porphyria and ALA-D deficiency (both extremely rare), which are inherited by a recessive autosomal mechanism. Porphyrias are classified as erythropoietic or hepatic in type, depending on the primary organ in which excess production of porphyrins ortheir precursors takes place. > Acute attacks occur in 4 of the porphyrias (acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP) and ALA-D deficiency); their diagnosis and management have been extensively reviewed (Anderson et al. Scriver, eighth edition, Deybach 2004). > The attacks consist of acute abdominal pain with vomiting and constipation, sometimes associated with neuro-psychiatric manifestations and may be followed by prolonged disability or end fatally. > The diagnosis of an acute attack of porphyria requires demonstration of increased urinary excretion of the haem precursor, porphobilinogen (PBG). Further investigation is needed to identify the type of porphyria, but this should not be allowed to delay treatment. > Specific treatment using intravenous haem should be started as soon as the diagnosis is established unless the attack is mild and clearly resolving. Any drugs or other potential provoking agents should be withdrawn. Care should be taken to avoid the risk of hyponatraemic seizures fromthe inappropriate use of intravenous fluids. > Family screening to identify those with the latent disease is essential for management of the autosomal dominant porphyrias. Patients and asymptomatic individuals who have inherited an acute porphyria must receive appropriate counselling, particularly about how to minimise the risk of an acute attack by avoiding drugs and other provoking factors.

[3] Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

  • Authors: A. Ricci, C. Guida, P. Manzini, Chiara Cuoghi, P. Ventura
  • Year: 2021
  • Venue: Diagnostics
  • URL: https://www.semanticscholar.org/paper/3e9f74d999680cb364ec6e0e900b7f5cbed27124
  • DOI: 10.3390/diagnostics11122324
  • PMCID: 8700387
  • Citations: 23
  • Influential citations: 1
  • Summary: The role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical features of renal involvement in acute hepatic porphyrias are outlined.
  • Evidence snippets:
  • Snippet 1 (score: 0.511) > Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest under drastically different clinical pictures. The most dramatic presentation of the four congenital acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a distinct, long-term degenerating condition with specific pathological and clinical features, for which a satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms possibly intervening in causing renal damage in AHPs are different: among others, δ-aminolevulinic acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical

[4] Orphan Peripheral Neuropathies

  • Authors: J. Finsterer, W. Löscher, J. Wanschitz, S. Iglseder
  • Year: 2020
  • Venue: Journal of Neuromuscular Diseases
  • URL: https://www.semanticscholar.org/paper/5312eea462296895ca08bbf73e9331ce2cc897eb
  • DOI: 10.3233/JND-200518
  • PMID: 32986679
  • PMCID: 7902989
  • Citations: 17
  • Summary: Though orphan neuropathies are rare per definition they constitute the majority of Neuropathies and should be considered as some of them are easy to identify and potentially treatable, as clarification of the underlying cause may contribute to the knowledge about etiology and pathophysiology of these conditions.
  • Evidence snippets:
  • Snippet 1 (score: 0.508) > Porphyrias are a group of ultrarare, mostly hereditary metabolic disorders due to a defective hem biosynthesis pathway [112]. Primary (hereditary) and secondary (acquired) porphyrias are differentiated. Primary porphyrias are subdivided into hepatic and erythropoetic forms. Among the hepatic porphyrias, acute porphyrias (acute intermittent porphyria, variegate porphyria, coproporphyria, DOSS porphyria (ALA-dehydratase (porphobilinogen synthase) deficiency), the most common of the porphyrias termed after Dr. Doss) and chronic porphyrias (porphyria cutanea tarda, hepato-erythropoetic porphyria) are delineated. The phenotype depends on the defective enzyme within the pathway and is due to accumulation of intermediate metabolites. Neuro-visceral porphyrias are characterized by recurrent, acute attacks, triggered by excessive hem synthesis, clinically manifesting as severe abdominal pain, vomiting, tachycardia, hypertension, hyponatremia, mild cognitive impairment, and peripheral neuropathy [112]. Severe attacks may manifest with seizures, psychosis, quadruparesis, respiratory failure, coma, or death [112]. Neuropathy occurs particularly in aminolevulinic acid dehydratase (ALAD1 gene) porphyria (DOSS porphyria), acute intermittent porphyria (HMBS gene), hereditary coproporphyria (CPOX gene), and variegate porphyria (PPOX gene) [112]. Not only peripheral nerves but also cranial nerves can be affected. Neuropathy is usually axonal and develops rapidly over 2-4 weeks with predominant proximal weakness [113]. Progression of neuropathy with affection of the nerves innervating respiratory muscles may lead to respiratory failure [112]. Porphyrias may respond to application of siRNA in the form of givosiran.

[5] ALAD Inhibition by Porphobilinogen Rationalizes the Accumulation of δ-Aminolevulinate in Acute Porphyrias

  • Authors: Itxaso San Juan, Tania Pereira-Ortuzar, Xabier Cendoya, A. Laín, J. To-Figueras et al.
  • Year: 2022
  • Venue: Biochemistry
  • URL: https://www.semanticscholar.org/paper/c1418aeeaf3560ef15ab2f3f8c621c85fc519515
  • DOI: 10.1021/acs.biochem.2c00434
  • PMID: 36241173
  • PMCID: 9631992
  • Citations: 10
  • Summary: Porphobilinogen, the natural product of δ-aminolevulinate deaminase, effectively inhibits its anabolic enzyme at abnormally low concentrations and can be explained by the interactions that porphobil inogen generates with the active site, most of them shared with the substrate.
  • Evidence snippets:
  • Snippet 1 (score: 0.507) > This bar plot is a semiquantitative estimate based on the reported literature and, for the acute porphyrias, it represents the situation after a crisis. Importantly, such abnormal metabolite accumulation is behind the molecular pathophysiology of porphyrias and, for instance, accumulation of ALA likely exerts toxic effects on nerves, either directly by interacting with receptors for the structurally similar neurotransmitter γ-aminobutyric acid or by forming free radicals and reactive oxygen species. 8 The observation that disorders associated with excess production of ALA but not PBG (hereditary tyrosinaemia or lead poisoning) have similar clinical presentations to acute porphyria 3 supports this hypothesis. > ALA accumulation is observed in ALA-dP and in AIP patients between 20-and 200-fold above normal levels (Figure 1B) 6 and, to a minor extent, in VP. AlP, the most common form of porphyria due to its autosomal dominant character, results from the deficiency in the activity of porphobilinogen deaminase (PBGD, hydroxymethylbilane synthase or uroporphyrinogen I synthase; EC 4.3.1.8). 9,10 Clinical expression of AIP is characterized by the intermittent occurrence of neurovisceral attacks, usually linked to environmental or acquired factors (nutritional status, steroid hormones or their metabolites, and drugs), which may intermittently induce acute exacerbations. 11 lbeit their clinical significance, the biochemical mechanism behind the accumulation of metabolites associated with acute porphyrias has not been experimentally demonstrated. It has been shown that some porphyrins are able to in vitro inactivate the ALAD enzyme. 12,13 Moreover, ALAD condensation reaction stalls at a covalently bound intermediate that resembles the product, 14 so ALAD inhibition by PBG seems plausible. Alternatively, an excess of PBG could also inhibit PBGD, providing an alternative explanation for the metabolite accumulation. Here, we have in vitro biophysically investigated the cytosolic moiety of the heme pathway to gain insight in the ALA accumulation under conditions resembling a crisis episode in AIP.

[6] An easily overlooked disease in the early stages: acute intermittent porphyria

  • Authors: Jing Wang, Jiurong Chen, Ke Xu, Zhizhong Li, Gang Yu et al.
  • Year: 2025
  • Venue: BMC Neurology
  • URL: https://www.semanticscholar.org/paper/5a4e4240439ac7bc4931294b46962a1e8f86607f
  • DOI: 10.1186/s12883-025-04064-0
  • PMID: 39948482
  • PMCID: 11823016
  • Citations: 2
  • Summary: This case unveils that AIP is a disease that can be easily overlooked in its early stages and timely screening through biochemical testing, including measurement of ALA, PBG and porphyrins in a random urine sample, is recommended.
  • Evidence snippets:
  • Snippet 1 (score: 0.501) > Porphyrias are inherited metabolic disorders characterized by defects in the enzymes involved in heme biosynthesis, leading to the abnormal accumulation of porphyrins or their precursors [1]. These disorders can be classified into eight types based on the specific enzyme defect. Among them, acute intermittent porphyria (AIP), an autosomal dominant inherited disease, is caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the heme biosynthesis pathway [2]. The prevalence of pathogenic variants in the HMBS gene is approximately 1 in 1700, with about 0.5-1% of carriers in the general population developing clinically overt AIP with acute porphyria attacks [3,4]. Female patients with AIP experience a higher proportion of acute exacerbations compared to male patients. These attacks are commonly triggered by factors such as progesterone elevations during the luteal phase of the cycle, progesterone-containing oral contraceptives, cytochrome P450-inducing drugs, stress, alcohol consumption, smoking, fasting, strict carbohydrate-restrictive diets, or infectious diseases. Factors that precipitate acute attacks induce the synthesis of δ-aminolevulinic acid synthase 1 (ALAS1), the first and rate-limiting enzyme in the heme biosynthetic pathway, by directly promoting its transcription through mechanisms such as dieting or fasting or by increasing hepatic heme demand or consumption due to factors like drug use or illness [5]. When hepatic ALAS1 is induced, the deficiency in HMBS becomes the rate-limiting step in hepatic heme biosynthesis, leading to a significant accumulation of the potentially neurotoxic porphyrin precursors aminolevulinic acid (ALA) and porphobilinogen (PBG) [6]. > AIP is an inherited metabolic disorder that can affect the central, peripheral, and autonomic nervous systems. Therefore, its clinical presentation is diverse and may include abdominal pain, as well as neurological and psychiatric symptoms.

[7] Acute hepatic porphyria - classification, diagnosis and treatment

  • Authors: Aleksandra Czekaj, K. Ruszel, Robert Dubel, Julia Dubel, Natalia Namroży
  • Year: 2022
  • Venue: Journal of Education, Health and Sport
  • URL: https://www.semanticscholar.org/paper/c529a7a2df86cdca8724f42249a9ef253cb79e93
  • DOI: 10.12775/jehs.2023.13.01.019
  • Summary: In diagnostics, particular attention should be paid to the circumstances of the symptoms and the history of the patient's disease, which often includes numerous episodes of unexplained abdominal pain, which was so severe that it forced the patient to report to emergency departments.
  • Evidence snippets:
  • Snippet 1 (score: 0.486) > Porphyrias belong to the group of inherited metabolic diseases. Each of the four types of acute hepatic porphyria is caused by a different mutation in the gene of an enzyme involved in the heme biosynthetic pathway. The literature distinguishes between: Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP) and Aminolevulinic Dehydratic ADP (ADP) deficiency. -deficient Porphyria). Deficiency of individual enzymes leads to ineffective heme production and accumulation of neurotoxic intermediates - the so-called porphyrins. Two excess metabolites are of major importance in diagnostics - ALA (amionolevulinic acid) and PBG (porphobilinogen). In most cases, the activity of the less functional enzyme is so high that the disease never becomes apparent (latent form). Excessive accumulation of porphyrin precursors is associated with exposure to porphyrinogenic factors, leading to a seizure whose symptoms are closely related to autonomic, peripheral neuropathy, and accompanying neuropsychiatric disorders. In diagnostics, particular attention should be paid to the circumstances of the symptoms and the history of the patient's disease, which often includes numerous episodes of unexplained abdominal pain, which was so severe that it forced the patient to report to emergency departments. A severe attack of porphyria is a medical emergency and requires hospitalization. Failure to diagnose or properly treat it may result in flaccid tetraplegia, respiratory failure, brain edema, coma, and sudden circulation detention.

[8] Self-efficacy and self-management strategies in acute intermittent porphyria

  • Authors: Marte H. Hammersland, A. Aarsand, S. Sandberg, J. Andersen
  • Year: 2019
  • Venue: BMC Health Services Research
  • URL: https://www.semanticscholar.org/paper/7f405bc87d6e97dab61ab1952a981e1925c10ebf
  • DOI: 10.1186/s12913-019-4285-9
  • PMID: 31269991
  • PMCID: 6607542
  • Citations: 9
  • Summary: This study indicates that continuing to provide information, counseling and education is beneficial in AIP, and that HMBS mutation carriers, both those self-assessed as asymptomatic and as symptomatic, are using their knowledge to avoid triggering factors.
  • Evidence snippets:
  • Snippet 1 (score: 0.485) > Porphyrias are a group of rare, inherited metabolic disorders. Each is caused by reduced, or-in one disease-increased activity in one of the enzymes in the heme biosynthetic pathway and leads to symptoms in the form of acute neurovisceral attacks, skin lesions, or both [1]. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in most countries, with an estimated prevalence of 5.9 per million inhabitants in Europe [2]. The disease is characterized by acute attacks in the form of severe abdominal pain, in combination with pain in the back and thighs, polyneuropathy, nausea, vomiting and constipation [1,3]. Tachycardia, hypertension, electrolyte disturbances and neurological and mental complications are also frequent. Attacks of AIP have by some patients been described as excruciatingly painful [4]. Though most patients experience only one or a few acute attacks during their lifetime, more severely affected patients report a reduced quality of life. They can experience major life event consequences such as failure to secure or loss of employment, impact on family size, increased anxiety, and depression [4][5][6]. AIP is an autosomal dominant disease and is caused by mutations of the HMBS gene. Prevalence of mutations in the HMBS gene is probably underestimated in the healthy population [7,8]. Clinical penetrance has been estimated to be about 10% [9], even lower in a recent population study [10]. Studies indicate that drug use including alcohol and hormonal changes are the most frequent inducers of acute attacks [11], with additional triggers being smoking, infections, physical and psychological stress, hunger and crash dieting [12,13]. Avoidance of these triggers is recommended both to prevent HMBS mutation carriers not yet having symptoms from manifesting the disease, and to reduce the frequency and severity of attacks in patients who have already had symptoms of AIP. Among behavioral measures, avoiding the use of porphyrinogenic drugs is considered the single most important effort. In addition, a balanced diet with no prolonged fasting or crash dieting is generally recommended [14].

[9] Renal Failure Affects the Enzymatic Activities of the Three First Steps in Hepatic Heme Biosynthesis in the Acute Intermittent Porphyria Mouse

  • Authors: Carmen Unzu, A. Sampedro, Eliane Sardh, I. Mauleón, R. Enríquez de Salamanca et al.
  • Year: 2012
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/01c0a1929871cf1777d0d620b3582ba7f0e95880
  • DOI: 10.1371/journal.pone.0032978
  • PMID: 22412963
  • PMCID: 3295788
  • Citations: 17
  • Influential citations: 3
  • Summary: In conclusion, high concentration of porphyrin precursors had little impact on renal function, however, progressive renal insufficiency aggravates porphyria attacks and increases the PBG/ALA ratio, which should be considered a warning sign for potentially life-threatening impairment in AIP patients with signs of renal failure.
  • Evidence snippets:
  • Snippet 1 (score: 0.484) > Acute intermittent porphyria (AIP, OMIM 176000) is an inherited metabolic disease characterized by partial deficiency of hepatic porphobilinogen deaminase (PBGD). The disease is inherited in an autosomal dominant manner and is the most common of the acute porphyrias [1]. The dominant clinical feature is characterized by acute attacks of abdominal pain, hypertension and neurovisceral and circulatory disturbances, a condition which if untreated may become life-threatening. An inherited deficiency of PBGD is not sufficient for the symptoms to appear. Acute attacks can be induced by various drugs, nutritional factors and hormonal changes [2]. Drugs metabolized by CYP450, such as phenobarbital, greatly increase hepatic heme demand and result in the up-regulation of hepatic aminolevulinate synthase (ALAS1), increasing the production of porphyrin precursors and precipitating the attack. Advances in medical care and self-care have improved the prognosis for symptomatic patients [3]. Still, some patients develop recurrent crises or progressive disease with disabling neurological dysfunction and/ or renal failure. > Chronic kidney disease may occur as a long-term complication of symptomatic disease in acute porphyrias, leading to vascular complications, progression of peripheral neuropathy and eventually need for dialysis. Chronic arterial hypertension and renal impairment become more common after middle age in AIP, especially in patients with frequent porphyric attacks [4,5]. Limited information is available on the characteristics and pathogenesis of renal disease in this patient group and little is known about the association between renal damage and acute porphyrias. The disease may be accompanied by electrolyte abnormalities. Hyponatremia is common during the acute attack and may be due to inappropriate secretion of antidiuretic hormones. The increased urinary excretion of catecholamines during an acute attack suggests up regulation of the sympathetic nervous system and may contribute to the etiology of renal damage. Chronic hypertension in AIP has an estimated incidence of 36-55% [3]. However, long-term treatment with modern antihypertensive drugs has

[10] Recent advances in the epidemiology and genetics of acute intermittent porphyria.

  • Authors: Liyan Ma, Yu Tian, Chenxing Peng, Yiran Zhang, Song-yun Zhang
  • Year: 2020
  • Venue: Intractable & rare diseases research
  • URL: https://www.semanticscholar.org/paper/e64f9792d907bc8cfb97cf85938db128f9961091
  • DOI: 10.5582/irdr.2020.03082
  • PMID: 33139978
  • Citations: 24
  • Influential citations: 3
  • Summary: The prevalence and penetrance of AIP are analyzed systematically, and the genetic traits of different populations and findings regarding the genotype-phenotype correlation are summarized.
  • Evidence snippets:
  • Snippet 1 (score: 0.459) > Porphyrias are a group of metabolic diseases that result from a specific abnormality in one of the eight enzymes of the heme biosynthetic pathway (1,2). In general, porphyrias are classified either as acute porphyrias or cutaneous porphyrias based on their clinical presentation or as hepatic and erythropoietic porphyrias based on the tissue where heme precursors are overproduced (3). > Acute intermittent porphyria (AIP, OMIM#176000), the most common and severe form of acute hepatic porphyrias (4), is an inherited metabolic disease that exhibits an autosomal dominant pattern of inheritance caused by partial deficiencies in hydroxymethylbilane synthase (HMBS; EC 2.5.1.61), the third enzyme in heme biosynthesis (5). AIP has significant molecular genetic heterogeneity and low penetrance (6). It leads to accumulation of upstream metabolites δ-aminolevulinic acid (ALA) and porphobilinogen (PBG), which induce toxicity to the neurologic system, and then trigger episodic, acute neurovisceral symptoms that can even be life-threatening (7)(8)(9)(10)(11). Studies of the prevalence, penetrance, and molecular genetic traits of AIP are crucial to its early diagnosis and rational management. Thanks to the rapid development of next-generation sequencing (NGS) technology, genetic sequencing has been widely used to detect HMBS gene mutations (12,13). Some studies based on genetic testing have revealed that the prevalence of HMBS variants was substantially underestimated, with extremely low penetrance in the general population but higher penetrance in families with AIP (14,15). > Findings regarding modifying genes and the correlation between genotype-phenotype warrant more attention in recent studies on AIP. Although a genotypephenotype correlation has not been identified, certain mutations may be relevant to penetrance or the severity of clinical manifestations.

[11] Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

  • Authors: K. Rodrigues, W. T. L. Yong, Md. Safiul Alam Bhuiyan, S. Siddiquee, M. D. Shah et al.
  • Year: 2022
  • Venue: Biology
  • URL: https://www.semanticscholar.org/paper/dca9e833a364acec7f67a0c6bc823862c525de2a
  • DOI: 10.3390/biology11091308
  • PMID: 36138787
  • PMCID: 9495729
  • Citations: 10
  • Summary: The review focuses on fourteen of the most widely studied inherited MD, which are familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, Maple syrup urine disease, Metachromatic leukodystrophy, Mitochondrial encephalopathy lactic acidosis stroke-like episodes, Niemann-Pick disease, Phenylketonuria, Porphyria, Tay-Sachs disease, Wilson’s disease and Galactosemia.
  • Evidence snippets:
  • Snippet 1 (score: 0.459) > A collection of eight metabolic diseases of the heme biosynthesis pathway known as hereditary porphyrias are characterized by acute neurovisceral symptoms, skin lesions, or both.Each porphyria is caused by aberrant enzyme action, resulting in a particular buildup of heme precursors [112].The appropriate concentrations of vitamins and minerals in the tissues are required for certain enzymes involved in heme production.Furthermore, micronutrients required for the biosynthesis of succinyl CoA and other intermediates in the Krebs (TCA) cycle are also critical for heme metabolism indirectly [113] Givosiran, a small interfering RNA (siRNA)-based therapeutic developed for the treatment of acute intermittent porphyria (AIP), a condition that is characterized by life-threatening acute neurovisceral episodes, was approved by the US Food and Drug Administration (FDA) in November 2019 [114].Patients with acute intermittent porphyria who were administered givosiran had a reduced rate of porphyria attacks and better results for a variety of other disease symptoms than those who were given a placebo.A higher prevalence of hepatic and renal side effects followed the enhanced efficacy [115]. > Tay-Sachs disease (TSD) is a progressive, fatal neurodegenerative disorder caused by a lack of the enzyme hexosaminidase-A, which results in the accumulation of GM2 gangliosides.The disease is divided into three categories based on the age of onset: infantile, juvenile, and adult.The limited clinical symptoms and nonspecific biochemical data contribute to the difficulty in the early diagnosis of TSD.Accurate diagnosis is critical for proper management and the reduction of disease-related consequences [116].TSD treatment is currently focused on symptom alleviation and, in the case of the late-onset variant, delaying progression.There have also been clinical reports of miglustat and bone marrow or hematopoietic stem cell transplantation being used to lower the concentration of substrate.Gene therapy has been explored using adeno-or adeno-associated viruses as vectors for delivering cDNA encoding HexA subunit genes.

[12] Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria

  • Authors: M. Longo, Daniel Jericó, K. Córdoba, J. Riezu-Boj, R. Urtasun et al.
  • Year: 2023
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/7f296f6980c32a15d01a1b08e422bad8e8ac1ee5
  • DOI: 10.3390/ijms241511938
  • PMID: 37569315
  • PMCID: 10418637
  • Citations: 4
  • Summary: Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a...
  • Evidence snippets:
  • Snippet 1 (score: 0.455) > Acute intermittent porphyria (AIP) is an autosomal dominant disorder characterized by a relatively high frequency of porphobilinogen deaminase (PBGD) gene mutations (1/1700 of newborns) [1,2] but low and incomplete clinical penetrance, encompassing ~1% of PBGD mutation carriers [3,4]. Although PBGD haploinsufficiency is at the core of the onset, upregulation of the first rate-limiting enzyme of the pathway, 5-aminolevulinic acid (ALA) synthase-1 (ALAS1), induces hepatic overproduction and a consequent accumulation of ALA and porphobilinogen (PBG) in plasma and urine. These heme precursors are associated with the complex set of neurotoxic manifestations exhibited by patients with AIP [5]. Chronic abdominal pain, gastrointestinal symptoms (abdominal pain, vomiting, nausea, and constipation), tachycardia, and hypertension are the major manifestations associated with these acute attacks. Peripheral motor neuropathy and central nervous system disturbances (seizures, weakness, insomnia, hallucinations, and confusion) are rare and occur only during severe and commonly prolonged attacks. Long-term complications in AIP include chronic pain, non-epicirrhotic hepatocellular carcinoma and nephropathy, thereby representing a long-life burden for patients and relatives [6][7][8][9]. > Acute attacks are associated with known trigger factors, including caloric deprivation and rapid weight loss, steroid hormones, medications and other chemicals, infections, stress and excess alcohol intake, which lead to the activation of hepatic ALAS1 transcription (see network resources of drugs database and acute porphyrias: "http://www. porphyriafoundation.com/drug-database (accessed on 22 July 2023))". Thus, disease stabilization consists of avoiding exposure to precipitating factors. For instance, AIP patients at-risk should not restrict calories, except for short periods and under the supervision of specialists.

[13] Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria.

  • Authors: U. Szlendak, K. Bykowska, A. Lipniacka
  • Year: 2016
  • Venue: Advances in clinical and experimental medicine : official organ Wroclaw Medical University
  • URL: https://www.semanticscholar.org/paper/6c0e19725e79b758c96a3f792a86f5f4e42891d3
  • DOI: 10.17219/acem/58955
  • PMID: 27627571
  • Citations: 47
  • Influential citations: 7
  • Summary: Molecular analysis of gene mutations responsible for each type of porphyria is the best diagnostic approach for symptomatic as well as presymptomatic gene carriers.
  • Evidence snippets:
  • Snippet 1 (score: 0.449) > Porphyrias are diverse disorders that arise from various inherited enzyme defects in the heme biosynthesis pathway, except for porphyria cutanea tarda (PCT), in which the enzyme deficiency in most cases is acquired. The biosynthetic blocks resulting from the defective enzymes are largely expressed either in the liver or bone marrow, the sites where the majority of heme is produced. Although the pathophysiologic mechanisms of the clinical manifestations of the porphyrias are not fully understood, two cardinal features prevail: skin photosensitivity and neurologic symptoms of intermittent autonomic neuropathy, acute neurovisceral attacks, and disorders of the nervous system. The primary diagnosis of the proband is based on biochemical testing, which is not always able to identify acute porphyrias, especially in asymptomatic family carriers when heme precursors and porphyrins excretion is normal, low-normal and high-reduced values of enzyme activity overlap, and hematological diseases responsible for abnormal blood cells distribution coexist. Molecular analysis of gene mutations responsible for each type of porphyria is the best diagnostic approach for symptomatic as well as presymptomatic gene carriers.

[14] Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators

  • Authors: H. J. Bustad, J. Kallio, M. Vorland, Valeria Fiorentino, S. Sandberg et al.
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/7e8827ef09c5e408054e4888593bb68701ca655c
  • DOI: 10.3390/ijms22020675
  • PMID: 33445488
  • PMCID: 7827610
  • Citations: 41
  • Influential citations: 2
  • Summary: The present scenario appears promising for upcoming patient-tailored interventions in AIP, and novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality are presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.449) > 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. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP.

[15] Neurofilament light chain as a biomarker for acute hepatic porphyrias

  • Authors: Paulo Sgobbi, P. Serrano, Bruno Mattos Lombardi Badia, I. Farias, Hélvia Bertoldo de Oliveira et al.
  • Year: 2024
  • Venue: Frontiers in Neurology
  • URL: https://www.semanticscholar.org/paper/3e916d18c6a85cad72dc9e9083738d946f03b670
  • DOI: 10.3389/fneur.2024.1384678
  • PMID: 38715693
  • PMCID: 11075149
  • Citations: 2
  • Summary: This study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence and reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP.
  • Evidence snippets:
  • Snippet 1 (score: 0.447) > Hereditary porphyrias are a rare group of inherited metabolic disorders due to dysfunction in the heme biosynthesis pathway. They can be classified depending on the principal site of accumulation of toxic intermediates, either as erythropoietic or hepatic. Additionally, they can be categorized based on clinical manifestations as acute porphyrias, characterized by neurovisceral attacks, or chronic porphyrias, which involve prominent cutaneous manifestations in photo exposed skin areas (1,2). > Acute hepatic porphyrias (AHPs) represents a rare group of four inherited metabolic disorders: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), with autosomal dominant trait inheritance caused by variants in the genes HBMS, PPOX and CPOX. These genes are responsible for encoding the porphobilinogen deaminase, protoporphyrinogen oxidase and coproporphyrinogen oxidase enzymes, respectively. Additionally, ALA (delta-aminolevulinic acid) dehydratase deficiency porphyria (also known as ALAD deficiency or Doss porphyria) is an autosomal recessive disease caused by biallelic variants on ALAD gene, which is responsible for the production of delta-aminolevulinate dehydratase enzyme (1,2). > AHPs are clinically characterized by life-threatening neurological manifestations that can occur either acutely or chronically, resulting in debilitating and progressive neurological impairment. The burden of these manifestations negatively impacts the quality of life (QoL) of patients. In addition, AHPs are associated with severe long-term complications such as hepatocellular carcinoma, chronic kidney disease and hypertension (1,2). > In AHPs, there is a pronounced overproduction of porphyrins in the liver, leading to the abnormal accumulation of toxic intermediate metabolites, primarily porphobilinogen (PBG) and ALA. This accumulation results in significant dysfunction of the nervous system through multiple mechanisms.

[16] Pathogenesis and clinical management of liver damage in porphyrias: Mechanisms and therapeutic approaches

  • Authors: Tao Zeng, Shuying Huang, Jian-ning Chen, Jia-Hui Pang, Yu-tian Chong et al.
  • Year: 2025
  • Venue: World Journal of Hepatology
  • URL: https://www.semanticscholar.org/paper/f3a1387e017ff27726ef71cb1e06dabf39201813
  • DOI: 10.4254/wjh.v17.i9.107705
  • PMID: 41024869
  • PMCID: 12476770
  • Summary: This review summarizes the pathophysiology, clinical manifestations, and diagnostic approaches for porphyria-associated liver injury, highlighting emerging therapies with the potential to improve patient outcomes.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > Porphyria refers to a group of rare inherited metabolic disorders caused by enzymatic deficiencies in the heme biosynthesis pathway. These deficiencies lead to the pathological accumulation of neurotoxic porphyrin precursors, resulting in multisystem damage. Currently, there are no curative therapeutic interventions, and patients frequently experience severe morbidity or life-threatening complications. Among the most critical manifestations is protoporphyric liver disease, in which hepatotoxic porphyrins and their precursors drive progressive hepatic injury and cholestasis. Persistent elevation of these metabolites can lead to irreversible parenchymal damage, significantly affecting both quality of life and long-term prognosis. The clinical presentation of porphyria-associated liver injury is highly variable and often has an insidious onset. However, a subset of patients may experience rapid progression to acute liver failure or fulminant hepatic dysfunction. Diagnosis is based on clinical evaluation and is confirmed by genetic testing. Current treatment strategies are focused on symptom management while underlying disease mechanisms remain unaddressed, posing significant therapeutic challenges. This review summarizes the pathophysiology, clinical manifestations, and diagnostic approaches for porphyria-associated liver injury, highlighting emerging therapies with the potential to improve patient outcomes.

[17] EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

  • Authors: L. Gouya, P. Ventura, M. Balwani, D. Bissell, D. Rees et al.
  • Year: 2018
  • Venue: Hepatology (Baltimore, Md.)
  • URL: https://www.semanticscholar.org/paper/9f5626b78e6dc16ca3c12c86393c58bccb49f85b
  • DOI: 10.1002/hep.30936
  • PMID: 31512765
  • PMCID: 7255459
  • Citations: 138
  • Influential citations: 6
  • Summary: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis that can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long‐term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.

[18] A novel mutation c.457C > T p.Q153 in the HMBS gene in a Mexican woman with acute intermittent porphyria

  • Authors: J. Malagón-Rangel, J. G. Solís, Luis Fernando Zavala-Jonguitud, M. R. Basile-Álvarez, A. Malagón-Liceaga
  • Year: 2023
  • Venue: Clinical Case Reports
  • URL: https://www.semanticscholar.org/paper/7f4a2005f9788af7d51cb434fd625cee8e70ff28
  • DOI: 10.1002/ccr3.8100
  • PMID: 37900716
  • PMCID: 10600359
  • Summary: The detection of a novel HMBS gene mutation (c.457C > T) in a Mexican woman with acute intermittent porphyria underscores the importance of expanding genetic analyses in diverse populations to improve diagnosis, management, and knowledge of the disease's clinical implications.
  • Evidence snippets:
  • Snippet 1 (score: 0.438) > Acute intermittent porphyria (AIP) represents an autosomal dominant disorder stemming from a partial deficiency in the enzymatic activity of porphobilinogen deaminase, which is also referred to as hydroxymethylbilane synthase (HMBS), the third enzyme involved in the synthesis of heme. This deficiency leads to the accumulation of toxic heme metabolites, namely aminolevulinic acid (ALA), and porphobilinogen (PBG). 1 The precise mechanisms through which porphyrin precursors trigger the symptoms of AIP are not fully understood. 1,2 IP presents with a range of clinical manifestations that can be categorized into three distinct phases: the prodromal phase, the symptom phase, and the neurological phase. Prominent clinical symptoms include the occurrence of acute neurovisceral episodes, marked by intense abdominal pain, mental disturbances, and heightened sympathetic activity. 2 cute attacks of porphyria can be precipitated by a range of factors, comprising alcohol ingestion, stress, fasting, menstruation, surgical procedures, infection, and the administration of certain drugs. 1,3 Preliminary assessment for AIP involves the detection of markedly elevated porphyrin levels in urinary, stool or serum during an acute attack, followed by subsequent genetic analysis to confirm the presence of HMBS gene mutations. 4 The management of AIP encompasses a comprehensive approach that includes the management of acute attacks, prevention of future episodes, long-term monitoring, and the treatment of associated complications. 2 Among the various acute porphyrias, AIP is recognized as a prevalent condition on a global scale, being both the most common and severe form among the acute hepatic porphyrias. 5 AIP affects both males and females, however, in the context of AIP episodes, females tend to experience more severe impacts in terms of higher frequencies of attacks, longer durations of attacks, and an increased likelihood of requiring hospitalization. 6 he HMBS gene is situated at the chromosomal position 11q23.3 and has been linked to more than 400 pathogenic mutations. 5 Individuals harboring pathogenic variants of the HMBS gene, regardless of their symptomatic or latent status, are prone to experiencing acute attacks.

[19] Use of intrathecal drug infusion pump with combined morphine and bupivacaine medication for the treatment of abdominal pain due to Acute Intermittent Porphyria (AIP)

  • Authors: R. D. De Oliveira, R. F. Souza, Rômulo Sarrazin De Andrade, Larissa de Oliveira Campelo, Fabiana Dantas et al.
  • Year: 2022
  • Venue: Brazilian Journal of Case Reports
  • URL: https://www.semanticscholar.org/paper/2c00fec1548d1c2dc80b2796039a44f0d4b230bb
  • DOI: 10.52600/2763-583x.bjcr.2023.3.1.4-9
  • Summary: A 32-years-old Woman presented with severe and continual abdominal pain, described by the patient as the worst pain she has ever felt in her life, colic type in the mesogastric area and that radiated throughout the entire abdomen for six months is described.
  • Evidence snippets:
  • Snippet 1 (score: 0.434) > Porphyrias consist of nine genetic disorders, acquired or congenital, resulting from failures in the biosynthesis process of the heme group, resulting in the accumulation of metabolic intermediates in the human body, causing toxicity [1]. The heme group is indispensable for the performance of oxidation-reduction reactions, in addition to being essential for the functionality of several enzymes and proteins related to energy metabolism. Thus, porphyrias are conditions that contribute to increased production of products from heme synthesis, such as 5-aminolevulinic acid (ALA), porphobilinogen (PBG) and porphyrins [2], which are present in blood, urine and feces. There is also the possibility of pathological deposition in tissues and organs [3]. Porphyrias can be classified as hepatic or erythropoietic, depending on whether porphyrins accumulate in the liver or bone marrow, or acute and cutaneous, depending on the clinical features of the disease [4,5]. > In most countries, such as the United States, a genetic prevalence of porphyria is estimated in the order of 1/10.000 individuals, while the manifestation of the aforementioned disease, in the USA, is approximately 5/100.000 inhabitants, with no indication of seasonal predominance in the incidence of porphyria [6]. Patients affected by this condition may present, as symptoms, neurological dysfunctions (neuropathies, alternations in the level of consciousness, seizures and behavioral abnormalities), neurovisceral alterations (gastrointestinal symptoms) and cutaneous manifestations (cutaneous photosensitivity and hemolysis) [1]. > Acute intermittent porphyria (AIP), a hepatic form of porphyria and the most common form of porphyria, is an autosomal dominant and hereditary disease caused by successive mutations in the hydroxymethylbilane synthase (HMB-synthase) gene, responsible for the conversion of porphobilinogen to hydroxymethylbilane within the heme biosynthesis pathway, culminating in the accumulation of substrates, such as PBG and deltaaminolevulinic acid, in the liver [4].

[20] Porphyria Cutanea Tarda: A Phenotypic Expression of Several Genes

  • Authors: Sebastián J Vázquez-Folch, Gabriel A Jiménez-Berríos, N. Izquierdo, Victor J Vazquez
  • Year: 2025
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/c34bbf568bf2728a38f62f1e9295ca644ffb4251
  • DOI: 10.7759/cureus.83955
  • PMID: 40510110
  • PMCID: 12158825
  • Summary: This study presents three cases of porphyria in Puerto Rico, including erythropoietic protoporphyria (EPP) and porphyria cutanea tarda (PCT), and reveals a heterozygous mutation in the FECH gene in the EPP case and an HFE gene mutation in a PCT case with hereditary hemochromatosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > Porphyria is a group of rare inherited or acquired disorders resulting from the malfunction of the heme biosynthetic pathway, leading to the accumulation of porphyrins or their precursors [1,2]. The heme biosynthetic pathway is crucial for the production of heme, an essential component of hemoglobin, myoglobin, and various cytochromes [3]. Defects in this pathway may result in a variety of clinical manifestations, including the skin and nervous system [4]. > Porphyrias are classified and include erythropoietic protoporphyria (EPP), porphyria cutanea tarda (PCT), acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and congenital erythropoietic porphyria [5]. > EPP is primarily caused by autosomal recessive mutations in the FECH gene, which encodes the enzyme ferrochelatase [6]. This enzyme is responsible for the last step in heme production, where iron is inserted into protoporphyrin IX to form heme [7]. A deficiency in ferrochelatase leads to the accumulation of protoporphyrin IX in erythrocytes, plasma, and tissues. Patients with EPP typically have photosensitivity, experiencing burning pain and erythema upon exposure to sunlight. Upon chronicity, the disease may lead to liver complications due to the buildup of protoporphyrins in the bile [6]. > PCT is the most common type of porphyria and is usually acquired, although it may also have a genetic inheritance. PCT is characterized by a deficiency in the enzyme uroporphyrinogen decarboxylase (UROD), which leads to the accumulation of uroporphyrins in the liver, plasma, and skin [8]. This accumulation causes photosensitivity, resulting in painful blistering, fragility, and hyperpigmentation of sun-exposed skin areas [9]. PCT can be associated with liver dysfunction and iron overload, and it is often linked with genetic variants such as mutations in the HFE gene, leading to hereditary hemochromatosis [10].

Notes

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