RARE DISEASE
Porphyria
Porphyria
Porphyria
Drug discovery
10
drugs
With orphan designations
Overview
Porphyria encompasses rare genetic disorders disrupting heme synthesis, leading to neurovisceral or cutaneous manifestations. Acute hepatic porphyrias (e.g., AIP, VP, HCP) cause severe abdominal pain, autonomic instability, and neurological symptoms, triggered by medications, fasting, or hormonal changes [1][5][6]. Cutaneous forms (e.g., PCT, EPP) present with photosensitivity and blistering [1][5]. Diagnosis relies on elevated porphyrin precursors in urine/blood and genetic testing [6][13]. Treatments include heme infusion, givosiran, and trigger avoidance [3][6][18].
Burden
≥60% of patients experience chronic symptoms (pain, fatigue, neuropathy), with 29% requiring daily opioids [9][19].
High hospitalization rates, reduced quality of life, and increased hepatocellular carcinoma risk [4][9][14].
Economic impact from recurrent ER visits, missed workdays, and costly therapies [4][9][19].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare renal diseases, rare skin diseases
Research Papers
1,250 drug discovery papers about Porphyria, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,250 drug discovery papers about Porphyria, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-20 | Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.Abbreviations: ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).
2026-08-08 | Challenges in Porphyria diagnosis and management: When variegate Porphyria meets HIV.
Variegate Porphyria (VP) is a rare autosomal dominant disorder characterized by deficient activity of protoporphyrinogen oxidase, resulting in the accumulation of potentially neurotoxic heme precursors. We present the case of a 32-year-old woman with HIV receiving antiretroviral therapy (dolutegravir, lamivudine, and ritonavir) who had generalized seizures, psychosis, and polyneuropathy, initially interpreted as secondary to infection. Brain magnetic resonance imaging suggested vasogenic edema, raising suspicion of autoimmune encephalitis. Despite treatment with methylprednisolone and intravenous immunoglobulins, her health worsened, requiring intensive care and extended mechanical ventilation. Markedly elevated urinary porphyrin precursors and porphyrins, a characteristic pattern of elevated fecal porphyrins, and a plasma fluorescence emission peak at 626 nm were diagnostic for VP. Genetic testing identified a pathogenic PPOX missense variant NM_001365398.1:c.428 A > T, p.(Asp143Val), consistent with VP. The patient required repeated courses of hemin and intravenous dextrose, which were followed by transient biochemical improvement. However, symptoms and biochemical markers recurred over time. Clinical stability was only achieved after the withdrawal of ritonavir from her antiretroviral regimen, emphasizing the need for careful medication review in patients with Acute Hepatic Porphyria. This case shows the complex interactions between genetic predisposition, environmental factors, and comorbidities in VP, emphasizing the importance of genetic and biochemical testing for accurate diagnosis, hemin administration during acute attacks, and careful medication review. Clinicians should remain vigilant about interactions between antiretroviral therapy and porphyria when treating HIV-positive patients with suspected or confirmed Acute Hepatic Porphyria.
2026-08-01 | Navigating tuberculosis therapy in acute intermittent porphyria: A case report and narrative review
Tuberculosis (TB) treatment in patients with acute intermittent porphyria (AIP) is challenging because several first-line antituberculous drugs can precipitate porphyric crises, and evidence to guide management is limited. We describe a 26-year-old woman with peritoneal TB who developed acute abdominal pain, hyponatraemia, seizures, and neuropsychiatric manifestations within 24 hours of standard isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) therapy. AIP was confirmed by elevated urinary porphobilinogen levels, and the patient required hemin for the acute crises. Antituberculous therapy was modified to a rifampicin-free regimen including moxifloxacin, linezolid, and ethambutol; isoniazid was cautiously reintroduced once the patient had stabilised. Recurrent porphyric crises and treatment-related toxicity ultimately led to therapy discontinuation after 167 doses. The patient achieved substantial neurological recovery without TB relapse after one year of follow-up. This case illustrates the need to balance TB control with porphyria safety, and to consider acute hepatic porphyria when patients develop unexplained abdominal pain, hyponatraemia, or neurological symptoms after starting antituberculous therapy. Rifampicin and isoniazid carry the highest porphyrinogenic risk, whereas moxifloxacin, ethambutol, and linezolid appear to be safer alternatives. Given limited evidence and the absence of standardised protocols for this rare coexistence, we offer a pragmatic framework to support shared decision-making in tuberculosis and porphyria.
2026-07-28 | Case Report: HCV-triggered porphyria cutanea tarda in a patient with SEC23B-mutated congenital dyserythropoietic anemia type II.
Porphyria cutanea tarda (PCT) is a hepatic porphyria often triggered by hepatitis C virus (HCV) infection, iron overload, or environmental exposure. Congenital dyserythropoietic anemia type II (CDA II) caused by SEC23B mutations leads to ineffective erythropoiesis and secondary iron accumulation. We report a 34-year-old man with genetically confirmed SEC23B-mutated CDA II who developed photosensitive bullae associated with chronic HCV genotype 1b infection, hyperbilirubinemia, and severe iron overload. Urinary porphyrins were positive, and skin biopsy showed subepidermal bullae with PAS-positive deposits, supporting the diagnosis of PCT. After unsuccessful therapy with hydroxychloroquine, treatment with sofosbuvir/velpatasvir achieved sustained virologic response, resolution of skin lesions, and marked ferritin reduction. This case illustrates that viral and metabolic stressors can trigger PCT in CDA II patients with possible hepatic involvement, underscoring the importance of recognizing combined genetic and infectious factors in rare hematologic disorders.
2026-07-12 | Tolerability of hormonal treatments in acute hepatic porphyria patients.
Acute hepatic porphyria (AHP) flares have been associated with female hormones and the use of hormonal treatments. Women with AHP are traditionally advised to avoid exogenous oestrogen and progesterone, limiting options for contraception and management of menorrhagia, dysmenorrhoea and menopausal symptoms. Evidence on specific hormonal therapies is limited; a 2003 study found that 25% of women with acute intermittent porphyria (AIP) experienced attacks with contraceptives containing progesterone, oestrogen or both. To update the current understanding of the tolerability of hormonal treatments in women with AHP. An anonymous questionnaire was distributed to women with AHP (acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) via hospital records and a national patient support group, capturing prior hormonal therapy use and associated flares. Thirty responses were analysed; 23 participants had used hormonal therapies. Flares were most frequent in hereditary coproporphyria (66%) and less common in variegate porphyria and acute intermittent porphyria (~20%). No flares were reported with hormone replacement therapy, the progesterone-only pill or progesterone implants. Flares occurred with combined oral contraceptives (46.6%) and progesterone-containing intrauterine devices (28.5%), particularly drospirenone-containing pills. Levonorgestrel-based therapies, including the Mirena IUD, were better tolerated and often improved symptoms. Although limited by sample size and retrospective design, this study provides clinically useful data on the tolerability of specific hormonal therapies in women with AHP, supporting personalised prescribing and patient counselling for contraception and symptom management.
cell therapies
2026-03-12 | Hematopoietic stem cell transplantation for erythropoietic porphyria-induced acute liver failure: a case report and literature review.
Protoporphyrias are rare genetic disorders in heme biosynthesis, causing protoporphyrin IX accumulation with progressive liver injury. Liver transplantation has traditionally treated protoporphyria-induced liver injury but does not correct the underlying hematopoietic defect. We present a 16-year-old male with painful cutaneous photosensitivity who developed cholestatic liver dysfunction and severe abdominal pain. After plasmapheresis, red blood cell (RBC) transfusions, and intravenous hemin, he had transient improvement and subsequently underwent hematopoietic stem cell transplantation (HSCT) without liver transplantation, which normalized his protoporphyrin levels, liver function, and symptoms. This case underscores HSCT as a disease-modifying therapy that may prevent liver transplantation when performed before irreversible hepatic damage.
2026-01-01 | O10 Reduced expression of PPOX , the variegate porphyria gene, causes intrinsic pathological changes to keratinocytes
Abstract Introduction and aims Variegate porphyria, caused by monoallelic mutations in protoporphyrinogen oxidase (PPOX), causes acute visceral attacks and skin photosensitivity, presenting in blistering and skin fragility. A more severe phenotype is seen with rare biallelic mutations. Fragility is due to accumulation of intermediate porphyrins from the liver, such as 5′-aminolaevulinic acid (ALA), close to the skin surface that are oxidized by sunlight and cause oxidative stress. We hypothesize that PPOX deficiency causes intrinsic pathological changes to keratinocytes that contribute to this skin phenotype. Method Short hairpin RNA was used to create a model of monoallelic (KD1) and of biallelic hypofunctional variants (KD2). A porphyria-like environment was then induced using ALA and/or an iron chelator. Porphyrin accumulation was measured using intrinsic fluorescent measurement and differentiation was assessed in monolayer and by using three-dimensional (3D) organotypics. Results Both KD lines displayed reduced PPOX expression (KD1, 50%; KD2, 25%) and significantly reduced proliferation with KD2 displaying reduced migration. Induction of a porphyria-like environment caused accumulation of intermediate porphyrins in both KDs, with significantly more in KD2, and intracellular oxidative stress, evidenced by reduced expression of electron transport complexes and altered glutathione/glutathione disulfide ratios. KD clones displayed reduced differentiation, proportional to KD, and this was replicated by 3D organotypic cultures, while KD2 models also had reduced stratification. Treatment of 3D organoids with ALA further reduced differentiation and stratification in KD models. Discussion In conclusion, we show that keratinocytes have an active haem synthetic pathway and contribute to porphyria pathology causing significant changes in keratinocyte proliferation, differentiation, migration and reducing epidermal thickness, which could facilitate the oxidation of porphyrins under the skin. The more severe effects seen with > 75% KD reflects the phenotype seen in individuals with biallelic mutations in PPOX. These 3D organotypics could therefore serve as models to trial therapeutic interventions to improve patient skincare.
2025-11-03 | From photosensitivity to cure: Hematopoeitic stem cell transplant for congenital erythropoeitic porphyria in a low-resource setting
Abstract Abstract: Congenital Erythropoeitic Porphyria is extremely rare autosomal recessive disorder caused by deficiency of uroporphyrin synthase III deficiency, leading to accumulation of toxic precursors of Heme biosynthesis. Severe Phenotypes present in neonatal period with reddish brown colored urine followed by photosensitivity and erythrodontia. Allogenic hematopoietic stem cell transplant is the only curative option. We retrospectively analyzed 4 patients (2 males , 2 females) with clinically and biochemically confirmed Congenital Erythropoeitic Porphyria who underwent fully matched sibling donor hematopoietic stem cell transplant with Myeloablative conditioning Busulphan (Bu) and Cyclophosphamide (Cy) at the Armed Forces Bone Marrow Transplant Centre Pakistan from 2020 to 2025.These four transplants were performed at a centre with over 1870 transplants to date, highlighting the extreme rarity of disease even within a high volume transplant centre. Median Age of onset of symptoms was 5 days (range 2-15), median age of diagnosis was 27 months (range12-72) and median age of hematopoietic stem cell transplant was 100.5 months (range 54-126). All patients received myeloablative conditioning (Bu16mg/kg, Cy160-200mg/kg). Peri-transplant period was complicated by febrile neutropenia and mucositis. Neutrophil engraftment was achieved at a median of Day+16 (range 14-18) and platelet engraftment at median of Day+21 (range 18-21). At a median follow up of 240 days (range 116-2555), all patients were alive, transfusion independent with complete resolution of photosensitivity. Additionally, serum and urine porphyrin levels became normal in all patients. This cohort, though very small supports the efficacy of early myeloablative Hematopoietic stem cell transplant with matched sibling donors to prevent irreversible tissue damage and significantly improve clinical outcomes. Keywords: Congenital Erythropoeitic porphyria, Hematopoietic stem cell transplant
2025-10-01 | Rare Report of Simultaneous Liver and Kidney Transplant for Acute Intermittent Porphyria
Introduction: AIP is a rare autosomal dominant disorder of heme biosynthesis characterized by acute porphyric episodes caused by a deficiency of the hydroxymethylbilane synthase (HMBS) enzyme. These episodes present as abdominal pain, autonomic instability, and neurologic dysfunction resulting in AKI. Most patients experience infrequent episodes, while a subset develop relapsing porphyria leading to chronic kidney disease. Liver transplantation has been shown to reduce attacks by decreasing hepatic overproduction of porphyrin metabolites by replacing with HMBS producing hepatocytes. However, in patients with end-stage kidney disease (ESKD) and refractory symptoms, options are limited. Simultaneous liver-kidney transplant (SLKT) offers a comprehensive solution for these patients but has been rarely reported as a cure for AIP. Case Description: A 47-year-old woman with confirmed AIP via HMBS gene mutation experienced recurrent porphyric attacks since adolescence, which progressively worsened despite regular hemin infusions and plasmapheresis. Her urine porphyrins were quantified at 99 uM at age 33 which increased to 665 uM at age 37. She was later started on Givosiran, siRNA against ALA synthetase, reducing the frequency of her attacks but not preventing them. Over time, she developed ESKD from porphyrin-associated nephropathy, worsened by hypertensive crises during attacks, requiring peritoneal dialysis. Due to refractory symptoms and kidney failure, she was listed for SLKT. At the time of transplant, she received simulect induction and was discharged on tacrolimus, cellcept, and prednisone. Her Model for End-Stage Liver Disease (MELD) 3.0 score was elevated to 21 mainly due to her high creatinine (Cr). One month later, she underwent uncomplicated SLKT. Both allografts functioned immediately. She was discharged on tacrolimus, mycophenolate mofetil, and prednisone. 3 month follow up shows excellent liver allograft function with normal synthetic function, and kidney allograft function with Cr 0.9-1.1mg/dl. She has been able to stop givosiran and has had no porphyric attacks since SLKT. Discussion: This case details a rare, successful SLKT for AIP, leading to complete remission of porphyric symptoms and full recovery of kidney function. AIP is among a group of select disorders where combined transplant should be considered for optimal outcomes.
2025-02-19 | Paternal Split-Liver Transplantation Followed by Haploidentical Hematopoietic Cell Transplantation in an Adult Patient With Protoporphyria-Induced Liver Failure.
Erythropoietic Protoporphyria (EPP) caused skin light sensitivity and liver cirrhosis in a 35-year-old patient who subsequently developed liver-failure. In absence of a human leukocyte antigens (HLA)-matched-unrelated donor, the father consented in donating for split liver transplantation (SLT) and allogeneic hematopoietic cell transplantation (HCT). After bridging therapy and successful SLT a first paternal HCT resulted in graft failure. For a second haploidentical HCT a different regimen was applied leading to engraftment while protoporphyrin (PP) blood-levels decreased to normal and skin light sensitivity skin disappeared, leading to complete remission in an immunosuppressive-free patient. Haploidentical transplantation is a feasible treatment approach in EPP-patients. The authors have confirmed clinical trial registration is not needed for this submission.
gene therapies
2026-08-14 | Long-term cutaneous and systemic manifestatıons at the 70th anniversary of the porphyria turcica outbreak: a three-case series
This case series a re-evaluation of a historical patient cohort after 42 years provides valuable insights into the natural history of Porphyria Turcica. It has been confirmed that Case 1 is one of the individuals clinically documented in the landmark cohort study published by Cripps, Peters, and others in the *British Journal of Dermatology* in 1984
2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
2026-07-15 | Red lines and green lights: Gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
2026-06-11 | Pathophysiological Consequences of Dysregulated Heme Levels: Insights into Hemolysis and Porphyria
(noch nicht zugänglich / not yet accessible)
2026-04-07 | A Case Report of Acute Intermittent Porphyria Mimicking Autoimmune Encephalitis
A 21-year-old female patient had recurrent visits to the ED with chest pain managed conservatively, then developed recurrent episodes of seizures and became encephalopathic. She eventually landed in the intensive care unit with extensive investigations to confirm or rule out infective and noninfective etiologies for encephalitis. Her cerebrospinal fluid examination was unremarkable, including autoimmune encephalitis screening. The MRI brain had juxtacortical and in places cortical signal change, with a possibility of an encephalitic process going on. Furthermore, influenza type B was detected on blood screening, and the EEG showed generalized slow-wave discharges. She had dilated pupils, raised blood pressure, and low sodium levels, which pointed toward autonomic instability. Keeping in view autonomic instability, new onset seizures, preceded chest pain, and encephalopathic EEG, she was screened for porphyria and diagnosed with the condition.
oligonucleotides
2026-09-29 | Givosiran for the Treatment of Hereditary Coproporphyria in Pregnancy: A Case Report.
Hereditary coproporphyria (HCP) is a rare autosomal dominant disorder of heme synthesis characterized by acute neurovisceral attacks that are often precipitated by exposure to medications or hormones. Patients with HCP who become pregnant have an elevated risk of more frequent neurovisceral attacks and other obstetric complications. Givosiran, a small interfering RNA therapeutic, is considered the gold-standard prophylactic treatment for acute hepatic porphyrias, but its use has not been studied during pregnancy. We describe our patient who successfully continued givosiran throughout pregnancy. This highlights the role of shared decision-making in managing medically complex patients during pregnancy when treatment data may be limited or non-existent and the need for further investigation into the safety profile of givosiran use in pregnancy.
2026-09-23 | Single-Dose Hemin Treatment, δ-Aminolevulinic Acid overflow and PEPT2-mediated nephrotoxicity in Acute Intermittent Porphyria (PAKD)
In acute intermittent porphyria (AIP), the empirical use of single-dose hemin does not ensure metabolic quiescence. Rapid HO-1 induction degrades exogenous heme before the excess porphobilinogen (PBG) upstream of the HMBS deficit can be cleared, forcing a continuous retrograde overflow of δ-aminolevulinic acid (δ-ALA). This patient-led longitudinal N-of-1 study, conducted in accordance with CARE guidelines and the CENT extension, correlates principles of physical chemistry, enzyme kinetics, and mass balance with clinical and laboratory data from seven years of follow-up (2016–2023). Analysis of 18 documented single-infusion cycles reveals a transient 24-hour reduction in δ-ALA (-53.8%) but a failure to clear PBG (post-dose: 17.45 µmol/mmol creatinine), followed by a rebound at 4 days and chronic drift (up to 34.80 µmol/mmol creatinine). Proximal tubular uptake of δ-ALA via PEPT2/SLC15A2 triggers mitochondrial peroxidation and activates the TGF-β1/SMAD axis, providing the biophysical basis for a severe decline in eGFR from 115 to 51 mL/min/1.73 m² (-55.7% over 31.1 months; nadir: CKD stage 3a). Silencing ALAS1 mRNA with givosiran (February 2021) halts synthesis at the source, arresting the decline in renal function and restoring function at 60–70 mL/min/1.73 m². This study suggests the risk of kinetic fallacy of single-dose administration and advocates for the mandatory use of cystatin C.
2026-09-08 | Acute intermittent porphyria presenting with rhabdomyolysis and polyneuropathy with severe quadriparesis and respiratory failure: A case report.
Acute intermittent porphyria (AIP) is the most common form of acute porphyria, a group of rare inherited disorders of heme biosynthesis. Severe attacks may be associated with life-threatening complications, including peripheral motor neuropathy, encephalopathy and seizures. Very rarely, an acute AIP attack can be complicated by rhabdomyolysis as illustrated in this case report. A 28-year-old female presented with severe abdominal pain and muscle weakness, which progressed to severe rhabdomyolysis and acute kidney injury requiring dialysis. The disease course was further complicated by an acute severe axonal peripheral motor neuropathy with quadriparesis and respiratory muscle weakness requiring prolonged invasive mechanical ventilation. An important clue for diagnosis was red urine without hematuria. The diagnosis was established by the finding of elevated δ-aminolevulinic acid and porphobilinogen in a random urine sample and later confirmed by genetic testing. The patient was initially treated with hemin and parenteral glucose. However, since she needed prolonged treatment, givosiran was commenced and continued after discharge. When the period between givosiran administrations was extended to two months, this led to a new (milder) attack. After 40 months of givosiran treatment and continued physical rehabilitation, the patient is ambulatory and without acute attacks. Our case illustrates that treatment with hemin and givosiran for longer than two years may be needed for neurological recovery after an AIP attack with severe motor polyneuropathy and multisystem involvement.
2026-08-21 | Unmasking clinical heterogeneity and diagnostic conundrums of acute intermittent porphyria: a case series from the middle east
Abstract Background Acute intermittent porphyria (AIP) is a rare inherited metabolic disorder caused by an alteration in the heme synthesis pathway leading to the accumulation of porphyrins and their precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). Although most patients are asymptomatic, AIP is typically characterized by a triad of abdominal pain, neurologic impairment, and psychiatric abnormalities; experienced by only a small percentage of symptomatic patients. The disease onset is usually reported to occur between the ages of 20 and 40. Due to its heterogeneity, the diagnosis of AIP is challenging and ruling out other diseases solely based on clinical assessment is difficult. Results This case series presents three cases of AIP with diverse clinical presentations encountered in Emirati patients at Burjeel Hospital in Abu Dhabi. Conclusions This case series highlights the diagnostic difficulties and the impact of novel therapeutic strategies such as givosiran in improving patient outcomes.
2026-07-14 | Treating a patient with ADP porphyria through suppression of both hepatic and erythroid ALA production.
δ-Aminolevulinic acid dehydratase deficient porphyria (ADP) is an exceedingly rare form of acute porphyria, with only fifteen published cases worldwide. This disorder has historically been considered an hepatic porphyria, as it was thought the overproduction of the toxic metabolite δ-Aminolevulinic acid (ALA) solely occurred in the liver. This case report demonstrates that treatments focused on reducing the hepatic ALA production had limited effect on this patient's symptoms. An earlier published hypothesis that patients with ADP also produce substantial levels of bone marrow derived ALA, was retested. We describe a Dutch patient in his early 60s, who has suffered from ADP since birth. His medical history mentions acute neurovisceral attacks, contractures of hand and feet, severe polyneuropathy, developmental delay, and renal insufficiency (eGFR 30-40 ml/min). For over a decade he was treated with weekly heme prophylaxis to reduce the frequency of neurovisceral attacks. Despite continuation, his chronic neurological symptoms aggravated and, in an attempt to suppress erythroid ALA production, weekly erythrocyte transfusions combined with hydroxyurea was started. The patient's symptoms improved and stabilized during this treatment. Oral chelation therapy was started to limit secondary iron overload caused by both heme and erythrocyte infusions. Years later we could trial givosiran, an ALAS1-siRNA to suppress the hepatic ALA production. After starting givosiran the heme infusions could be stopped without an increase in symptoms, but discontinuation of erythrocyte transfusions led to new onset neurovisceral attacks. His current schedule consists of continued givosiran and erythrocyte transfusions. This case report illustrates that ADP can be treated successfully with both hepatic and erythroid suppression. It also illustrates the challenges of treating a patient with a rare, complex and poorly understood disease, and the difficulty to balance the complications, side effects and the benefits of treatments.
other
2025-12-31 | Congenital Erythropoietic Porphyria with Persistent Severe Biochemical Abnormalities and a Non-Mutilating Clinical Course: A Case Report
Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by deficiency of uroporphyrinogen III synthase, leading to accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. We report 32-year-old women diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade yet followed a relatively non-mutilating clinical course. Genetic testing identified a low penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without need for transfusion therapy or stem cell transplantation. This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.
2025-08-27 | Erythropoietic protoporphyria in childhood: clinical clues, missed diagnoses and emerging therapy.
Erythropoietic protoporphyria (EPP) is a rare photodermatosis presenting in early childhood with severe pain upon exposure to visible light, including sunlight and artificial sources, often without visible skin changes in the early phase. However, skin changes such as erythema, oedema or crusting may develop after prolonged exposure. This mini-review highlights key clinical features and proposes a structured diagnostic approach, illustrated by a representative paediatric case. Emerging therapies, including off-label afamelanotide and experimental visible light protection, are discussed alongside practical management in primary care. The review also addresses the psychosocial impact and systemic challenges in European care structures. The aim is to raise awareness among paediatricians and general practitioners, promote earlier diagnosis and support equitable care for affected children. What is Known: • EPP is the most common porphyria in childhood. It typically manifests with painful photosensitivity and no visible skin changes. Despite characteristic features, diagnosis is often delayed due to low awareness in paediatric care. What is New: • This mini-review proposes a practical diagnostic algorithm for paediatric primary care and highlights key clinical clues to sensitise general paediatricians to EPP. It also reviews emerging treatment options such as afamelanotide, already approved for adults, with promising adolescent data. These advances must now be widely communicated and translated into equitable access for children across Europe.
2025-03-14 | German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP).
Afamelanotide 16 mg (SCENESSE) is the first approved treatment for erythropoietic protoporphyria (EPP). EPP is a rare autosomal recessive inherited disorder of the haem biosynthesis pathway, where patients experience severe and debilitating acute phototoxicity. It affects at least one in 140,000 of the European population. A postauthorisation safety study (PASS) and a disease registry were imposed as conditions of the European marketing authorisation. Evaluate the short- and long-term safety and clinical effectiveness of afamelanotide 16 mg in EPP patients enrolled in the PASS in Germany. The PASS (EUPAS13004) is an ongoing observational study collecting safety and effectiveness variables from treated and untreated EPP patients in the European EPP Disease Registry. Patients (n = 200, none untreated) received afamelanotide according to the summary of product characteristics. Treatment-emergent adverse events were collected as safety variables. Clinical effectiveness was assessed with the EPP-QoL tool and through treatment continuity. The short- and long-term safety and benefit-risk profile of afamelanotide under real-world conditions is consistent with the positive safety profile seen in clinical trials. EPP patients reported a significant increase in QoL compared with baseline values (p < 0.0001) and 91.0% of patients who started treatment continue being treated. The safety profile of afamelanotide in patients over 70 years of age is consistent with the overall patient population. Afamelanotide treatment was highly effective and associated with a higher QoL in EPP patients. The study shows a positive safety profile of afamelanotide, with the treatment providing an ongoing clinical benefit.
2024-08-01 | PORPHYRIA CUTANEA TARDA IN A PATIENT, TREATED WITH HAEMODIALYSIS AFTER A KIDNEY TRANSPLANT REJECTION REACTION: A CASE REPORT
Porphyrias are a group of inherited metabolic disorders of haem biosynthesis, involving a deficiency in the enzyme uroporphyrinogen decarboxylase. In this case report we present a case of a patient with porphyria cutanea tarda (PCT). A 40-year-old man on haemodialysis after a kidney transplant rejection reaction, complaining of skin changes, with a history of smoking and alcohol intake. Treated with Fusidic acid and Betamethasone cream, and erythropoietin. Porhyria cutanea tarda can be considered in patient who complains of skin changes. History of alcohol intake, smoking, high ferritin levels and increased hepatic markers can raise suspicion of disease. In patient with ESRD treatment with erythropoietin, SPF 50+ sun cream, Fusidic acid and Betamethasone can be effective.
2024-07-16 | Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management.
The erythropoietic protoporphyrias consist of three ultra-rare genetic disorders of the erythroid heme biosynthesis, including erythropoietic protoporphyria (EPP1), X-linked protoporphyria (XLEPP) and CLPX-protoporphyria (EPP2), which all lead to the accumulation of protoporphyrin IX (PPIX) in erythrocytes. Affected patients usually present from early childhood with episodes of severe phototoxic pain in the skin exposed to visible light. The quantification of PPIX in erythrocytes with a metal-free PPIX ≥3 times the upper limit of normal confirms the diagnosis. Protoporphyria-related complications include liver failure, gallstones, mild anaemia and vitamin D deficiency with reduced bone mineral density. The management is focused on preventing phototoxic reactions and treating the complications. Vitamin D should be supplemented, and DEXA scans in adults should be considered. In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage. Because of its rarity, there is little data on the management of EPP-related liver disease. As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory. Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is currently the only approved specific treatment that increases pain-free sunlight exposure and quality of life.
small molecules
2026-08-20 | Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.Abbreviations: ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).
2026-08-08 | Challenges in Porphyria diagnosis and management: When variegate Porphyria meets HIV.
Variegate Porphyria (VP) is a rare autosomal dominant disorder characterized by deficient activity of protoporphyrinogen oxidase, resulting in the accumulation of potentially neurotoxic heme precursors. We present the case of a 32-year-old woman with HIV receiving antiretroviral therapy (dolutegravir, lamivudine, and ritonavir) who had generalized seizures, psychosis, and polyneuropathy, initially interpreted as secondary to infection. Brain magnetic resonance imaging suggested vasogenic edema, raising suspicion of autoimmune encephalitis. Despite treatment with methylprednisolone and intravenous immunoglobulins, her health worsened, requiring intensive care and extended mechanical ventilation. Markedly elevated urinary porphyrin precursors and porphyrins, a characteristic pattern of elevated fecal porphyrins, and a plasma fluorescence emission peak at 626 nm were diagnostic for VP. Genetic testing identified a pathogenic PPOX missense variant NM_001365398.1:c.428 A > T, p.(Asp143Val), consistent with VP. The patient required repeated courses of hemin and intravenous dextrose, which were followed by transient biochemical improvement. However, symptoms and biochemical markers recurred over time. Clinical stability was only achieved after the withdrawal of ritonavir from her antiretroviral regimen, emphasizing the need for careful medication review in patients with Acute Hepatic Porphyria. This case shows the complex interactions between genetic predisposition, environmental factors, and comorbidities in VP, emphasizing the importance of genetic and biochemical testing for accurate diagnosis, hemin administration during acute attacks, and careful medication review. Clinicians should remain vigilant about interactions between antiretroviral therapy and porphyria when treating HIV-positive patients with suspected or confirmed Acute Hepatic Porphyria.
2026-08-01 | Navigating tuberculosis therapy in acute intermittent porphyria: A case report and narrative review
Tuberculosis (TB) treatment in patients with acute intermittent porphyria (AIP) is challenging because several first-line antituberculous drugs can precipitate porphyric crises, and evidence to guide management is limited. We describe a 26-year-old woman with peritoneal TB who developed acute abdominal pain, hyponatraemia, seizures, and neuropsychiatric manifestations within 24 hours of standard isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) therapy. AIP was confirmed by elevated urinary porphobilinogen levels, and the patient required hemin for the acute crises. Antituberculous therapy was modified to a rifampicin-free regimen including moxifloxacin, linezolid, and ethambutol; isoniazid was cautiously reintroduced once the patient had stabilised. Recurrent porphyric crises and treatment-related toxicity ultimately led to therapy discontinuation after 167 doses. The patient achieved substantial neurological recovery without TB relapse after one year of follow-up. This case illustrates the need to balance TB control with porphyria safety, and to consider acute hepatic porphyria when patients develop unexplained abdominal pain, hyponatraemia, or neurological symptoms after starting antituberculous therapy. Rifampicin and isoniazid carry the highest porphyrinogenic risk, whereas moxifloxacin, ethambutol, and linezolid appear to be safer alternatives. Given limited evidence and the absence of standardised protocols for this rare coexistence, we offer a pragmatic framework to support shared decision-making in tuberculosis and porphyria.
2026-07-28 | Case Report: HCV-triggered porphyria cutanea tarda in a patient with SEC23B-mutated congenital dyserythropoietic anemia type II.
Porphyria cutanea tarda (PCT) is a hepatic porphyria often triggered by hepatitis C virus (HCV) infection, iron overload, or environmental exposure. Congenital dyserythropoietic anemia type II (CDA II) caused by SEC23B mutations leads to ineffective erythropoiesis and secondary iron accumulation. We report a 34-year-old man with genetically confirmed SEC23B-mutated CDA II who developed photosensitive bullae associated with chronic HCV genotype 1b infection, hyperbilirubinemia, and severe iron overload. Urinary porphyrins were positive, and skin biopsy showed subepidermal bullae with PAS-positive deposits, supporting the diagnosis of PCT. After unsuccessful therapy with hydroxychloroquine, treatment with sofosbuvir/velpatasvir achieved sustained virologic response, resolution of skin lesions, and marked ferritin reduction. This case illustrates that viral and metabolic stressors can trigger PCT in CDA II patients with possible hepatic involvement, underscoring the importance of recognizing combined genetic and infectious factors in rare hematologic disorders.
2026-07-12 | Tolerability of hormonal treatments in acute hepatic porphyria patients.
Acute hepatic porphyria (AHP) flares have been associated with female hormones and the use of hormonal treatments. Women with AHP are traditionally advised to avoid exogenous oestrogen and progesterone, limiting options for contraception and management of menorrhagia, dysmenorrhoea and menopausal symptoms. Evidence on specific hormonal therapies is limited; a 2003 study found that 25% of women with acute intermittent porphyria (AIP) experienced attacks with contraceptives containing progesterone, oestrogen or both. To update the current understanding of the tolerability of hormonal treatments in women with AHP. An anonymous questionnaire was distributed to women with AHP (acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) via hospital records and a national patient support group, capturing prior hormonal therapy use and associated flares. Thirty responses were analysed; 23 participants had used hormonal therapies. Flares were most frequent in hereditary coproporphyria (66%) and less common in variegate porphyria and acute intermittent porphyria (~20%). No flares were reported with hormone replacement therapy, the progesterone-only pill or progesterone implants. Flares occurred with combined oral contraceptives (46.6%) and progesterone-containing intrauterine devices (28.5%), particularly drospirenone-containing pills. Levonorgestrel-based therapies, including the Mirena IUD, were better tolerated and often improved symptoms. Although limited by sample size and retrospective design, this study provides clinically useful data on the tolerability of specific hormonal therapies in women with AHP, supporting personalised prescribing and patient counselling for contraception and symptom management.
cell therapies
2026-03-12 | Hematopoietic stem cell transplantation for erythropoietic porphyria-induced acute liver failure: a case report and literature review.
Protoporphyrias are rare genetic disorders in heme biosynthesis, causing protoporphyrin IX accumulation with progressive liver injury. Liver transplantation has traditionally treated protoporphyria-induced liver injury but does not correct the underlying hematopoietic defect. We present a 16-year-old male with painful cutaneous photosensitivity who developed cholestatic liver dysfunction and severe abdominal pain. After plasmapheresis, red blood cell (RBC) transfusions, and intravenous hemin, he had transient improvement and subsequently underwent hematopoietic stem cell transplantation (HSCT) without liver transplantation, which normalized his protoporphyrin levels, liver function, and symptoms. This case underscores HSCT as a disease-modifying therapy that may prevent liver transplantation when performed before irreversible hepatic damage.
2026-01-01 | O10 Reduced expression of PPOX , the variegate porphyria gene, causes intrinsic pathological changes to keratinocytes
Abstract Introduction and aims Variegate porphyria, caused by monoallelic mutations in protoporphyrinogen oxidase (PPOX), causes acute visceral attacks and skin photosensitivity, presenting in blistering and skin fragility. A more severe phenotype is seen with rare biallelic mutations. Fragility is due to accumulation of intermediate porphyrins from the liver, such as 5′-aminolaevulinic acid (ALA), close to the skin surface that are oxidized by sunlight and cause oxidative stress. We hypothesize that PPOX deficiency causes intrinsic pathological changes to keratinocytes that contribute to this skin phenotype. Method Short hairpin RNA was used to create a model of monoallelic (KD1) and of biallelic hypofunctional variants (KD2). A porphyria-like environment was then induced using ALA and/or an iron chelator. Porphyrin accumulation was measured using intrinsic fluorescent measurement and differentiation was assessed in monolayer and by using three-dimensional (3D) organotypics. Results Both KD lines displayed reduced PPOX expression (KD1, 50%; KD2, 25%) and significantly reduced proliferation with KD2 displaying reduced migration. Induction of a porphyria-like environment caused accumulation of intermediate porphyrins in both KDs, with significantly more in KD2, and intracellular oxidative stress, evidenced by reduced expression of electron transport complexes and altered glutathione/glutathione disulfide ratios. KD clones displayed reduced differentiation, proportional to KD, and this was replicated by 3D organotypic cultures, while KD2 models also had reduced stratification. Treatment of 3D organoids with ALA further reduced differentiation and stratification in KD models. Discussion In conclusion, we show that keratinocytes have an active haem synthetic pathway and contribute to porphyria pathology causing significant changes in keratinocyte proliferation, differentiation, migration and reducing epidermal thickness, which could facilitate the oxidation of porphyrins under the skin. The more severe effects seen with > 75% KD reflects the phenotype seen in individuals with biallelic mutations in PPOX. These 3D organotypics could therefore serve as models to trial therapeutic interventions to improve patient skincare.
2025-11-03 | From photosensitivity to cure: Hematopoeitic stem cell transplant for congenital erythropoeitic porphyria in a low-resource setting
Abstract Abstract: Congenital Erythropoeitic Porphyria is extremely rare autosomal recessive disorder caused by deficiency of uroporphyrin synthase III deficiency, leading to accumulation of toxic precursors of Heme biosynthesis. Severe Phenotypes present in neonatal period with reddish brown colored urine followed by photosensitivity and erythrodontia. Allogenic hematopoietic stem cell transplant is the only curative option. We retrospectively analyzed 4 patients (2 males , 2 females) with clinically and biochemically confirmed Congenital Erythropoeitic Porphyria who underwent fully matched sibling donor hematopoietic stem cell transplant with Myeloablative conditioning Busulphan (Bu) and Cyclophosphamide (Cy) at the Armed Forces Bone Marrow Transplant Centre Pakistan from 2020 to 2025.These four transplants were performed at a centre with over 1870 transplants to date, highlighting the extreme rarity of disease even within a high volume transplant centre. Median Age of onset of symptoms was 5 days (range 2-15), median age of diagnosis was 27 months (range12-72) and median age of hematopoietic stem cell transplant was 100.5 months (range 54-126). All patients received myeloablative conditioning (Bu16mg/kg, Cy160-200mg/kg). Peri-transplant period was complicated by febrile neutropenia and mucositis. Neutrophil engraftment was achieved at a median of Day+16 (range 14-18) and platelet engraftment at median of Day+21 (range 18-21). At a median follow up of 240 days (range 116-2555), all patients were alive, transfusion independent with complete resolution of photosensitivity. Additionally, serum and urine porphyrin levels became normal in all patients. This cohort, though very small supports the efficacy of early myeloablative Hematopoietic stem cell transplant with matched sibling donors to prevent irreversible tissue damage and significantly improve clinical outcomes. Keywords: Congenital Erythropoeitic porphyria, Hematopoietic stem cell transplant
2025-10-01 | Rare Report of Simultaneous Liver and Kidney Transplant for Acute Intermittent Porphyria
Introduction: AIP is a rare autosomal dominant disorder of heme biosynthesis characterized by acute porphyric episodes caused by a deficiency of the hydroxymethylbilane synthase (HMBS) enzyme. These episodes present as abdominal pain, autonomic instability, and neurologic dysfunction resulting in AKI. Most patients experience infrequent episodes, while a subset develop relapsing porphyria leading to chronic kidney disease. Liver transplantation has been shown to reduce attacks by decreasing hepatic overproduction of porphyrin metabolites by replacing with HMBS producing hepatocytes. However, in patients with end-stage kidney disease (ESKD) and refractory symptoms, options are limited. Simultaneous liver-kidney transplant (SLKT) offers a comprehensive solution for these patients but has been rarely reported as a cure for AIP. Case Description: A 47-year-old woman with confirmed AIP via HMBS gene mutation experienced recurrent porphyric attacks since adolescence, which progressively worsened despite regular hemin infusions and plasmapheresis. Her urine porphyrins were quantified at 99 uM at age 33 which increased to 665 uM at age 37. She was later started on Givosiran, siRNA against ALA synthetase, reducing the frequency of her attacks but not preventing them. Over time, she developed ESKD from porphyrin-associated nephropathy, worsened by hypertensive crises during attacks, requiring peritoneal dialysis. Due to refractory symptoms and kidney failure, she was listed for SLKT. At the time of transplant, she received simulect induction and was discharged on tacrolimus, cellcept, and prednisone. Her Model for End-Stage Liver Disease (MELD) 3.0 score was elevated to 21 mainly due to her high creatinine (Cr). One month later, she underwent uncomplicated SLKT. Both allografts functioned immediately. She was discharged on tacrolimus, mycophenolate mofetil, and prednisone. 3 month follow up shows excellent liver allograft function with normal synthetic function, and kidney allograft function with Cr 0.9-1.1mg/dl. She has been able to stop givosiran and has had no porphyric attacks since SLKT. Discussion: This case details a rare, successful SLKT for AIP, leading to complete remission of porphyric symptoms and full recovery of kidney function. AIP is among a group of select disorders where combined transplant should be considered for optimal outcomes.
2025-02-19 | Paternal Split-Liver Transplantation Followed by Haploidentical Hematopoietic Cell Transplantation in an Adult Patient With Protoporphyria-Induced Liver Failure.
Erythropoietic Protoporphyria (EPP) caused skin light sensitivity and liver cirrhosis in a 35-year-old patient who subsequently developed liver-failure. In absence of a human leukocyte antigens (HLA)-matched-unrelated donor, the father consented in donating for split liver transplantation (SLT) and allogeneic hematopoietic cell transplantation (HCT). After bridging therapy and successful SLT a first paternal HCT resulted in graft failure. For a second haploidentical HCT a different regimen was applied leading to engraftment while protoporphyrin (PP) blood-levels decreased to normal and skin light sensitivity skin disappeared, leading to complete remission in an immunosuppressive-free patient. Haploidentical transplantation is a feasible treatment approach in EPP-patients. The authors have confirmed clinical trial registration is not needed for this submission.
gene therapies
2026-08-14 | Long-term cutaneous and systemic manifestatıons at the 70th anniversary of the porphyria turcica outbreak: a three-case series
This case series a re-evaluation of a historical patient cohort after 42 years provides valuable insights into the natural history of Porphyria Turcica. It has been confirmed that Case 1 is one of the individuals clinically documented in the landmark cohort study published by Cripps, Peters, and others in the *British Journal of Dermatology* in 1984
2026-07-29 | From one-size-fits-all to on-demand: personalized crispr gene editing for rare genetic liver diseases.
Rare genetic liver diseases collectively affect millions of individuals worldwide and encompass a heterogeneous group of monogenic disorders including Wilson disease, alpha-1 antitrypsin deficiency, glycogen storage diseases, urea cycle disorders, progressive familial intrahepatic cholestasis, and acute hepatic porphyrias. While conventional management relies on dietary modification, pharmacotherapy, and ultimately liver transplantation, the advent of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has opened transformative therapeutic avenues. This review provides a comprehensive and critical appraisal of the current landscape of CRISPR-based therapies for genetic liver diseases, from preclinical proof-of-concept studies to landmark clinical trials. We examine the evolution from conventional Cas9 nuclease-mediated editing to precision tools including base editors and prime editors, which enable single-nucleotide corrections without inducing double-strand DNA breaks. The role of lipid nanoparticle delivery systems in achieving efficient hepatocyte-targeted delivery is discussed, alongside emerging challenges in pediatric dosing and immunogenicity. We highlight the paradigm shift toward personalized, patient-specific CRISPR therapies, exemplified by the first-in-human bespoke gene editing treatment delivered in 2025. Competing nucleic acid technologies, including RNA interference and antisense oligonucleotides, are compared in terms of durability, safety, and cost-effectiveness. Finally, we critically evaluate the evolving regulatory landscape and propose a priority framework for selecting genetic liver diseases most amenable to CRISPR-based correction. This review underscores that CRISPR gene editing is transitioning from experimental promise to clinical reality for genetic liver diseases, with personalized approaches poised to redefine the treatment paradigm.
2026-07-15 | Red lines and green lights: Gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.
2026-06-11 | Pathophysiological Consequences of Dysregulated Heme Levels: Insights into Hemolysis and Porphyria
(noch nicht zugänglich / not yet accessible)
2026-04-07 | A Case Report of Acute Intermittent Porphyria Mimicking Autoimmune Encephalitis
A 21-year-old female patient had recurrent visits to the ED with chest pain managed conservatively, then developed recurrent episodes of seizures and became encephalopathic. She eventually landed in the intensive care unit with extensive investigations to confirm or rule out infective and noninfective etiologies for encephalitis. Her cerebrospinal fluid examination was unremarkable, including autoimmune encephalitis screening. The MRI brain had juxtacortical and in places cortical signal change, with a possibility of an encephalitic process going on. Furthermore, influenza type B was detected on blood screening, and the EEG showed generalized slow-wave discharges. She had dilated pupils, raised blood pressure, and low sodium levels, which pointed toward autonomic instability. Keeping in view autonomic instability, new onset seizures, preceded chest pain, and encephalopathic EEG, she was screened for porphyria and diagnosed with the condition.
oligonucleotides
2026-09-29 | Givosiran for the Treatment of Hereditary Coproporphyria in Pregnancy: A Case Report.
Hereditary coproporphyria (HCP) is a rare autosomal dominant disorder of heme synthesis characterized by acute neurovisceral attacks that are often precipitated by exposure to medications or hormones. Patients with HCP who become pregnant have an elevated risk of more frequent neurovisceral attacks and other obstetric complications. Givosiran, a small interfering RNA therapeutic, is considered the gold-standard prophylactic treatment for acute hepatic porphyrias, but its use has not been studied during pregnancy. We describe our patient who successfully continued givosiran throughout pregnancy. This highlights the role of shared decision-making in managing medically complex patients during pregnancy when treatment data may be limited or non-existent and the need for further investigation into the safety profile of givosiran use in pregnancy.
2026-09-23 | Single-Dose Hemin Treatment, δ-Aminolevulinic Acid overflow and PEPT2-mediated nephrotoxicity in Acute Intermittent Porphyria (PAKD)
In acute intermittent porphyria (AIP), the empirical use of single-dose hemin does not ensure metabolic quiescence. Rapid HO-1 induction degrades exogenous heme before the excess porphobilinogen (PBG) upstream of the HMBS deficit can be cleared, forcing a continuous retrograde overflow of δ-aminolevulinic acid (δ-ALA). This patient-led longitudinal N-of-1 study, conducted in accordance with CARE guidelines and the CENT extension, correlates principles of physical chemistry, enzyme kinetics, and mass balance with clinical and laboratory data from seven years of follow-up (2016–2023). Analysis of 18 documented single-infusion cycles reveals a transient 24-hour reduction in δ-ALA (-53.8%) but a failure to clear PBG (post-dose: 17.45 µmol/mmol creatinine), followed by a rebound at 4 days and chronic drift (up to 34.80 µmol/mmol creatinine). Proximal tubular uptake of δ-ALA via PEPT2/SLC15A2 triggers mitochondrial peroxidation and activates the TGF-β1/SMAD axis, providing the biophysical basis for a severe decline in eGFR from 115 to 51 mL/min/1.73 m² (-55.7% over 31.1 months; nadir: CKD stage 3a). Silencing ALAS1 mRNA with givosiran (February 2021) halts synthesis at the source, arresting the decline in renal function and restoring function at 60–70 mL/min/1.73 m². This study suggests the risk of kinetic fallacy of single-dose administration and advocates for the mandatory use of cystatin C.
2026-09-08 | Acute intermittent porphyria presenting with rhabdomyolysis and polyneuropathy with severe quadriparesis and respiratory failure: A case report.
Acute intermittent porphyria (AIP) is the most common form of acute porphyria, a group of rare inherited disorders of heme biosynthesis. Severe attacks may be associated with life-threatening complications, including peripheral motor neuropathy, encephalopathy and seizures. Very rarely, an acute AIP attack can be complicated by rhabdomyolysis as illustrated in this case report. A 28-year-old female presented with severe abdominal pain and muscle weakness, which progressed to severe rhabdomyolysis and acute kidney injury requiring dialysis. The disease course was further complicated by an acute severe axonal peripheral motor neuropathy with quadriparesis and respiratory muscle weakness requiring prolonged invasive mechanical ventilation. An important clue for diagnosis was red urine without hematuria. The diagnosis was established by the finding of elevated δ-aminolevulinic acid and porphobilinogen in a random urine sample and later confirmed by genetic testing. The patient was initially treated with hemin and parenteral glucose. However, since she needed prolonged treatment, givosiran was commenced and continued after discharge. When the period between givosiran administrations was extended to two months, this led to a new (milder) attack. After 40 months of givosiran treatment and continued physical rehabilitation, the patient is ambulatory and without acute attacks. Our case illustrates that treatment with hemin and givosiran for longer than two years may be needed for neurological recovery after an AIP attack with severe motor polyneuropathy and multisystem involvement.
2026-08-21 | Unmasking clinical heterogeneity and diagnostic conundrums of acute intermittent porphyria: a case series from the middle east
Abstract Background Acute intermittent porphyria (AIP) is a rare inherited metabolic disorder caused by an alteration in the heme synthesis pathway leading to the accumulation of porphyrins and their precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). Although most patients are asymptomatic, AIP is typically characterized by a triad of abdominal pain, neurologic impairment, and psychiatric abnormalities; experienced by only a small percentage of symptomatic patients. The disease onset is usually reported to occur between the ages of 20 and 40. Due to its heterogeneity, the diagnosis of AIP is challenging and ruling out other diseases solely based on clinical assessment is difficult. Results This case series presents three cases of AIP with diverse clinical presentations encountered in Emirati patients at Burjeel Hospital in Abu Dhabi. Conclusions This case series highlights the diagnostic difficulties and the impact of novel therapeutic strategies such as givosiran in improving patient outcomes.
2026-07-14 | Treating a patient with ADP porphyria through suppression of both hepatic and erythroid ALA production.
δ-Aminolevulinic acid dehydratase deficient porphyria (ADP) is an exceedingly rare form of acute porphyria, with only fifteen published cases worldwide. This disorder has historically been considered an hepatic porphyria, as it was thought the overproduction of the toxic metabolite δ-Aminolevulinic acid (ALA) solely occurred in the liver. This case report demonstrates that treatments focused on reducing the hepatic ALA production had limited effect on this patient's symptoms. An earlier published hypothesis that patients with ADP also produce substantial levels of bone marrow derived ALA, was retested. We describe a Dutch patient in his early 60s, who has suffered from ADP since birth. His medical history mentions acute neurovisceral attacks, contractures of hand and feet, severe polyneuropathy, developmental delay, and renal insufficiency (eGFR 30-40 ml/min). For over a decade he was treated with weekly heme prophylaxis to reduce the frequency of neurovisceral attacks. Despite continuation, his chronic neurological symptoms aggravated and, in an attempt to suppress erythroid ALA production, weekly erythrocyte transfusions combined with hydroxyurea was started. The patient's symptoms improved and stabilized during this treatment. Oral chelation therapy was started to limit secondary iron overload caused by both heme and erythrocyte infusions. Years later we could trial givosiran, an ALAS1-siRNA to suppress the hepatic ALA production. After starting givosiran the heme infusions could be stopped without an increase in symptoms, but discontinuation of erythrocyte transfusions led to new onset neurovisceral attacks. His current schedule consists of continued givosiran and erythrocyte transfusions. This case report illustrates that ADP can be treated successfully with both hepatic and erythroid suppression. It also illustrates the challenges of treating a patient with a rare, complex and poorly understood disease, and the difficulty to balance the complications, side effects and the benefits of treatments.
other
2025-12-31 | Congenital Erythropoietic Porphyria with Persistent Severe Biochemical Abnormalities and a Non-Mutilating Clinical Course: A Case Report
Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by deficiency of uroporphyrinogen III synthase, leading to accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. We report 32-year-old women diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade yet followed a relatively non-mutilating clinical course. Genetic testing identified a low penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without need for transfusion therapy or stem cell transplantation. This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.
2025-08-27 | Erythropoietic protoporphyria in childhood: clinical clues, missed diagnoses and emerging therapy.
Erythropoietic protoporphyria (EPP) is a rare photodermatosis presenting in early childhood with severe pain upon exposure to visible light, including sunlight and artificial sources, often without visible skin changes in the early phase. However, skin changes such as erythema, oedema or crusting may develop after prolonged exposure. This mini-review highlights key clinical features and proposes a structured diagnostic approach, illustrated by a representative paediatric case. Emerging therapies, including off-label afamelanotide and experimental visible light protection, are discussed alongside practical management in primary care. The review also addresses the psychosocial impact and systemic challenges in European care structures. The aim is to raise awareness among paediatricians and general practitioners, promote earlier diagnosis and support equitable care for affected children. What is Known: • EPP is the most common porphyria in childhood. It typically manifests with painful photosensitivity and no visible skin changes. Despite characteristic features, diagnosis is often delayed due to low awareness in paediatric care. What is New: • This mini-review proposes a practical diagnostic algorithm for paediatric primary care and highlights key clinical clues to sensitise general paediatricians to EPP. It also reviews emerging treatment options such as afamelanotide, already approved for adults, with promising adolescent data. These advances must now be widely communicated and translated into equitable access for children across Europe.
2025-03-14 | German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP).
Afamelanotide 16 mg (SCENESSE) is the first approved treatment for erythropoietic protoporphyria (EPP). EPP is a rare autosomal recessive inherited disorder of the haem biosynthesis pathway, where patients experience severe and debilitating acute phototoxicity. It affects at least one in 140,000 of the European population. A postauthorisation safety study (PASS) and a disease registry were imposed as conditions of the European marketing authorisation. Evaluate the short- and long-term safety and clinical effectiveness of afamelanotide 16 mg in EPP patients enrolled in the PASS in Germany. The PASS (EUPAS13004) is an ongoing observational study collecting safety and effectiveness variables from treated and untreated EPP patients in the European EPP Disease Registry. Patients (n = 200, none untreated) received afamelanotide according to the summary of product characteristics. Treatment-emergent adverse events were collected as safety variables. Clinical effectiveness was assessed with the EPP-QoL tool and through treatment continuity. The short- and long-term safety and benefit-risk profile of afamelanotide under real-world conditions is consistent with the positive safety profile seen in clinical trials. EPP patients reported a significant increase in QoL compared with baseline values (p < 0.0001) and 91.0% of patients who started treatment continue being treated. The safety profile of afamelanotide in patients over 70 years of age is consistent with the overall patient population. Afamelanotide treatment was highly effective and associated with a higher QoL in EPP patients. The study shows a positive safety profile of afamelanotide, with the treatment providing an ongoing clinical benefit.
2024-08-01 | PORPHYRIA CUTANEA TARDA IN A PATIENT, TREATED WITH HAEMODIALYSIS AFTER A KIDNEY TRANSPLANT REJECTION REACTION: A CASE REPORT
Porphyrias are a group of inherited metabolic disorders of haem biosynthesis, involving a deficiency in the enzyme uroporphyrinogen decarboxylase. In this case report we present a case of a patient with porphyria cutanea tarda (PCT). A 40-year-old man on haemodialysis after a kidney transplant rejection reaction, complaining of skin changes, with a history of smoking and alcohol intake. Treated with Fusidic acid and Betamethasone cream, and erythropoietin. Porhyria cutanea tarda can be considered in patient who complains of skin changes. History of alcohol intake, smoking, high ferritin levels and increased hepatic markers can raise suspicion of disease. In patient with ESRD treatment with erythropoietin, SPF 50+ sun cream, Fusidic acid and Betamethasone can be effective.
2024-07-16 | Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management.
The erythropoietic protoporphyrias consist of three ultra-rare genetic disorders of the erythroid heme biosynthesis, including erythropoietic protoporphyria (EPP1), X-linked protoporphyria (XLEPP) and CLPX-protoporphyria (EPP2), which all lead to the accumulation of protoporphyrin IX (PPIX) in erythrocytes. Affected patients usually present from early childhood with episodes of severe phototoxic pain in the skin exposed to visible light. The quantification of PPIX in erythrocytes with a metal-free PPIX ≥3 times the upper limit of normal confirms the diagnosis. Protoporphyria-related complications include liver failure, gallstones, mild anaemia and vitamin D deficiency with reduced bone mineral density. The management is focused on preventing phototoxic reactions and treating the complications. Vitamin D should be supplemented, and DEXA scans in adults should be considered. In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage. Because of its rarity, there is little data on the management of EPP-related liver disease. As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory. Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is currently the only approved specific treatment that increases pain-free sunlight exposure and quality of life.
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Drug Discovery Landscape
10 orphan drug designations for Porphyria, including 2 approved therapies.
10 orphan drug designations for Porphyria, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Afamelanotide | peptides | EMA | Clinuvel Europe Limited | |
Dersimelagon | small molecules | EMA | Tanabe Pharma GmbH | |
(1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl) pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid-phosphoric acid (1/1)) | small molecules | FDA | Tanabe Pharma America Inc. | |
afamelanotide | peptides | FDA | Clinuvel Inc. | |
Adeno-associated viral vector serotype 5 containing the hydroxymethylbilane synthase gene | gene therapies | EMA | uniQure Biopharma B.V | |
afamelanotide [SCENESSE®] | peptides | FDA | Approved | Clinuvel Inc. |
RECOMBINANT HUMAN PORPHOBILINOGEN DEAMINASE [Porphozym (iv) / Porphogen (sc)] | proteins | EMA | Chiesi Farmaceutici S.p.A. | |
Hemin and zinc mesoporphyrin | small molecules | FDA | — | Bonkovsky, Herbert L. M.D. |
Histrelin | small molecules | FDA | — | Anderson, Karl E., M.D. |
Hemin [Panhematin] | proteins | FDA | Approved | Abbott Laboratories |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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