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Zhang J, Kinch L, Katsonis P, Lichtarge O, Jagota M, Song YS, Sun Y, Shen Y, Kuru N, Dereli O, Adebali O, Alladin MA, Pal D, Capriotti E, Turina MP, Savojardo C, Martelli PL, Babbi G, Casadio R, Pucci F, Rooman M, Cia G, Tsishyn M, Strokach A, Hu Z, van Loggerenberg W, Roth FP, Radivojac P, Brenner SE, Cong Q, Grishin NV. Assessing predictions on fitness effects of missense variants in HMBS in CAGI6. Hum Genet 2025; 144:173-189. [PMID: 39110250 PMCID: PMC12085147 DOI: 10.1007/s00439-024-02680-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 05/17/2024] [Indexed: 02/21/2025]
Abstract
This paper presents an evaluation of predictions submitted for the "HMBS" challenge, a component of the sixth round of the Critical Assessment of Genome Interpretation held in 2021. The challenge required participants to predict the effects of missense variants of the human HMBS gene on yeast growth. The HMBS enzyme, critical for the biosynthesis of heme in eukaryotic cells, is highly conserved among eukaryotes. Despite the application of a variety of algorithms and methods, the performance of predictors was relatively similar, with Kendall's tau correlation coefficients between predictions and experimental scores around 0.3 for a majority of submissions. Notably, the median correlation (≥ 0.34) observed among these predictors, especially the top predictions from different groups, was greater than the correlation observed between their predictions and the actual experimental results. Most predictors were moderately successful in distinguishing between deleterious and benign variants, as evidenced by an area under the receiver operating characteristic (ROC) curve (AUC) of approximately 0.7 respectively. Compared with the recent two rounds of CAGI competitions, we noticed more predictors outperformed the baseline predictor, which is solely based on the amino acid frequencies. Nevertheless, the overall accuracy of predictions is still far short of positive control, which is derived from experimental scores, indicating the necessity for considerable improvements in the field. The most inaccurately predicted variants in this round were associated with the insertion loop, which is absent in many orthologs, suggesting the predictors still heavily rely on the information from multiple sequence alignment.
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Affiliation(s)
- Jing Zhang
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Lisa Kinch
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Panagiotis Katsonis
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Olivier Lichtarge
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Milind Jagota
- Computer Science Division, University of California, Berkeley, CA, 94720, USA
| | - Yun S Song
- Computer Science Division, University of California, Berkeley, CA, 94720, USA
- Department of Statistics, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Yuanfei Sun
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Yang Shen
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Nurdan Kuru
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Turkey
| | - Onur Dereli
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Turkey
| | - Ogun Adebali
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Turkey
| | - Muttaqi Ahmad Alladin
- Department of Computational and Data Sciences, Indian Institute of Science, Bangaluru, 560012, India
| | - Debnath Pal
- Department of Computational and Data Sciences, Indian Institute of Science, Bangaluru, 560012, India
| | - Emidio Capriotti
- Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy
| | - Maria Paola Turina
- Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy
| | - Castrense Savojardo
- Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy
| | - Pier Luigi Martelli
- Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy
| | - Giulia Babbi
- Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy
| | - Rita Casadio
- Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy
| | - Fabrizio Pucci
- Computational Biology and Bioinformatics, Université Libre de Bruxelles, 50 Roosevelt Ave, 1050, Brussels, Belgium
| | - Marianne Rooman
- Computational Biology and Bioinformatics, Université Libre de Bruxelles, 50 Roosevelt Ave, 1050, Brussels, Belgium
| | - Gabriel Cia
- Computational Biology and Bioinformatics, Université Libre de Bruxelles, 50 Roosevelt Ave, 1050, Brussels, Belgium
| | - Matsvei Tsishyn
- Computational Biology and Bioinformatics, Université Libre de Bruxelles, 50 Roosevelt Ave, 1050, Brussels, Belgium
| | - Alexey Strokach
- Department of Computer Science, University of Toronto, Toronto, ON, M5S 2E4, Canada
| | - Zhiqiang Hu
- Department of Plant and Microbial Biology, University of California, Berkeley, CA, 94720, USA
- Center for Computational Biology, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Warren van Loggerenberg
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
- Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada
| | - Frederick P Roth
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
- Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada
| | - Predrag Radivojac
- Khoury College of Computer Sciences, Northeastern University, Boston, MA, 02115, USA
| | - Steven E Brenner
- Department of Plant and Microbial Biology, University of California, Berkeley, CA, 94720, USA
- Center for Computational Biology, University of California, Berkeley, Berkeley, CA, 94720, USA
- Biophysics Graduate Group, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Qian Cong
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
| | - Nick V Grishin
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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Lei JJ, Li S, Dong BX, Yang J, Ren Y. Acute intermittent porphyria: a disease with low penetrance and high heterogeneity. Front Genet 2024; 15:1374965. [PMID: 39188285 PMCID: PMC11345236 DOI: 10.3389/fgene.2024.1374965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 07/29/2024] [Indexed: 08/28/2024] Open
Abstract
Acute intermittent porphyria (AIP) is caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS), a key enzyme in the heme biosynthesis pathway. AIP is an autosomal dominant disorder characterized by low penetrance and a highly heterogenous clinical presentation. The estimated prevalence of AIP is 5-10 cases per 100,000 persons, with acute attacks manifesting in less than 1% of the at-risk population. This low frequency of attacks suggests significant roles for oligogenic inheritance and environmental factors in the pathogenesis of the disease. In recent years, identification of several modifier genes has advanced our understanding of the factors influencing AIP penetrance and disease severity. This review summarizes these factors including the impact of specific HMBS mutations, oligogenic inheritance, mitochondrial DNA copy number, age, sex, the influence of sex hormones, and the role of environmental factors. Further studies into the etiology of AIP disease penetrance should inform pathogenesis, potentially allowing for the development of more precise diagnostic and therapeutic approaches.
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Affiliation(s)
- Jia-Jia Lei
- Department of First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Shuang Li
- Department of First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Bai-Xue Dong
- Department of First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Jing Yang
- Department of Endocrinology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yi Ren
- Department of Endocrinology, The First Hospital of Shanxi Medical University, Taiyuan, China
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Credo R, Kesey J, Bharadia D, Griswold J, Pang A. Acute Intermittent Porphyria in a Burn Patient: Case Study and Review of the Literature. J Burn Care Res 2024; 45:790-795. [PMID: 37728521 DOI: 10.1093/jbcr/irad135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Indexed: 09/21/2023]
Abstract
Healthcare providers evaluating patients presenting with neurological, visceral, or cutaneous symptoms that are disproportionate to the expected severity may need to consider porphyria in the differential. Porphyria is an inherited condition in which toxic metabolites of the heme pathway are increased. Carriers of porphyrias are asymptomatic and will not present with classical symptoms, nor will levels be elevated, until the disease is induced by certain drugs, hormones, or idiopathic causes such as the stress of trauma. Acute intermittent porphyria (AIP), a form of acute porphyria, is a rare autosomal dominant disease that results in a dysfunctional porphobilinogen deaminase. This consequently increases neurotoxic porphobilinogen and subsequent increase in δ-aminolevulinic acid. Both of these metabolites cause neurovisceral symptoms that afflict the patient in acute attacks. We present a rare case of AIP manifested in a burn patient suffering a burn injury. The patient presented with symptoms indicative of AIP, including altered mental status and abdominal pain accompanied with a chronic history of alcoholism and smoking. A negative work-up, including imaging and findings of associated manifestations consistent with AIP led to a discovery of elevated porphyrins. The patient's course and death due to his injuries gives insight into the presentation of AIP in a burn patient.
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Affiliation(s)
- Roald Credo
- Department of Surgery, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX 79430, USA
| | - Jennifer Kesey
- Department of Surgery, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX 79430, USA
| | - Deepak Bharadia
- Department of Surgery, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX 79430, USA
| | - John Griswold
- Department of Surgery, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX 79430, USA
| | - Alan Pang
- Department of Surgery, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX 79430, USA
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Ren Y, Li S, Lei JJ, Li R, Dong BX, Yang J. Clinical feature and genetic analysis of HMBS gene in Chinese patients with acute intermittent porphyria: a systematic review. Front Genet 2023; 14:1291719. [PMID: 38148975 PMCID: PMC10750365 DOI: 10.3389/fgene.2023.1291719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/22/2023] [Indexed: 12/28/2023] Open
Abstract
Background: Early detection and diagnosis are important crucial to prevent life-threatening acute attacks in patients with acute intermittent porphyria (AIP). We aim to provide comprehensive data on the clinical and hydroxymethylbilane synthase (HMBS) gene variant characteristics and genotype-phenotype association of Chinese patients with AIP in order to improve clinicians' knowledge of AIP and reduce misdiagnosis and mistaken treatment. Methods: We searched the literature on Chinese patients with AIP in PubMed, Web of Science, Wiley Online Library, ScienceDirect and Chinese literature databases up to August 2023 in our analysis to explore the clinical and HMBS gene variant characteristics of Chinese patients with AIP. Results: A total of 41 original articles associated with Chinese AIP patients were included for analysis: 97 variants were detected in 160 unrelated families, including 35 missense, 29 frameshift, 24 splicing and 9 nonsense variants, with c.517C>T being the most common variant. Clinical data were reported in 77 of 160 patients: Most of them were female (67/77) and the age was 28.8 ± 9.9 years. The most common symptom was abdominal pain (73/77, 94.8%), followed by central nervous system symptoms (45/77, 58.4%). 13.0% (10/77) of patients experienced psychiatric symptoms. Hyponatremia was the most common electrolyte abnormality (42/77). 31 patients received carbohydrate loading therapy, and 30 of them were improved. 6 patients were treated with carbohydrate loading combined with hemin therapy and 5 eventually improved. All variants causing premature stop codons, frameshifts or enzyme activity center may experience more severe clinical phenotypes such as seizures, respiratory paralysis, intracranial hemorrhage disorder or respiratory failure. Conclusion: The most common presenting symptom in Chinese AIP patients was abdominal pain, followed by central nervous system symptoms. The HMBS gene analysis in Chinese AIP patients revealed that the heterogeneity is strong and the most common variant was missense mutation, with c.517C>T being the most common variant. The genotype-phenotype association helps guide clinical diagnosis and treatment. However, the treatment for AIP in China is limited and monolithic, and more attention needs to be paid to the treatment.
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Affiliation(s)
- Yi Ren
- Department of Endocrinology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Shuang Li
- Department of First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Jia-Jia Lei
- Department of First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Ru Li
- Department of First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Bai-Xue Dong
- Department of First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Jing Yang
- Department of Endocrinology, The First Hospital of Shanxi Medical University, Taiyuan, China
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Li S, Lei JJ, Dong BX, Ren Y, Yang J. HMBS gene mutations and hydroxymethylbilane synthase activity in acute intermittent porphyria: A systematic review. Medicine (Baltimore) 2023; 102:e35144. [PMID: 37773850 PMCID: PMC10545320 DOI: 10.1097/md.0000000000035144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 08/18/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Acute intermittent porphyria (AIP) is caused by a partial deficiency of hydroxymethylbilane synthase and affects heme biosynthesis. Mutations in the HMBS gene result in HMBS deficiency. AIP is a rare disease, and there been insufficient studies on it. This report describes the molecular epidemiology of HMBS gene defects and hydroxymethylbilane synthase activity levels in classical AIP. METHODS Databases of PubMed, CNKI, and Wang Fang Database were searched for eligible studies to investigate HMBS gene mutations in peripheral blood samples and HMBS activity in erythrocytes of patients with classical AIP. Relevant studies published up to July 15, 2023, from several databases were independently searched and selected by 2 reviewers. Accuracy data and relevant information were extracted from each eligible study by 2 independent researchers and analyzed using statistical software. RESULTS After pooling the accuracy data from 232 patients of the 15 eligible studies, 90.5% (210/232) of AIP patients had decreased erythrocyte hydroxymethylbilane synthase activity (<70%), and 96 different mutations were identified in 232 patients, including 33 missense (34.4%), 27 splice (28.1%), 19 deletion (19.8%), 8 nonsense (8.3%), 9 insertion (9.4%) mutations. Residual enzyme activities (%) for different groups of type were expressed using mean and 95% confidence interval (95% CI): missense (51.2, 48.5-53.9), splice (57.5, 52.0-59.1), deletion (54.9, 50.7-59.1), nonsense (52.2, 44.4-60.0), insertion (53.2, 47.4-59.0), group analysis P = .17. Subgroups of missense mutations, domain 1 (50.2, 46.0-54.4), domain 2 (52.8, 49.1-56.4), and domain 3 (49.2, 38.3-60.0), Subgroup analysis, P = .62. CONCLUSION Different mutation types and mutation positions are not associated with the level of hydroxymethylbilane synthase activity. Erythrocyte hydroxymethylbilane synthase activity is often reduced to half of normal in patients with AIP, and the enzyme activity assay has a high diagnostic value in AIP. AIP is highly molecularly heterogeneous, with missense mutations being the most common, followed by splice mutations. R173W and G111R are high-frequency mutations and have been found in multiple families from different countries.
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Affiliation(s)
- Shuang Li
- Department of the First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Jia-Jia Lei
- Department of the First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Bai-Xue Dong
- Department of the First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Yi Ren
- Department of Endocrinology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jing Yang
- Department of Endocrinology, The First Hospital of Shanxi Medical University, Taiyuan, China
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Belosevic A, Minder AE, Gueuning M, van Breemen F, Thun GA, Mattle-Greminger MP, Meyer S, Baumer A, Minder EI, Schneider-Yin X, Barman-Aksözen J. First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria. Life (Basel) 2023; 13:1889. [PMID: 37763293 PMCID: PMC10533070 DOI: 10.3390/life13091889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Acute porphyrias are a group of monogenetic inborn errors of heme biosynthesis, characterized by acute and potentially life-threatening neurovisceral attacks upon exposure to certain triggering factors. Biochemical analyses can determine the type of acute porphyria, and subsequent genetic analysis allows for the identification of pathogenic variants in the specific gene, which provides information for family counselling. In 2017, a male Swiss patient was diagnosed with an acute porphyria while suffering from an acute attack. The pattern of porphyrin metabolite excretion in urine, faeces, and plasma was typical for an acute intermittent porphyria (AIP), which is caused by inherited autosomal dominant mutations in the gene for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. However, the measurement of HMBS enzymatic activity in the erythrocytes was within the normal range and Sanger sequencing of the HMBS gene failed to detect any pathogenic variants. To explore the molecular basis of the apparent AIP in this patient, we performed third-generation long-read single-molecule sequencing (nanopore sequencing) on a PCR product spanning the entire HMBS gene, including the intronic sequences. We identified a known pathogenic variant, c.77G>A, p.(Arg26His), in exon 3 at an allelic frequency of ~22% in the patient's blood. The absence of the pathogenic variant in the DNA of the parents and the results of additional confirmatory studies supported the presence of a de novo mosaic mutation. To our knowledge, such a mutation has not been previously described in any acute porphyria. Therefore, de novo mosaic mutations should be considered as potential causes of acute porphyrias when no pathogenic genetic variant can be identified through routine molecular diagnostics.
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Affiliation(s)
- Adrian Belosevic
- Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Anna-Elisabeth Minder
- Division of Endocrinology, Diabetology, Porphyria and Clinical Nutrition, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Morgan Gueuning
- Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland
| | - Franziska van Breemen
- Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Gian Andri Thun
- Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland
| | - Maja P. Mattle-Greminger
- Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland
| | - Stefan Meyer
- Department of Molecular Diagnostics and Cytometry, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland
| | - Alessandra Baumer
- Institute of Medical Genetics, University of Zürich, 8952 Schlieren, Switzerland
| | - Elisabeth I. Minder
- Division of Endocrinology, Diabetology, Porphyria and Clinical Nutrition, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Xiaoye Schneider-Yin
- Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Jasmin Barman-Aksözen
- Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
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Liang L, Meng H, Wu H, Zhao J. Genetic analysis of acute intermittent porphyria caused by novel classical splicing variant in the insertion region of 29-residue specific to human HMBS protein. Front Mol Biosci 2023; 10:1230798. [PMID: 37635937 PMCID: PMC10448817 DOI: 10.3389/fmolb.2023.1230798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 08/03/2023] [Indexed: 08/29/2023] Open
Abstract
Background: Acute intermittent porphyria (AIP; OMIM#176000) is a genetic disorder that is caused by mutations in the hydroxymethylbilane synthetase (HMBS) gene. This gene encodes the third enzyme in the heme biosynthesis pathway. Human HMBS (hHMBS) contains a 29-residue insert (residues 296-324) at the interface between domains 1 and 3. The function of this insert is currently unknown. In this study, a previously unidentified classical Splicing variant was discovered in the HMBS gene of a female AIP patient from China. The variant was validated through comparison with the patient's husband and daughter. Methods: Peripheral blood samples were obtained from the patient, the patient's husband, and their daughter. Gene expression was analyzed using whole exon sequencing and Sanger sequencing. To validate alternative splicing, RNA was extracted from the patient's peripheral blood and reverse transcribed into cDNA. Aberrant splicing caused by variants was predicted using I-TASSER and PyMOL software to simulate protein structures. Finally, molecular dynamics of the proteins were simulated using the AMBER14sb software. Results: The patient and her daughter have a classical Splicing variant c.912 + 1G>C of the HMBS gene. This variant was not found in the patient's husband and has not been previously reported in scientific literature. Analysis of the patient's peripheral blood transcripts revealed that c.912 + 1G>C retained intron 13 and resulted in an exon 13 skipping. Further analysis through homology modelling and molecular dynamics showed that this variant alters the secondary structure of the HMBS protein, leading to functional differences. Conclusion: This research has discovered a new classical Splicing variant c.912 + 1G>C in the HMBS gene that has been identified as pathogenic. This finding not only expands the molecular heterogeneity of AIP but also provides crucial information for genetic diagnosis.
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Affiliation(s)
- Lei Liang
- Center for Prenatal Diagnosis and Medical Genetics, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Haixia Meng
- Center for Prenatal Diagnosis and Medical Genetics, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Haotian Wu
- School of Public Health, Inner Mongolia Medical University, Hohhot, China
| | - Jianrong Zhao
- Department of Nephrology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
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Wang B, Bonkovsky HL, Lim JK, Balwani M. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. Gastroenterology 2023; 164:484-491. [PMID: 36642627 PMCID: PMC10335308 DOI: 10.1053/j.gastro.2022.11.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/20/2022] [Indexed: 01/17/2023]
Abstract
DESCRIPTION The acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of 5-aminolevulinic acid dehydratase. Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging. Acute attacks occur mainly in women in their childbearing years. AHP should be considered in the evaluation of all patients, and especially women aged 15-50 years with recurrent severe abdominal pain not ascribable to common causes. The screening tests of choice include random urine porphobilinogen and δ-aminolevulinic acid corrected to creatinine. All patients with elevations in urinary porphobilinogen and/or δ-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes. AHP is also associated with chronic symptoms and long-term risk of systemic arterial hypertension, chronic renal and liver disease, and hepatocellular carcinoma. Patients who have recurrent acute attacks (4 or more per year) should be considered for prophylactic therapy with intravenous hemin or subcutaneous givosiran. Liver transplantation is curative and reserved for patients with intractable symptoms who have failed other treatment options. METHODS This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Women aged 15-50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP. BEST PRACTICE ADVICE 2: Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample. BEST PRACTICE ADVICE 3: Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing. BEST PRACTICE ADVICE 4: Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. BEST PRACTICE ADVICE 5: In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present. BEST PRACTICE ADVICE 6: Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications. BEST PRACTICE ADVICE 7: Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year). BEST PRACTICE ADVICE 8: Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy. BEST PRACTICE ADVICE 9: Patients with AHP should be monitored annually for liver disease. BEST PRACTICE ADVICE 10: Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months. BEST PRACTICE ADVICE 11: Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate. BEST PRACTICE ADVICE 12: Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring.
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Affiliation(s)
- Bruce Wang
- Department of Medicine and Division of Gastroenterology, University of California San Francisco, San Francisco, California.
| | - Herbert L Bonkovsky
- Section of Gastroenterology and Hepatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Joseph K Lim
- Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut
| | - Manisha Balwani
- Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
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9
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Zhou YQ, Wang XQ, Jiang J, Huang SL, Dai ZJ, Kong QQ. Novel hydroxymethylbilane synthase gene mutation identified and confirmed in a woman with acute intermittent porphyria: A case report. World J Clin Cases 2022; 10:12319-12327. [PMID: 36483813 PMCID: PMC9724524 DOI: 10.12998/wjcc.v10.i33.12319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 10/10/2022] [Accepted: 11/02/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Acute intermittent porphyria (AIP) is a rare autosomal dominant porphyrin metabolic disease caused by a mutation in the hydroxymethylbilane synthase(HMBS) gene. This study aimed to explore the clinical manifestations of a patient with AIP, to identify a novel HMBS gene mutation in the proband and some of her family members, and to confirm the pathogenicity of the variant.
CASE SUMMARY A 22-year-old Chinese woman developed severe abdominal pain, lumbago, sinus tachycardia, epileptic seizure, hypertension, and weakness in lower limbs in March, 2018. Biochemical examinations indicated hypohepatia and hyponatremia. Her last menstrual period was 45 d prior to admission, and she was unaware of the pregnancy, which was confirmed by a pregnancy test after admission. Sunlight exposure of her urine sample for 1 h turned it from yellow to wine red. Urinary porphyrin test result was positive. Based on these clinical manifestations, AIP was diagnosed. After increasing her daily glucose intake (250–300 g/d), abdominal pain was partially relieved. Three days after hospitalization, spontaneous vaginal bleeding occurred, which was confirmed as spontaneous abortion; thereafter, her clinical symptoms completely resolved. Genetic testing revealed a novel heterozygous splicing variant of the HMBS gene in exon 10 (c.648_651+1delCCAGG) in the proband and four other family members. The pathogenicity of the variant was verified through bioinformatic methods and a minigene assay.
CONCLUSION We identified a novel HMBS gene mutation in a Chinese patient with AIP and confirmed its pathogenicity.
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Affiliation(s)
- Yu-Qing Zhou
- Department of Endocrinology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan 523003, Guangdong Province, China
| | - Xiao-Qing Wang
- Department of Endocrinology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan 523003, Guangdong Province, China
| | - Jun Jiang
- Department of Science and Technology ServicesChina Beijing Macro and Micro Test Biotech Co. Ltd, Beijing 100318, China
| | - Shu-Ling Huang
- Department of Endocrinology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan 523003, Guangdong Province, China
| | - Zhuo-Jin Dai
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang 523003, Guangdong Province, China
| | - Qiao-Qiong Kong
- Department of Medicine, Wanjiang People's Hospital of Dongguan, Dongguan 523003, Guangdong Province, China
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10
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Kazamel M, Pischik E, Desnick RJ. Pain in acute hepatic porphyrias: Updates on pathophysiology and management. Front Neurol 2022; 13:1004125. [PMID: 36479055 PMCID: PMC9719963 DOI: 10.3389/fneur.2022.1004125] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/07/2022] [Indexed: 11/22/2022] Open
Abstract
Acute hepatic porphyrias (AHPs) typically present with recurrent acute attacks of severe abdominal pain and acute autonomic dysfunction. While chronic symptoms were historically overlooked in the literature, recent studies have reported increased prevalence of chronic, mainly neuropathic, pain between the attacks. Here we characterize acute and chronic pain as prominent manifestations of the AHPs and discuss their pathophysiology and updated management. In addition to the severe abdominal pain, patients could experience low back pain, limb pain, and headache during acute attacks. Chronic pain between the attacks is typically neuropathic and reported mainly by patients who undergo recurrent attacks. While the acute abdominal pain during attacks is likely mediated by autonomic neuropathy, chronic pain likely represents delayed recovery of the acute neuropathy with ongoing small fiber neuropathy in addition to peripheral and/or central sensitization. δ-aminolaevulinic acid (ALA) plays a major role in acute and chronic pain via its neurotoxic effect, especially where the blood-nerve barrier is less restrictive or absent i.e., the autonomic ganglia, nerve roots, and free nerve endings. For earlier diagnosis, we recommend testing a spot urine porphobilinogen (PBG) analysis in any patient with recurrent severe acute abdominal pain with no obvious explanation, especially if associated with neuropathic pain, hyponatremia, autonomic dysfunction, or encephalopathy. Of note, it is mandatory to exclude AHPs in any acute painful neuropathy. Between the attacks, diagnostic testing for AHPs should be considered for patients with a past medical history of acute/subacute neuropathy, frequent emergency room visits with abdominal pain, and behavioral changes. Pain during the attacks should be treated with opiates combined with hemin infusions. Symptomatic treatment of chronic pain should start with gabapentinoids and certain antidepressants before opiates. Givosiran reduces levels of ALA and PBG and likely has long-term benefits for chronic pain, especially if started early during the course of the disease.
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Affiliation(s)
- Mohamed Kazamel
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
- *Correspondence: Mohamed Kazamel
| | - Elena Pischik
- Department of Neurology, Consultative and Diagnostic Center With Polyclinics, St. Petersburg, Russia
| | - Robert J. Desnick
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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11
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Longo M, Paolini E, Meroni M, Dongiovanni P. Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution. Biomedicines 2022; 10:biomedicines10030648. [PMID: 35327450 PMCID: PMC8945550 DOI: 10.3390/biomedicines10030648] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 12/24/2022] Open
Abstract
Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by the hepatic deficiency of porphobilinogen deaminase (PBGD) and the slowdown of heme biosynthesis. AIP symptomatology includes life-threatening, acute neurovisceral or neuropsychiatric attacks manifesting in response to precipitating factors. The latter promote the upregulation of 5-aminolevulinic acid synthase-1 (ALAS1), the first enzyme of heme biosynthesis, which promotes the overload of neurotoxic porphyrin precursors. Hemin or glucose infusions are the first-line therapies for the reduction of ALAS1 levels in patients with mild to severe AIP, while liver transplantation is the only curative treatment for refractory patients. Recently, the RNA-interference against ALAS1 was approved as a treatment for adult and adolescent patients with AIP. These emerging therapies aim to substitute dysfunctional PBGD with adeno-associated vectors for genome editing, human PBGD mRNA encapsulated in lipid nanoparticles, or PBGD protein linked to apolipoprotein A1. Finally, the impairment of glucose metabolism linked to insulin resistance, and mitochondrial aberrations during AIP pathophysiology provided new therapeutic targets. Therefore, the use of liver-targeted insulin and insulin-mimetics such as α-lipoic acid may be useful for overcoming metabolic dysfunction in these subjects. Herein, the present review aims to provide an overview of AIP pathophysiology and management, focusing on conventional and recent therapeutical approaches.
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Affiliation(s)
- Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Correspondence: ; Tel.: +39-02-5503-3467; Fax: +39-02-5503-4229
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12
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Two Novel Hydroxymethylbilane Synthase Splicing Mutations Predispose to Acute Intermittent Porphyria. Int J Mol Sci 2021; 22:ijms222011008. [PMID: 34681668 PMCID: PMC8541332 DOI: 10.3390/ijms222011008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/04/2021] [Accepted: 10/08/2021] [Indexed: 11/16/2022] Open
Abstract
Acute intermittent porphyria (AIP) is an autosomal dominant genetic disease caused by a lack or decrease in hydroxymethylbilane synthase (HMBS) activity. It is characterized by acute nerve and visceral attacks caused by factors in the process of heme synthesis. The penetrance rate of this disease is low, and the heterogeneity is strong. Here, we reported two novel HMBS mutations from two unrelated Chinese AIP patients and confirmed the pathogenicity of these two mutations. We found the HMBS c.760–771+2delCTGAGGCACCTGGTinsGCTGCATCGCTGAA and HMBS c.88-1G>C mutations by second-generation sequencing and Sanger sequencing. The in vitro expression analysis showed that these mutations caused abnormal HMBS mRNA splicing and premature termination or partial missing of HMBS protein. Homologous modeling analysis showed that the HMBS mutants lacked the amino acids which are crucial for the enzyme activity or the protein stability. Consistently, enzyme activity analysis confirmed that the HMBS mutants’ overexpression cells exhibited the reduced enzyme activity compared with the HMBS wildtype overexpression cells. Our study identified and confirmed two novel pathogenic HMBS mutations which will expand the molecular heterogeneity of AIP and provide further scientific basis for the clinical diagnosis of AIP.
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13
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Bustad HJ, Kallio JP, Laitaoja M, Toska K, Kursula I, Martinez A, Jänis J. Characterization of porphobilinogen deaminase mutants reveals that arginine-173 is crucial for polypyrrole elongation mechanism. iScience 2021; 24:102152. [PMID: 33665570 PMCID: PMC7907807 DOI: 10.1016/j.isci.2021.102152] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/03/2020] [Accepted: 02/02/2021] [Indexed: 11/16/2022] Open
Abstract
Porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis, catalyzes the sequential coupling of four porphobilinogen (PBG) molecules into a heme precursor. Mutations in PBGD are associated with acute intermittent porphyria (AIP), a rare metabolic disorder. We used Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) to demonstrate that wild-type PBGD and AIP-associated mutant R167W both existed as holoenzymes (Eholo) covalently attached to the dipyrromethane cofactor, and three intermediate complexes, ES, ES2, and ES3, where S represents PBG. In contrast, only ES2 was detected in AIP-associated mutant R173W, indicating that the formation of ES3 is inhibited. The R173W crystal structure in the ES2-state revealed major rearrangements of the loops around the active site, compared to wild-type PBGD in the Eholo-state. These results contribute to elucidating the structural pathogenesis of two common AIP-associated mutations and reveal the important structural role of Arg173 in the polypyrrole elongation mechanism.
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Affiliation(s)
- Helene J Bustad
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
| | - Juha P Kallio
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
| | - Mikko Laitaoja
- Department of Chemistry, University of Eastern Finland, 80130 Joensuu, Finland
| | - Karen Toska
- Norwegian Porphyria Centre (NAPOS), Department for Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway
| | - Inari Kursula
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.,Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90570 Oulu, Finland
| | - Aurora Martinez
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
| | - Janne Jänis
- Department of Chemistry, University of Eastern Finland, 80130 Joensuu, Finland
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14
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Sato H, Sugishima M, Tsukaguchi M, Masuko T, Iijima M, Takano M, Omata Y, Hirabayashi K, Wada K, Hisaeda Y, Yamamoto K. Crystal structures of hydroxymethylbilane synthase complexed with a substrate analog: a single substrate-binding site for four consecutive condensation steps. Biochem J 2021; 478:1023-1042. [PMID: 33600566 PMCID: PMC7959689 DOI: 10.1042/bcj20200996] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 11/30/2022]
Abstract
Hydroxymethylbilane synthase (HMBS), which is involved in the heme biosynthesis pathway, has a dipyrromethane cofactor and combines four porphobilinogen (PBG) molecules to form a linear tetrapyrrole, hydroxymethylbilane. Enzyme kinetic study of human HMBS using a PBG-derivative, 2-iodoporphobilinogen (2-I-PBG), exhibited noncompetitive inhibition with the inhibition constant being 5.4 ± 0.3 µM. To elucidate the reaction mechanism of HMBS in detail, crystal structure analysis of 2-I-PBG-bound holo-HMBS and its reaction intermediate possessing two PBG molecules (ES2), and inhibitor-free ES2 was performed at 2.40, 2.31, and 1.79 Å resolution, respectively. Their overall structures are similar to that of inhibitor-free holo-HMBS, and the differences are limited near the active site. In both 2-I-PBG-bound structures, 2-I-PBG is located near the terminus of the cofactor or the tetrapyrrole chain. The propionate group of 2-I-PBG interacts with the side chain of Arg173, and its acetate group is associated with the side chains of Arg26 and Ser28. Furthermore, the aminomethyl group and pyrrole nitrogen of 2-I-PBG form hydrogen bonds with the side chains of Gln34 and Asp99, respectively. These amino acid residues form a single substrate-binding site, where each of the four PBG molecules covalently binds to the cofactor (or oligopyrrole chain) consecutively, ultimately forming a hexapyrrole chain. Molecular dynamics simulation of the ES2 intermediate suggested that the thermal fluctuation of the lid and cofactor-binding loops causes substrate recruitment and oligopyrrole chain shift needed for consecutive condensation. Finally, the hexapyrrole chain is hydrolyzed self-catalytically to produce hydroxymethylbilane.
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Affiliation(s)
- Hideaki Sato
- Department of Medical Biochemistry, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Masakazu Sugishima
- Department of Medical Biochemistry, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Mai Tsukaguchi
- Department of Medical Biochemistry, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
| | - Takahiro Masuko
- Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Mikuru Iijima
- Department of Pure and Applied Physics, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan
| | - Mitsunori Takano
- Department of Pure and Applied Physics, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan
| | - Yoshiaki Omata
- Department of Molecular Biology, Faculty of Pharmaceutical Science, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan
| | - Kei Hirabayashi
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
| | - Kei Wada
- Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
| | - Yoshio Hisaeda
- Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Ken Yamamoto
- Department of Medical Biochemistry, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
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15
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Heckl C, Eisel M, Lang A, Homann C, Paal M, Vogeser M, Rühm A, Sroka R. Spectroscopic methods to quantify molecules of the heme‐biosynthesis pathway: A review of laboratory work and point‐of‐care approaches. TRANSLATIONAL BIOPHOTONICS 2021. [DOI: 10.1002/tbio.202000026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Affiliation(s)
- Christian Heckl
- Laser‐Forschungslabor, LIFE Center, Department of Urology University Hospital, LMU Munich Munich Germany
- Department of Urology University Hospital, LMU Munich Munich Germany
| | - Maximilian Eisel
- Laser‐Forschungslabor, LIFE Center, Department of Urology University Hospital, LMU Munich Munich Germany
- Department of Urology University Hospital, LMU Munich Munich Germany
| | - Alexander Lang
- Laser‐Forschungslabor, LIFE Center, Department of Urology University Hospital, LMU Munich Munich Germany
- Department of Urology University Hospital, LMU Munich Munich Germany
| | - Christian Homann
- Laser‐Forschungslabor, LIFE Center, Department of Urology University Hospital, LMU Munich Munich Germany
- Department of Urology University Hospital, LMU Munich Munich Germany
| | - Michael Paal
- Institute of Laboratory Medicine University Hospital, LMU Munich Munich Germany
| | - Michael Vogeser
- Institute of Laboratory Medicine University Hospital, LMU Munich Munich Germany
| | - Adrian Rühm
- Laser‐Forschungslabor, LIFE Center, Department of Urology University Hospital, LMU Munich Munich Germany
- Department of Urology University Hospital, LMU Munich Munich Germany
| | - Ronald Sroka
- Laser‐Forschungslabor, LIFE Center, Department of Urology University Hospital, LMU Munich Munich Germany
- Department of Urology University Hospital, LMU Munich Munich Germany
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16
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Buendía-Martínez J, Barreda-Sánchez M, Rodríguez-Peña L, Ballesta-Martínez MJ, López-González V, Sánchez-Soler MJ, Serrano-Antón AT, Pérez-Tomás ME, Gil-Ferrer R, Avilés-Plaza F, Glover-López G, Carazo-Díaz C, Guillén-Navarro E. Health impact of acute intermittent porphyria in latent and non-recurrent attacks patients. Orphanet J Rare Dis 2021; 16:106. [PMID: 33639982 PMCID: PMC7913433 DOI: 10.1186/s13023-021-01742-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 02/11/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Acute intermittent porphyria (AIP) is a genetic disease characterized by acute neurovisceral attacks. Long-term clinical conditions, chronic symptoms and impaired health related quality of life (HRQoL) have been reported during non-attack periods but mainly in patients with recurrent attacks. Our aim was to investigate these aspects in sporadic AIP (SA-AIP) and latent AIP (L-AIP) patients. Fifty-five participants, 27 SA-AIP (< 4 attacks/year) and 28 L-AIP patients with a prevalent founder mutation from Spain were included. Medical records were reviewed, and individual interviews, physical examinations, biochemical analyses, and abdominal ultrasound scans were conducted. HRQoL was assessed through an EQ-5D-5L questionnaire. A comparative study was made between SA-AIP and L-AIP patients. RESULTS The earliest long-term clinical condition associated with SA-AIP was chronic kidney disease. Chronic symptoms were reported in 85.2 % of SA-AIP and 46.4 % of L-AIP patients. Unspecific abdominal pain, fatigue, muscle pain and insomnia were significantly more frequent in SA-AIP than in L-AIP patients. The EQ-5D-5L index was lower in SA-AIP (0.809 vs. 0.926, p = 0.0497), and the impact of "pain", "anxiety-depression" and "mobility" was more intense in the EQ-5D-5L domains in SA-AIP than in L-AIP subjects and the general Spanish population. CONCLUSIONS AIP remains a chronically symptomatic disease that adversely affects health and quality of life, even in patients with low rate of acute attacks. We suggest a regular monitoring of patients with symptomatic AIP regardless of their attack rate or the time since their last attack, with proper pain management and careful attention to kidney function.
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Affiliation(s)
- Juan Buendía-Martínez
- Servicio de Neurología, Hospital General Universitario Morales Meseguer, Av Marqués de los Vélez, s/n, 30008, Murcia, Spain. .,Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Murcia, Spain.
| | - María Barreda-Sánchez
- Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Murcia, Spain
| | - Lidya Rodríguez-Peña
- Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Ctra. Madrid-Cartagena s/n., CP 30120, El Palmar (Murcia), Spain
| | - María Juliana Ballesta-Martínez
- Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Murcia, Spain.,Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Ctra. Madrid-Cartagena s/n., CP 30120, El Palmar (Murcia), Spain.,CIBERER-ISCIII, Madrid, Spain
| | - Vanesa López-González
- Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Ctra. Madrid-Cartagena s/n., CP 30120, El Palmar (Murcia), Spain.,CIBERER-ISCIII, Madrid, Spain.,Departamento de Cirugía, Pediatría y Obstetricia y Ginecología, Facultad de Medicina, Universidad de Murcia (UMU), Murcia, Spain
| | - María José Sánchez-Soler
- Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Murcia, Spain.,Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Ctra. Madrid-Cartagena s/n., CP 30120, El Palmar (Murcia), Spain.,CIBERER-ISCIII, Madrid, Spain
| | - Ana Teresa Serrano-Antón
- Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Ctra. Madrid-Cartagena s/n., CP 30120, El Palmar (Murcia), Spain.,Departamento de Cirugía, Pediatría y Obstetricia y Ginecología, Facultad de Medicina, Universidad de Murcia (UMU), Murcia, Spain
| | - María Elena Pérez-Tomás
- Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain
| | - Remedios Gil-Ferrer
- Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Ctra. Madrid-Cartagena s/n., CP 30120, El Palmar (Murcia), Spain
| | | | - Guillermo Glover-López
- Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,CIBERER-ISCIII, Madrid, Spain.,Centro de Bioquímica y Genética Clínica, HCUVA, Murcia, Spain
| | - Carmen Carazo-Díaz
- Applied Statistical Methods in Medical Research Group, UCAM, Murcia, Spain
| | - Encarna Guillén-Navarro
- Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain. .,Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Ctra. Madrid-Cartagena s/n., CP 30120, El Palmar (Murcia), Spain. .,CIBERER-ISCIII, Madrid, Spain. .,Departamento de Cirugía, Pediatría y Obstetricia y Ginecología, Facultad de Medicina, Universidad de Murcia (UMU), Murcia, Spain.
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17
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Agarwal S, Habtemarium B, Xu Y, Simon AR, Kim JB, Robbie GJ. Normal reference ranges for urinary δ-aminolevulinic acid and porphobilinogen levels. JIMD Rep 2021; 57:85-93. [PMID: 33473344 PMCID: PMC7802627 DOI: 10.1002/jmd2.12173] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 08/12/2020] [Accepted: 09/17/2020] [Indexed: 12/30/2022] Open
Abstract
Acute hepatic porphyria (AHP) is a family of rare, serious, and potentially life-threatening metabolic disorders caused by mutations in genes encoding enzymes involved in hepatic heme biosynthesis. AHP is characterized by accumulation of neurotoxic heme intermediates, δ-aminolevulinic acid (ALA), and porphobilinogen (PBG), which are thought to be causal for the disease manifestations. Novel therapeutic treatments such as givosiran, an RNA interference therapeutic that was recently approved for treatment of adults with AHP, are focused on reducing the levels of ALA and PBG in patients toward levels observed in a healthy population. While there are two published reports on the distribution of urinary ALA and PBG levels in healthy subjects, these lacked the required details to enable the calculation of reference limits for ALA and PBG. Therefore, urinary ALA and PBG levels were quantified in 150 healthy subjects using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method that is highly sensitive, specific, accurate, and reproducible. These data were used to establish the upper limit of normal (ULN) values for ALA and PBG as 1.47 and 0.137 mmol/mol Cr, respectively. Relative to these ULN values, baseline urinary ALA and PBG levels in AHP patients were found to be 9.3- to 12-fold, and 238- to 336-fold higher, respectively. Results from this study can serve as a guide to assess the effectiveness of therapeutic interventions in lowering ALA and PBG.
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Affiliation(s)
| | | | - Yuanxin Xu
- Alnylam PharmaceuticalsCambridgeMassachusettsUSA
| | - Amy R. Simon
- Alnylam PharmaceuticalsCambridgeMassachusettsUSA
| | - Jae B. Kim
- Alnylam PharmaceuticalsCambridgeMassachusettsUSA
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18
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Ma L, Tian Y, Peng C, Zhang Y, Zhang S. Recent advances in the epidemiology and genetics of acute intermittent porphyria. Intractable Rare Dis Res 2020; 9:196-204. [PMID: 33139978 PMCID: PMC7586877 DOI: 10.5582/irdr.2020.03082] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/07/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023] Open
Abstract
Acute intermittent porphyria (AIP) is a dominant inherited disorder with a low penetrance that is caused by mutations in the gene coding for hydroxymethylbilane synthase (HMBS). Information about the epidemiology and molecular genetic features of this rare disorder is crucial to clinical research, and particularly to the evaluation of new treatments. Variations in the prevalence and penetrance of AIP in various studies may due to the different inclusion criteria and methods of assessment. Here, 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. In addition, quite a few studies have indicated that AIP susceptibility was affected by other factors, such as modifying genes. Findings regarding possible modifying genes are documented here, helping to reveal the pathogenesis of and treatments for AIP. The status of research on AIP in China reveals the lack of epidemiological and genetic studies of the Chinese population, a situation that needs to be promptly remedied.
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Affiliation(s)
- Liyan Ma
- Department of Endocrinology, The second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yu Tian
- Department of Endocrinology, The second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Chenxing Peng
- Department of Endocrinology, The second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yiran Zhang
- School of First Clinical Medical College, Southern Medical University, Guangzhou, Guangdong, China
| | - Songyun Zhang
- Department of Endocrinology, The second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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19
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Porphyric Neuropathy: Pathophysiology, Diagnosis, and Updated Management. Curr Neurol Neurosci Rep 2020; 20:56. [PMID: 33026560 DOI: 10.1007/s11910-020-01078-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2020] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW To review the peripheral neurological complications of the acute hepatic porphyrias, as well as the latest advances in their pathophysiology and management. RECENT FINDINGS The diagnosis of porphyric neuropathy remains challenging as varying neuropathic patterns are encountered depending on disease stage, including a non-length-dependent distribution pattern. The major pathophysiologic mechanism is δ-aminolevulinic acid (ALA)-induced neurotoxicity. The less restrictive blood-nerve barrier in the autonomic ganglia and myenteric plexus may explain the frequency of dysautonomic manifestations. Recently, a prophylactic small interfering RNA (siRNA)-based therapy that reduces hepatic ALA Synthase-1 mRNA was approved for patients with recurrent neuro-visceral attacks. Neurologists should appreciate the varying patterns of porphyric neuropathy. As with most toxin-induced axonopathies, long-term outcomes depend on early diagnosis and treatment. While the short-term clinical and biochemical benefits of siRNA-based therapy are known, its long-term effects on motor recovery, chronic pain, and dysautonomic manifestations are yet to be determined.
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20
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Baumann K, Kauppinen R. Penetrance and predictive value of genetic screening in acute porphyria. Mol Genet Metab 2020; 130:87-99. [PMID: 32067921 DOI: 10.1016/j.ymgme.2020.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Penetrance, predictive value and female patients' perspectives on genetic testing were evaluated among Finnish patients with acute porphyria. We conducted a retrospective study to evaluate prognosis among at-risk female family members depending on the primary method of diagnosis. METHODS The penetrance was calculated among 23 genetically heterogeneous families selected from the Finnish porphyria registry (n = 515, AIP 333; VP 182). We included kindreds with ≥9 patients in a family (range 9-23 patients, total 216 AIP; 129 VP). In 2015, the registry included 164 living female subjects between 14 and 85 years of age. A questionnaire was sent to 143 women, of whom 107 (75%, AIP 67; VP 40) replied. Female at-risk relatives (AIP 54; VP 30) were divided into two groups based on the primary method of diagnosis: mutation analysis (Group A, n = 40) or biochemical analysis (Group B, n = 44). RESULTS Mean penetrance for all acute symptoms was 35% among AIP and 40% among VP families. In both study groups, the penetrance was higher among female (AIP 50%; VP 44%) than male patients (AIP 17%; VP 33%). Penetrance for hospitalized attacks was 30% among AIP families (range 10-80%, for women 41%) and 25% in VP (range 0-50%, for women 27%) demonstrating wide variations among families even with the similar genotype. Acute porphyria was diagnosed at the median age of 26 years (range 0-76 years) among female patients, commonly after the onset of acute symptoms. Diagnostic delay was an average of 7.4 years (range 1-30 years). Acute symptoms occurred at the median age of 24 years (range 10-57 years) and the first hospitalization at the median age of 26.5 years (range 15-57 years). At the onset of symptoms, 38% of the women were ≤ 20 years of age. According to the life table analysis, acute attacks occurred mainly during the following five years after the diagnosis and the attack risk diminished after 35 years of age. The annual risk for hospitalization due to an acute attack during fertile years was lower in Group A than Group B (0.002 vs. 0.010, p = .018), but the risk of all subsequent acute symptoms did not diminish (Group A 0.017 vs. Group B 0.019, p = .640). The cumulative risk of acute symptoms among asymptomatic patients at the time of diagnosis was 26.7% for Group A and 58.3% for Group B. The cumulative risk of the first subsequent attack requiring hospitalization after the diagnosis among all at-risk relatives was similarly less frequent in Group A than in Group B (OR 0.180; 95% CI 0.041-0.789, p = .041). If attacks were followed among symptomatic patients only, attack-free years were more frequent in Group A than in Group B. Patients preferred genetic screening before puberty to minimize the risk of acute symptoms and genetic discrimination was rare. 44% of the patients reported social, psychological or physical impairment due to acute hepatic porphyria, emphasizing the importance of supporting patients' emotional and resilience capacity. CONCLUSIONS Among female at-risk relatives the annual risk for hospitalization due to an acute attack is <1% and for acute symptoms <2% during the fertile years. Genetic testing of relatives diminishes the risk of acute attacks. Diagnosis before symptom onset is key for subjects to remain asymptomatic during follow-up, and genetic screening should be done earlier than currently.
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Affiliation(s)
- K Baumann
- Helsinki University Hospital, Department of Obstetrics and Gynecology, Finland; Helsinki University Hospital, Department of Medicine, Finland
| | - R Kauppinen
- Helsinki University Hospital, Department of Medicine, Finland.
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21
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Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stölzel U, Phillips JD, Kauppinen R, Langendonk JG, Desnick RJ, Deybach J, Bonkovsky HL, Parker C, Naik H, Badminton M, Stein PE, Minder E, Windyga J, Bruha R, Cappellini MD, Sardh E, Harper P, Sandberg S, Aarsand AK, Andersen J, Alegre F, Ivanova A, Talbi N, Chan A, Querbes W, Ko J, Penz C, Liu S, Lin T, Simon A, Anderson KE. EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks. Hepatology 2020; 71:1546-1558. [PMID: 31512765 PMCID: PMC7255459 DOI: 10.1002/hep.30936] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 09/04/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS 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. APPROACH AND RESULTS EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.
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Affiliation(s)
- Laurent Gouya
- Centre de Référence Maladies Rares PorphyriesColombesFrance
- University of ParisParisFrance
- Laboratory of Excellence GR‐ExParisFrance
| | - Paolo Ventura
- Università degli Studi di Modena e Reggio EmiliaEmilia‐RomagnaItaly
| | | | | | - David C. Rees
- King’s College HospitalKing’s College LondonLondonUK
| | | | | | | | - Janneke G. Langendonk
- Porphyria CenterCenter for Lysosomal and Metabolic DiseaseDepartment of Internal MedicineErasmus MCUniversity Medical Center Rotterdamthe Netherlands
| | | | - Jean‐Charles Deybach
- Centre de Référence Maladies Rares PorphyriesColombesFrance
- University of ParisParisFrance
- Laboratory of Excellence GR‐ExParisFrance
| | - Herbert L. Bonkovsky
- Section on Gastroenterology & HepatologyWake Forest University/NC Baptist Medical CenterWinston‐SalemNC
| | | | | | | | | | | | - Jerzy Windyga
- Department of Hemostatic Disorders and Internal MedicineInstitute of Hematology and Transfusion MedicineWarsawPoland
| | - Radan Bruha
- 4th Internal ClinicGeneral University HospitalCharles UniversityPragueCzech Republic
| | | | - Eliane Sardh
- Porphyria Centre Sweden, Centre for Inherited Metabolic DiseasesKarolinska Institutet, Karolinska University HospitalStockholmSweden
| | - Pauline Harper
- Porphyria Centre Sweden, Centre for Inherited Metabolic DiseasesKarolinska Institutet, Karolinska University HospitalStockholmSweden
| | - Sverre Sandberg
- Norwegian Porphyria CentreHaukeland University HospitalBergenNorway
| | - Aasne K. Aarsand
- Norwegian Porphyria CentreHaukeland University HospitalBergenNorway
| | - Janice Andersen
- Norwegian Porphyria CentreHaukeland University HospitalBergenNorway
| | | | | | - Neila Talbi
- Centre de Référence Maladies Rares PorphyriesColombesFrance
- University of ParisParisFrance
- Laboratory of Excellence GR‐ExParisFrance
| | - Amy Chan
- Alnylam PharmaceuticalsCambridgeMA
| | | | - John Ko
- Alnylam PharmaceuticalsCambridgeMA
| | | | | | - Tim Lin
- Alnylam PharmaceuticalsCambridgeMA
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22
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Chen B, Wang M, Gan L, Zhang B, Desnick RJ, Yasuda M. Characterization of the hepatic transcriptome following phenobarbital induction in mice with AIP. Mol Genet Metab 2019; 128:382-390. [PMID: 30777612 PMCID: PMC6612539 DOI: 10.1016/j.ymgme.2018.12.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 12/03/2018] [Accepted: 12/24/2018] [Indexed: 12/12/2022]
Abstract
Acute Intermittent Porphyria (AIP), an autosomal dominant hepatic disorder, results from hydroxymethylbilane synthase (HMBS) mutations that decrease the encoded enzymatic activity, thereby predisposing patients to life-threatening acute neurovisceral attacks. The ~1% penetrance of AIP suggests that other genetic factors modulate the onset and severity of the acute attacks. Here, we characterized the hepatic transcriptomic response to phenobarbital (PB) administration in AIP mice, which mimics the biochemical attacks of AIP. At baseline, the mRNA profiles of 14,138 hepatic genes prior to treatment were remarkably similar between AIP and the congenic wild-type (WT) mice. After PB treatment (~120 mg/kg x 3d), 1347 and 1120 genes in AIP mice and 422 and 404 genes in WT mice were uniquely up- and down-regulated, respectively, at a False Discovery Rate < 0.05. As expected, the ALAS1 expression increased 4.5-fold and 15.9-fold in the WT and AIP mice, respectively. ALA-dehydrogenase also was induced ~1.7-fold in PB-induced AIP mice, but was unchanged in PB-induced WT mice. There was no statistically significant difference in the overall expression of 155 hepatic cytochrome P450 enzymes, although Cyp2c40, Cyp2c68, Cyp2c69, Mgst3 were upregulated only in PB-induced AIP mice (>1.9-fold) and Cyp21a1 was upregulated only in PB-induced WT mice (>9-fold). Notably, the genes differentially expressed in induced AIP mice were enriched in circadian rhythm, mitochondria biogenesis and electron transport, suggesting these pathways were involved in AIP mice responding to PB treatment. These results advance our understanding of the hepatic metabolic changes in PB-induced AIP mice and have implications in the pathogenesis of AIP acute attacks.
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Affiliation(s)
- Brenden Chen
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Minghui Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Lin Gan
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Robert J Desnick
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Makiko Yasuda
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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23
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Stölzel U, Doss MO, Schuppan D. Clinical Guide and Update on Porphyrias. Gastroenterology 2019; 157:365-381.e4. [PMID: 31085196 DOI: 10.1053/j.gastro.2019.04.050] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 04/07/2019] [Accepted: 04/10/2019] [Indexed: 12/24/2022]
Abstract
Physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An α-melanocyte-stimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or X-linked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development.
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Affiliation(s)
- Ulrich Stölzel
- Saxony Porphyria Center, Department of Internal Medicine II, Klinikum Chemnitz, Chemnitz, Germany
| | - Manfred O Doss
- German Competence Center for Porphyria Diagnosis and Consultation, Marburg, Germany; Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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24
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Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, Desnick R, Parker C, Phillips J, Bonkovsky HL, Vassiliou D, Penz C, Chan-Daniels A, He Q, Querbes W, Fitzgerald K, Kim JB, Garg P, Vaishnaw A, Simon AR, Anderson KE. Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria. N Engl J Med 2019; 380:549-558. [PMID: 30726693 DOI: 10.1056/nejmoa1807838] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis. METHODS We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated. RESULTS A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point). CONCLUSIONS Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372 .).
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Affiliation(s)
- Eliane Sardh
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Pauline Harper
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Manisha Balwani
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Penelope Stein
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - David Rees
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - D Montgomery Bissell
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Robert Desnick
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Charles Parker
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - John Phillips
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Herbert L Bonkovsky
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Daphne Vassiliou
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Craig Penz
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Amy Chan-Daniels
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Qiuling He
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - William Querbes
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Kevin Fitzgerald
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Jae B Kim
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Pushkal Garg
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Akshay Vaishnaw
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Amy R Simon
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
| | - Karl E Anderson
- From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
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Chen B, Solis-Villa C, Erwin AL, Balwani M, Nazrenko I, Phillips JD, Desnick RJ, Yasuda M. Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria. J Inherit Metab Dis 2019; 42:186-194. [PMID: 30740734 PMCID: PMC6162174 DOI: 10.1002/jimd.12040] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Acute intermittent porphyria (AIP), an autosomal dominant disorder due to the half-normal activity of hydroxymethylbilane synthase (HMBS), is characterized by acute neurovisceral attacks that are precipitated by factors that induce heme biosynthesis. Molecular diagnosis is the most sensitive and specific diagnostic test for AIP, and importantly, it permits the identification of asymptomatic family members for genetic counseling and avoidance of precipitating factors. Here, we report the identification of 40 novel HMBS mutations, including 11 missense, four nonsense, 16 small insertions or deletions, eight consensus splice site mutations, and a complex insertion-deletion mutation in unrelated individuals with AIP. Prokaryotic expression of the missense mutations demonstrated that all mutants had ≤5% of expressed wildtype activity, except for c.1039G>C (p.A347P), which had 51% residual HMBS activity but was markedly thermolabile. Of note, the mutation c.612G>T (p.Q204H) altered the last nucleotide of exon 10, which resulted in an alternative HMBS transcript with an in-frame nine base-pair deletion at the 3'-terminus of exon 10 (encoding protein Q204HΔ3). When expressed, Q204HΔ3 and an in-frame three base-pair deletion (c.639_641delTGC) had no detectable HMBS activity. Western blot analyses and mapping of the missense mutations on the human HMBS crystal structure revealed that mutations near the active site or at the dimerization interface resulted in stably expressed proteins, while most that altered surface residues resulted in unstable proteins, presumably due to improper protein folding. These studies identified novel pathogenic HMBS mutations and expanded the molecular heterogeneity of AIP.
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Affiliation(s)
- Brenden Chen
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Constanza Solis-Villa
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Angelika L. Erwin
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Manisha Balwani
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Irina Nazrenko
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - John D. Phillips
- Department of Internal Medicine, University of Utah, Salt Lake City, UT
| | - Robert J. Desnick
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Makiko Yasuda
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
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Validation and evaluation of two porphobilinogen deaminase activity assays for diagnosis of acute intermittent porphyria. Clin Chim Acta 2018; 479:1-6. [PMID: 29317194 DOI: 10.1016/j.cca.2018.01.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/28/2017] [Accepted: 01/06/2018] [Indexed: 11/20/2022]
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Fortgens P, Pienaar E, Corrigall A, Sonderup M, Spearman CW, Meissner P. Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants. J Clin Pathol 2016; 70:515-520. [PMID: 27849156 DOI: 10.1136/jclinpath-2016-203907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 10/20/2016] [Accepted: 10/25/2016] [Indexed: 11/04/2022]
Abstract
AIMS Acute intermittent porphyria (AIP) is a disorder of the haem biosynthetic pathway caused by mutations in the hydroxymethylbilane synthase (HMBS) gene. Knowledge of the spectrum of mutations present in South Africa is limited. This study presents the molecular profile of 20 South African patients with AIP, and the kinetic analysis of one novel expressed mutated HMBS enzyme and a previously identified mutation at the same position. METHODS Genomic DNA was isolated from affected probands and selected family members, the HMBS gene amplified and mutations characterised by direct sequencing and restriction enzyme analysis. One of the novel mutations (p.Lys98Glu), a previously characterised mutation at the same position (p.Lys98Arg), and the wild-type enzyme were expressed, purified and subjected to partial kinetic characterisation. RESULTS Four new mutations, p.Lys98Glu, p.Asp230Aspfs*20, c.161-1G>A and c.422+3_6delAAGT, are described. Seven previously described mutations were found, while four patients revealed no mutations. Mutation analysis of five offspring of one of the probands carrying the p.Trp283X mutation revealed two asymptomatic carriers. Kinetic analysis showed that the p.Lys98Glu mutation results in loss of substrate affinity, whereas the previously described p.Lys98Arg mutation causes the loss of binding between the enzyme and its dipyrromethane cofactor, rendering the enzyme inactive. CONCLUSIONS This study comprises the most comprehensive characterisation of HMBS gene mutations in patients with AIP in South Africa. The biochemical characterisation of expressed HMBS mutants reveals insight into the mechanism of catalytic activity loss, which may inspire investigation into individualised therapy based on the molecular lesion identified.
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Affiliation(s)
- Philip Fortgens
- Division of Chemical Pathology, Department of Pathology, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa
| | - Elaine Pienaar
- Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Lennox Eales Porphyria Laboratory, University of Cape Town, Observatory, South Africa
| | - Anne Corrigall
- Lennox Eales Porphyria Laboratory, University of Cape Town, Observatory, South Africa
| | - Mark Sonderup
- Division of Hepatology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa
| | - C Wendy Spearman
- Division of Hepatology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Observatory, South Africa
| | - Peter Meissner
- Department of Integrative Biomedical Sciences, Lennox Eales Porphyria Laboratory, Structural Biology Research Unit, University of Cape Town, Observatory, South Africa
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Abstract
Acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) are caused by mutations in the hydroxymethylbilane synthase (HMBS), protoporphyrinogen oxidase (PPOX), and coproporphyrinogen oxidase (CPOX) genes, respectively. This study aimed to identify mutations in seven Bulgarian families with AIP, six with VP, and one with HCP. A total of 33 subjects, both symptomatic (n = 21) and asymptomatic (n = 12), were included in this study. The identification of mutations was performed by direct sequencing of all the coding exons of the corresponding enzymes in the probands. The available relatives were screened for the possible mutations. A total of six different mutations in HMBS were detected in all seven families with AIP, three of which were previously described: c.76C>T [p.R26C] in exon 3, c.287C>T [p.S96F] in exon 7, and c.445C>T [p.R149X] in exon 9. The following three novel HMBS mutations were found: c.345-2A>C in intron 7-8, c.279-280insAT in exon 7, and c.887delC in exon 15. A total of three different novel mutations were identified in the PPOX gene in the VP families: c.441-442delCA in exon 5, c.917T>C [p.L306P] in exon 9, and c.1252T>C [p.C418R] in exon 12. A novel nonsense mutation, c.364G>T [p.E122X], in exon 1 of the CPOX gene was identified in the HCP family. This study, which identified mutations in Bulgarian families with AHP for the first time, established seven novel mutation sites. Seven latent carriers were also diagnosed and, therefore, were able to receive crucial counseling to prevent attacks.
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Sardh E, Wahlin S, Björnstedt M, Harper P, Andersson DEH. High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria. J Inherit Metab Dis 2013; 36:1063-71. [PMID: 23344888 DOI: 10.1007/s10545-012-9576-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 11/21/2012] [Accepted: 12/12/2012] [Indexed: 12/29/2022]
Abstract
BACKGROUND/AIMS Previous studies have indicated a high risk of hepatocellular carcinoma in acute hepatic porphyrias. In this retrospective study we present the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years. METHODS Twenty-three cases with primary liver cancer were found either by a surveillance program or due to clinical suspicion. Standardized rate ratio was used to estimate the relative risk of primary liver cancer after indirect standardization. Survival data were calculated using the Kaplan-Meier method. RESULTS The mean age at diagnosis was 69 years. Hepatocellular carcinoma was found in 19 patients while four patients had cholangiocarcinoma or a combination of the two. Four patients had underlying cirrhosis. Mean tumour size was 4.3 cm in the surveillance group and 10.3 cm in the non-surveillance group (p = 0.01). The overall relative risk of primary liver cancer was 86 above the age of 50: 150 for women and 37 for men. Mean survival time was 5.7 years. CONCLUSION Acute hepatic porphyria carries a high risk of primary liver cancer above the age of 50 which warrants ultrasound surveillance. Sex distribution and frequency of cirrhosis differs from more common aetiologies of primary liver cancer.
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Affiliation(s)
- Eliane Sardh
- Department of Internal Medicine, Karolinska Institutet, Stockholm South Hospital, 11883, Stockholm, Sweden,
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Marsden JT, Rees DC. Urinary excretion of porphyrins, porphobilinogen and δ-aminolaevulinic acid following an attack of acute intermittent porphyria. J Clin Pathol 2013; 67:60-5. [DOI: 10.1136/jclinpath-2012-201367] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Abstract
Porphyric neuropathy often poses a diagnostic dilemma; it is typically associated with the hepatic porphyrias, characterized by acute life-threatening attacks of neurovisceral symptoms that mimic a range of acute medical and psychiatric conditions. The development of acute neurovisceral attacks is responsive to environmental factors, including drugs, hormones, and diet. This chapter reviews the clinical manifestations, genetics, pathophysiology, and mechanisms of neurotoxicity of the acute hepatic porphyrias. While the etiology of the neurological manifestations in the acute porphyrias remains undefined, the main hypotheses include toxicity of porphyrin precursors and deficiency of heme synthesis. These hypotheses will be discussed with reference to novel experimental models of porphyric neuropathy.
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Affiliation(s)
- Cindy Shin-Yi Lin
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
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Aarsand AK, Villanger JH, Støle E, Deybach JC, Marsden J, To-Figueras J, Badminton M, Elder GH, Sandberg S. European Specialist Porphyria Laboratories: Diagnostic Strategies, Analytical Quality, Clinical Interpretation, and Reporting As Assessed by an External Quality Assurance Program. Clin Chem 2011; 57:1514-23. [DOI: 10.1373/clinchem.2011.170357] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND
The porphyrias are a group of rare metabolic disorders whose diagnosis depends on identification of specific patterns of porphyrin precursor and porphyrin accumulation in urine, blood, and feces. Diagnostic tests for porphyria are performed by specialized laboratories in many countries. Data regarding the analytical and diagnostic performance of these laboratories are scarce.
METHODS
We distributed 5 sets of multispecimen samples from different porphyria patients accompanied by clinical case histories to 18–21 European specialist porphyria laboratories/centers as part of a European Porphyria Network organized external analytical and postanalytical quality assessment (EQA) program. The laboratories stated which analyses they would normally have performed given the case histories and reported results of all porphyria-related analyses available, interpretative comments, and diagnoses.
RESULTS
Reported diagnostic strategies initially showed considerable diversity, but the number of laboratories applying adequate diagnostic strategies increased during the study period. We found an average interlaboratory CV of 50% (range 12%–152%) for analytes in absolute concentrations. Result normalization by forming ratios to the upper reference limits did not reduce this variation. Sixty-five percent of reported results were within biological variation–based analytical quality specifications. Clinical interpretation of the obtained analytical results was accurate, and most laboratories established the correct diagnosis in all distributions.
CONCLUSIONS
Based on a case-based EQA scheme, variations were apparent in analytical and diagnostic performance between European specialist porphyria laboratories. Our findings reinforce the use of EQA schemes as an essential tool to assess both analytical and diagnostic processes and thereby to improve patient care in rare diseases.
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Affiliation(s)
- Aasne K Aarsand
- Norwegian Porphyria Centre (NAPOS), Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway
| | - Jørild H Villanger
- Norwegian Porphyria Centre (NAPOS), Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway
| | - Egil Støle
- Norwegian Porphyria Centre (NAPOS), Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway
| | - Jean-Charles Deybach
- Assistance Publique-Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, Colombes CEDEX and INSERM Unité 773, Centre de Recherche Biomedicale Bichat-Beaujon, Université Paris Diderot, Paris, France
| | - Joanne Marsden
- Department of Clinical Biochemistry, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK
| | - Jordi To-Figueras
- Biochemistry and Molecular Genetics Unit, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Mike Badminton
- Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Heath Park, Cardiff, UK
| | - George H Elder
- Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Heath Park, Cardiff, UK
| | - Sverre Sandberg
- Norwegian Porphyria Centre (NAPOS), Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway
- Norwegian Quality Improvement of Primary Care Laboratories (NOKLUS), Section for General Practice, University of Bergen, Bergen, Norway
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Lin CSY, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol 2011; 122:2336-44. [PMID: 21855406 DOI: 10.1016/j.clinph.2011.07.036] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 07/07/2011] [Accepted: 07/08/2011] [Indexed: 10/15/2022]
Abstract
The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features. Definitive diagnosis often encompasses a combination of biochemical, enzyme analysis and genetic testing, with clinical neurophysiological findings of a predominantly motor axonal neuropathy. Symptomatic and supportive treatment are the mainstays during an acute attack. If administered early, intravenous haemin may prevent progression of neuropathy. While the pathophysiology of AIP neuropathy remains unclear, axonal dysfunction appears intrinsically linked to the effects of neural energy deficits acquired through haem deficiency coupled to the neurotoxic effects of porphyrin precursors. The present review will provide an overview of AIP neuropathy, including discussion of recent advances in understanding developed through neurophysiological approaches that have further delineated the pathophysiology of axonal degeneration.
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Affiliation(s)
- Cindy S-Y Lin
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
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Tollånes MC, Aarsand AK, Sandberg S. Excess risk of adverse pregnancy outcomes in women with porphyria: a population-based cohort study. J Inherit Metab Dis 2011; 34:217-23. [PMID: 20978938 PMCID: PMC3026662 DOI: 10.1007/s10545-010-9231-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 10/01/2010] [Accepted: 10/07/2010] [Indexed: 12/19/2022]
Abstract
The porphyrias comprise a heterogeneous group of rare, primarily hereditary, metabolic diseases caused by a partial deficiency in one of the eight enzymes involved in the heme biosynthesis. Our aim was to assess whether acute or cutaneous porphyria has been associated with excess risks of adverse pregnancy outcomes. A population-based cohort study was designed by record linkage between the Norwegian Porphyria Register, covering 70% of all known porphyria patients in Norway, and the Medical Birth Registry of Norway, based on all births in Norway during 1967-2006. The risks of the adverse pregnancy outcomes preeclampsia, delivery by caesarean section, low birth weight, premature delivery, small for gestational age (SGA), perinatal death, and congenital malformations were compared between porphyric mothers and the rest of the population. The 200 mothers with porphyria had 398 singletons during the study period, whereas the 1,100,391 mothers without porphyria had 2,275,317 singletons. First-time mothers with active acute porphyria had an excess risk of perinatal death [adjusted odds ratio (OR) 4.9, 95% confidence interval (CI) 1.5-16.0], as did mothers with the hereditable form of porphyria cutanea tarda (PCT) (3.0, 1.2-7.7). Sporadic PCT was associated with an excess risk of SGA [adjusted relative risk (RR) 2.0, 1.2-3.4], and for first-time mothers, low birth weight (adjusted OR 3.4, 1.2-10.0) and premature delivery (3.5, 1.2-10.5) in addition. The findings suggest women with porphyria should be monitored closely during pregnancy.
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Affiliation(s)
- Mette Christophersen Tollånes
- The Norwegian Porphyria Centre (NAPOS), Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.
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Surin VL, Luchinina YA, Selivanova DS, Pustovoit YS, Karpova IV, Pivnik AV, Luk’ianenko AV, Kravchenko SK. Molecular genetic study of acute intermittent porphyria in Russia: Mutation analysis and functional polymorphism search in porphobilinogen deaminase gene. RUSS J GENET+ 2010. [DOI: 10.1134/s1022795410040149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Abstract
Hereditary porphyrias are a group of eight metabolic disorders of the haem biosynthesis pathway that are characterised by acute neurovisceral symptoms, skin lesions, or both. Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors. Seven porphyrias are the result of a partial enzyme deficiency, and a gain of function mechanism has been characterised in a new porphyria. Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic haemolysis or chronic neurological symptoms with or without photosensitivity. Porphyrias are still underdiagnosed, but when they are suspected, and dependent on clinical presentation, simple first-line tests can be used to establish the diagnosis in all symptomatic patients. Diagnosis is essential to enable specific treatments to be started as soon as possible. Screening of families to identify presymptomatic carriers is crucial to decrease risk of overt disease of acute porphyrias through counselling about avoidance of potential precipitants.
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Affiliation(s)
- Hervé Puy
- Assistance Publique Hôpitaux de Paris, Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France
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Clavero S, Bishop DF, Haskins ME, Giger U, Kauppinen R, Desnick RJ. Feline acute intermittent porphyria: a phenocopy masquerading as an erythropoietic porphyria due to dominant and recessive hydroxymethylbilane synthase mutations. Hum Mol Genet 2009; 19:584-96. [PMID: 19934113 DOI: 10.1093/hmg/ddp525] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Human acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is an autosomal dominant inborn error of heme biosynthesis due to the half-normal activity of hydroxymethylbilane synthase (HMB-synthase). Here, we describe the first naturally occurring animal model of AIP in four unrelated cat lines who presented phenotypically as congenital erythropoietic porphyria (CEP). Affected cats had erythrodontia, brownish urine, fluorescent bones, and markedly elevated urinary uroporphyrin (URO) and coproporphyrin (COPRO) consistent with CEP. However, their uroporphyrinogen-III-synthase (URO-synthase) activities (deficient in CEP) were normal. Notably, affected cats had half-normal HMB-synthase activities and elevated urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), the deficient enzyme and accumulated metabolites in human AIP. Sequencing the feline HMB-synthase gene revealed different mutations in each line: a duplication (c.189dupT), an in-frame 3 bp deletion (c.842_844delGAG) identical to that causing human AIP and two missense mutations, c.250G>A (p.A84T) and c.445C>T (p.R149W). Prokaryotic expression of mutations c.842_844delGAG and c.445C>T resulted in mutant enzymes with <1% wild-type activity, whereas c.250G>A expressed a stable enzyme with approximately 35% of wild-type activity. The discolored teeth from the affected cats contained markedly elevated URO I and III, accounting for the CEP-like phenocopy. In three lines, the phenotype was an autosomal dominant trait, while affected cats with the c.250G>A (p.A84T) mutation were homozygous, a unique recessive form of AIP. These animal models may permit further investigation of the pathogenesis of the acute, life-threatening neurological attacks in human AIP and the evaluation of therapeutic strategies. GenBank Accession Numbers: GQ850461-GQ850464.
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Affiliation(s)
- Sonia Clavero
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029-6574, USA
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Bylesjö I, Wikberg A, Andersson C. Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. Scandinavian Journal of Clinical and Laboratory Investigation 2009; 69:612-8. [PMID: 19401933 DOI: 10.1080/00365510902935979] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The objective of this study was to update the clinical issues of acute intermittent porphyria (AIP), as they have not been in focus for years, and to be aware of potentially associated disorders and social consequences. A total of 356 gene carriers of AIP from northern Sweden participated in this retrospective population-based study. Eight mutations were found with a predominance of W198X (89%). Clinical manifestations of AIP (manifest AIP) were identified in 42%, 65% were women. Women were more severely stricken by AIP attacks concerning number and duration, hospital admission and early onset. Men reporting most attacks were > 40 years of age. In addition to traditional symptoms during attacks, fatigue was commonly described. Chronic AIP symptoms and disability pension due to AIP were reported in about 20% of subjects. Precipitating factors were reported with evident sex differences. Half of the gene carriers who were on medications used drugs considered not safe (in 1999), mainly antihypertensive drugs. Smoking was associated with high AIP attack frequency. Elevated levels of ALT, bile acids, creatinine, U-ALA and U-PBG and decreased levels of creatinine clearance were associated with manifest AIP. The same was true for hypertension and myalgia in the legs. Hepatoma was strikingly overrepresented. The high prevalence of manifest AIP in this study could be explained by a mutation-dependent penetrance. Our results emphasize the importance of early diagnosis, counselling and treatment of attacks, screening and treatment of associated disorders.
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Affiliation(s)
- Ingemar Bylesjö
- Department of Family Medicine, University of Umeå, Umeå, Sweden.
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Ventura P, Cappellini MD, Rocchi E. The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine. Intern Emerg Med 2009; 4:297-308. [PMID: 19479318 DOI: 10.1007/s11739-009-0261-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2009] [Accepted: 04/29/2009] [Indexed: 10/20/2022]
Abstract
The porphyrias are a heterogeneous group of metabolic diseases resulting from a variable catalytic defect of one of the eight enzymes involved in the heme biosynthesis pathway; they are mostly inherited diseases, but in some circumstances the metabolic disturbance may be acquired. The specific patterns of tissue overproduction (and hence accumulation and excretion) of toxic heme precursors, associated with each enzymatic deficiency, are responsible for the characteristic biochemical and clinical features of each of these diseases. Moreover, even in the presence of a specific inherited enzymatic defect, many different environmental factors (such as drugs, calorie restriction, hormones, sunlight exposition, infections, etc.) often play a key role in triggering the clinical expression of the various forms of porphyrias. The porphyrias are often misdiagnosed diseases, due their multiform clinical manifestations, able to mimic many other more common diseases. For this reason, many different specialists, such as surgeons, psychiatrists, gastroenterologists, neurologists, emergency physicians and dermatologists may be variably involved in the diagnostic process, especially for the forms presenting with acute and life-threatening clinical features. According to the clinical features, the porphyrias can be classified into neuropsychiatric (characterized by neurovisceral crises involving autonomic and central nervous system but also the liver and the kidney with possible consequences in terms of neurological, psychic, cardiac, respiratory, liver and kidney functions), dermatological (mostly presenting with cutaneous lesions due to photosensitivity), and mixed forms. From a strictly clinical point of view, porphyrias presenting with neurovisceral attacks are also referred as acute porphyrias: they are the object of the present review. An accurate diagnosis of acute porphyria requires knowledge and the use of correct diagnostic tools, and it is mandatory to provide a more appropriate therapeutic approach and prevent the use of potentially unsafe drugs, able to severely precipitate these diseases, especially in the presence of life-threatening symptoms. To date, availability of a relatively stable haem preparation (haem arginate) has significantly improved the treatment outcome of acute porphyric attacks, so the knowledge about the diagnosis and the management of these diseases may be relevant for physicians working in internal medicine, neurology and emergency units.
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Affiliation(s)
- Paolo Ventura
- Department of Medicines and Medical Specialties, Ambulatorio delle Porfirie e delle Malattie da Disturbo del Metabolismo degli Aminoacidi, University of Modena and Reggio Emilia, Policlinico of Modena, Largo del Pozzo 71, Modena, Italy.
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Pfäfflin A. Remarks on the acute intermittent porphyria. Ann Clin Biochem 2009; 46:347-8; author reply 348. [DOI: 10.1258/acb.2009.009069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Albrecht Pfäfflin
- Department of Internal Medicine IV, Clinical Chemistry Unit, University Hospital of Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany
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Aarsand AK, Boman H, Sandberg S. Familial and Sporadic Porphyria Cutanea Tarda: Characterization and Diagnostic Strategies. Clin Chem 2009; 55:795-803. [DOI: 10.1373/clinchem.2008.117432] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Abstract
Background: Porphyria cutanea tarda (PCT) occurs in sporadic (sPCT) and familial (fPCT) forms, which are generally clinically indistinguishable and have traditionally been differentiated by erythrocyte uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) activity. We used UROD gene sequencing as the reference standard in assessing the diagnostic accuracy of UROD activity, evaluating the mutation spectrum of the UROD gene, determining the frequency and disease attributes of PCT and its subtypes in Norway, and developing diagnostic models that use clinical and laboratory characteristics for differentiating fPCT and sPCT.
Methods: All consecutive patients with PCT diagnosed within a 6-year period were used for incidence calculations. UROD activity analysis, UROD gene sequencing, analysis of hemochromatosis mutations, and registration of clinical and laboratory data were carried out for 253 patients.
Results: Fifty-three percent of the patients had disease-relevant mutations, 74% of which were c.578G>C or c.636+1G>C. The UROD activity at the optimal cutoff had a likelihood ratio (LR) of 9.2 for fPCT, whereas a positive family history had an LR of 19. A logistic regression model indicated that low UROD activity, a high uroporphyrin-heptaporphyrin ratio, a young age at diagnosis, male sex, and low alcohol consumption were predictors of fPCT. The incidence of PCT was 1 in 100 000.
Conclusions: Two commonly occurring mutations are responsible for the high frequency of fPCT in Norway. UROD activity has a high diagnostic accuracy for differentiating the 2 PCT types, and a model that takes into account both clinical information and laboratory test results can be used to predict fPCT.
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Affiliation(s)
- Aasne K Aarsand
- Norwegian Porphyria Centre (NAPOS), Laboratory of Clinical Biochemistry; and
| | - Helge Boman
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
- Section of Medical Genetics and Molecular Medicine, Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Sverre Sandberg
- Norwegian Porphyria Centre (NAPOS), Laboratory of Clinical Biochemistry; and
- Norwegian Quality Improvement of Primary Care Laboratories (NOKLUS), Section for General Practice, University of Bergen, Bergen, Norway
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Sardh E, Harper P, Andersson DEH, Floderus Y. Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks. Eur J Intern Med 2009; 20:201-7. [PMID: 19327613 DOI: 10.1016/j.ejim.2008.06.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Revised: 05/08/2008] [Accepted: 06/09/2008] [Indexed: 11/23/2022]
Abstract
BACKGROUND Acute intermittent porphyria (AIP) is a metabolic disease affecting hepatic heme biosynthesis. The clinical course in overt disease is characterized by acute attacks of neurovisceral symptoms. Treatment is based on symptomatic relief together with carbohydrate loading and in more severe attacks heme therapy. During an acute attack the heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) are produced in high amounts by the liver and are found in high concentrations in plasma and urine. These metabolites represent the acute phase reactants confirming an ongoing attack and are used to evaluate therapeutic measures. The aim of this study was to measure PBG and ALA in plasma and urine during an acute attack and to match the biochemical pattern with the clinical and therapeutical course. METHODS Three consecutive AIP patients were included during four acute attacks. Plasma PBG and ALA were measured by a LC-MS method and in urine by ion-exchange chromatography. The patients received symptomatic and glucose treatment at admission to hospital, and four days later, if necessary, heme therapy. RESULTS In the three attacks that required heme therapy, plasma PBG concentrations had further increased after admission (p=0.01). In the patient that did not require heme therapy, plasma PBG had decreased after admission. CONCLUSIONS Biochemical monitoring of an acute attack was more accurately reflected by plasma PBG than plasma ALA or urinary PBG and ALA. Glucose administration, in contrast to heme therapy, was not sufficient to achieve clinical and biochemical remission in the more serious attacks.
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Affiliation(s)
- Eliane Sardh
- Department of Internal Medicine, Karolinska Institutet, Stockholm Söder Hospital, Sweden.
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Elder GH, Sandberg S. Identifying acute porphyria in patients with acute polyneuropathy or encephalopathy. ACTA ACUST UNITED AC 2008; 4:648-9. [DOI: 10.1038/ncpneuro0946] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2008] [Accepted: 10/01/2008] [Indexed: 11/09/2022]
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Yang CC, Kuo HC, You HL, Wang J, Huang CC, Liu CY, Lan MY, Stephenson DA, Lee MJ. HMBSMutations in Chinese Patients with Acute Intermittent Porphyria. Ann Hum Genet 2008; 72:683-6. [DOI: 10.1111/j.1469-1809.2008.00463.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Schneider-Yin X, Ulbrichova D, Mamet R, Martasek P, Marohnic CC, Goren A, Minder EI, Schoenfeld N. Characterization of two missense variants in the hydroxymethylbilane synthase gene in the Israeli population, which differ in their associations with acute intermittent porphyria. Mol Genet Metab 2008; 94:343-6. [PMID: 18406650 DOI: 10.1016/j.ymgme.2008.03.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2008] [Accepted: 03/06/2008] [Indexed: 10/22/2022]
Abstract
Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis caused by molecular defects in the hydroxymethylbilane synthase (HMBS) gene. In this study, we report two novel missense sequence variations in the HMBS gene, T59I (C176T) and V215M (G643A), in two patients with clinical symptoms compatible with acute attacks of porphyria. However, only the patient who carried V215M presented with full AIP-affirming biochemical evidence. Both variant proteins were expressed in a prokaryotic system and characterized in vitro. Recombinant T59I and V215M had residual activity of 80.6% and 19.4%, respectively, of that of the wild type enzyme. Moreover, changes in K(m), V(max) and thermostability observed in the recombinant V215M suggest a causal relationship between V215M and AIP. The association between the T59I substitution and AIP is less obvious. Based on our investigation, substitution T59I is more likely to be a mutation with a weak effect than a rare form of polymorphism. This study demonstrates that in vitro characterization of missense variations in the HMBS gene can provide valuable information for the interpretation of clinical, biochemical and genetic data, for establishing a diagnosis of AIP. It also highlights the fact that there are still many aspects to be investigated concerning AIP and corroborates the need to report new data that can help to clarify the genotype-phenotype relationship.
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Pischik E, Kazakov V, Kauppinen R. Is screening for urinary porphobilinogen useful among patients with acute polyneuropathy or encephalopathy? J Neurol 2008; 255:974-9. [PMID: 18574620 DOI: 10.1007/s00415-008-0779-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2007] [Revised: 10/02/2007] [Accepted: 10/16/2007] [Indexed: 11/30/2022]
Abstract
Acute porphyrias are a group of inherited metabolic disorders representing overproduction syndromes with the formation of neurotoxic haem precursors. Clinical manifestations consist of acute attacks, which include abdominal pain, dysautonomia, mental symptoms, polyneuropathy and seizures mimicking many other acute neurological disorders.Porphyrin metabolites were screened in 108 patients with acute polyneuropathy or encephalopathy associated with pain and/or dysautonomia, who attended neurological wards, in order to evaluate the number of patients with acute porphyria.Urinary porphyrins and their precursors were increased in 21% of the cases. Surprisingly many patients (11%) had previously undiagnosed acute porphyria. Half of these patients had had mild to moderate symptoms of acute porphyria previously. Secondary porphyrinuria, which was mainly transient coproporphyrinuria because of hepatopathy, was also common (10%). Of the 108 patients studied, the levels of urinary porphyrins or their precursors were normal in the majority (79%) of the cases, who commonly had Guillain-Barré syndrome (40%). Epileptic seizures were also frequent (18%), but none of the patients with acute porphyria had solely epileptic seizures without prolonged confusion (>or= 1 day).Based on our findings, acute inherited porphyria is not infrequent among the selected group of neurological patients and screening of urinary PBG is cost-beneficial. Since the correct diagnosis of a hereditary disease is essential, genetic screening should be performed whenever possible for patients with clinically and biochemically confirmed acute porphyria.
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Affiliation(s)
- Elena Pischik
- Research Program in Molecular Medicine, Porphyria Research Centre, Biomedicum-Helsinki, C427a, University of Helsinki, 700, Haartmaninkatu 8, 00029 HUS Helsinki, Finland.
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Raigal Martín MY, Lledó Navarro JL, Raigal Martín JM, Muriel Patino E, Pérez Pérez E, Moreno Prat M. [Acute intermittent porphyria and chronic transaminase elevation]. GASTROENTEROLOGIA Y HEPATOLOGIA 2008; 31:225-8. [PMID: 18405488 DOI: 10.1157/13117900] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Acute intermittent porphyria is an autosomal dominant inherited disorder resulting from a deficiency of porphobilinogen deaminase activity, the third enzyme in the heme biosynthesis pathway. This disease is uncommon, although the prevalence is higher in asymptomatic heterozygotic carriers; however, this prevalence is difficult to establish because of the absence of symptoms. Although acute intermittent porphyria is a multisystemic disease, its most common form of presentation is abdominal pain and neurological or mental symptoms, which can sometimes be due to precipitating factors such as reduced energy intake, smoking, alcohol, some drugs, and stress. Diagnosis can be made by testing urinary porphobilinogen levels, with subsequent measurement of enzyme activity and DNA testing. Treatment is based on prevention of porphyria attacks by avoiding precipitating factors and early administration of intravenous glucose or hemin therapy. We present the case of a patient diagnosed with acute intermittent porphyria based on study of chronic mild alanine aminotransferase (ALT) elevation.
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Hsieh CH, Tsai HH, Lu TH, Chen YC, Hsieh MW, Chuang YC. Acute intermittent porphyria with peripheral neuropathy complicated by small-fiber neuropathy. Neuropathology 2007; 27:133-8. [PMID: 17494514 DOI: 10.1111/j.1440-1789.2006.00751.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We describe a 60-year-old male patient with acute intermittent porphyria (AIP) who presented with initial abdominal pain and subsequent quadriplegia and respiratory failure. Small fiber neuropathy was demonstrated by measuring intra-epidermal nerve fiber density (IENFD) using protein gene product 9.5 (PGP 9.5) immunostaining on three consecutive skin punch biopsies of the distal lower limb. The biopsy findings demonstrated some correlation with progression of the patient's clinical condition. Neuropathy in AIP can have a small-fiber component rather than being solely a large-fiber neuropathy.
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Affiliation(s)
- Ching-Hua Hsieh
- Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan
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Bosworth BP, Landzberg BR. Neurological Manifestations of Gastrointestinal and Hepatic Diseases. Neurobiol Dis 2007. [DOI: 10.1016/b978-012088592-3/50065-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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