Recent advances in the epidemiology and genetics of acute intermittent porphyria

Ma, Li-na; Tian, Yu; Peng, Chenxing; Zhang, Yiran; Zhang, Songyun

doi:10.5582/irdr.2020.03082

Cited by 15 publications

(32 citation statements)

References 119 publications

(107 reference statements)

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“… 5 There are also reported instances of cardiac arrhythmias, electrolyte abnormalities (secondary to SIADH), hypertension, hyperthyroidism, and bladder dysfunction (such as urine retention with urgency to void). 5 , 9 As noted in our patient, SIADH is a common presentation in approximately 25% to 60% of patients, and intriguingly, the degree of hyponatremia can indicate the gravity of the AIP exacerbation. 5 …”

Section: Discussionsupporting

confidence: 54%

A Perfect Storm: Abdominal Pain and Ileus Explained by Acute Intermittent Porphyria Caused by Prehospitalization and Intrahospitalization Factors

Ortega

Cherukuri

Kalas

et al. 2022

Journal of Investigative Medicine High Impact Case Reports

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Acute intermittent porphyria (AIP) is a rare autosomal dominant inherited disease, predominantly seen in female patients, caused by mutations in the hydroxymethylbilane synthase gene. When impaired, elevated heme biosynthesis precursor levels accumulate in the liver, resulting in neurological symptoms, psychiatric disturbances, darkened urine color, abdominal pain, nausea, vomiting, and ileus. We present a 22-year-old Hispanic female with diffuse abdominal pain and no bowel movements for 8 days. She reported recent antibiotic and oral contraceptive pill use. Computerized tomography of her abdomen revealed a dilated small bowel and marked colonic distension. A colonoscopy found mild nonspecific inflammation in the rectosigmoid and terminal ileum. Her abdominal pain persisted despite interventions and improvements in appetite, bowel movements, abdominal imaging, and treatment of an identified Clostridium difficile infection. A random urine porphobilinogen was then obtained and found to be elevated. Fractionation of plasma and urine porphyrins was suggestive of AIP. Her symptoms improved with 3 days of intravenous (IV) hematin and IV dextrose. This is a unique case of a rare disease due to her clinical presentation with ileus, unremarkable past medical history, family history, and the prehospitalization and intrahospitalization factors that likely exacerbated the patient AIP.

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Section: Discussionsupporting

confidence: 54%

A Perfect Storm: Abdominal Pain and Ileus Explained by Acute Intermittent Porphyria Caused by Prehospitalization and Intrahospitalization Factors

Ortega

Cherukuri

Kalas

et al. 2022

Journal of Investigative Medicine High Impact Case Reports

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“…Regarding the 400 mutations in the HMBS gene, there are 31 CpG dinucleotides in the 1086 base-pair coding sequence that are considered mutable as a consequence of the oxidative deamination of methylated cytosines [21,22]. Although AIP is a low-penetrance disorder, it has been identified that few HMBS mutations are relatively common, such as the p.R173W and p.R167Q variants, caused by CpG methylation, and the p.G111R and p.W198X variants, which are most frequent in Argentina and Sweden due to the founder effect [23][24][25].…”

Section: The Link Between Penetrance Prevalence and Genetic Traits In...mentioning

confidence: 99%

Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution

et al. 2022

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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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“…HMBS encodes an enzyme from the heme biosynthetic pathway, and mutations are associated with acute intermittent porphyria 45 and leukoencephalopathy, for which anomalies in the thalamus and cerebral white matter can be identified with MRI 46 . This gene was not found to be associated with any T2* IDPs.…”

Section: Iron Transport and Homeostasismentioning

confidence: 99%

“…HMBS encodes an enzyme from the heme biosynthetic pathway. HMBS mutations are associated with acute intermittent porphyria 48 and leukoencephalopathy, which exhibit MRI anomalies in thalamus and cerebral white matter 49 .…”

Section: Iron Transport and Homeostasismentioning

confidence: 99%

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

Wang

Martins-Bach

Alfaro-Almagro

et al. 2021

Preprint

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A key aim of epidemiological neuroscience studies is the identification of novel markers to assess brain health and evaluate the efficacy of therapeutic interventions. A broad range of tissue constituents associated with healthy brain functions and diseases (e.g., iron, myelin and calcium) are characterised by unique magnetic properties, motivating the development of measurements sensitive to these effects. Quantitative susceptibility mapping (QSM) is an emerging MRI technique which enables in vivo quantification of tissue magnetic susceptibility, providing the opportunity to identify such markers. In this study, we developed a robust QSM modelling pipeline and evaluated the potential of QSM in a cohort of 35,885 subjects (ages 45-82), alongside extensive genetic and phenotypic associations as part of UK Biobank. Our analysis identified a rich set of distinctive phenotypic and genetic associations with QSM. This included phenotypic associations with body iron, diet, alcohol and diseases, and genetic associations related to a broad range of biological functions including iron, calcium homeostasis, myelination, extracellular matrix. Importantly, we found that QSM and T2* have unique patterns of associations, demonstrating the added value in including QSM IDPs in the UK Biobank brain imaging resource, with considerable promise to identify novel in vivo brain health markers.

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Recent advances in the epidemiology and genetics of acute intermittent porphyria

Cited by 15 publications

References 119 publications

A Perfect Storm: Abdominal Pain and Ileus Explained by Acute Intermittent Porphyria Caused by Prehospitalization and Intrahospitalization Factors

A Perfect Storm: Abdominal Pain and Ileus Explained by Acute Intermittent Porphyria Caused by Prehospitalization and Intrahospitalization Factors

Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

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