Dersimelagon in Erythropoietic Protoporphyrias.

Background: Erythropoietic protoporphyria and X-linked protoporphyria are inborn errors of heme biosynthesis that cause elevated circulating levels of metal-free protoporphyrin and phototoxicity. Both disorders are characterized by excruciating phototoxic attacks after exposure to visible light. Dersimelagon is a new, orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin.

A pilot study of oral iron therapy in erythropoietic protoporphyria and X-linked protoporphyria.

The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study.

Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium.

Background And Aims: The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States.

Approach And Results: This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP.

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

Background: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.

Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.

Altered structural brain network topology in chronic migraine.

Despite its prevalence and high disease burden, the pathophysiological mechanisms underlying chronic migraine (CM) are not well understood. As CM is a complex disorder associated with a range of sensory, cognitive, and affective comorbidities, examining structural network disruption may provide additional insights into CM symptomology beyond studies of focal brain regions. Here, we compared structural interconnections in patients with CM (n = 52) and healthy controls (HC) (n = 48) using MRI measures of cortical thickness and subcortical volume combined with graph theoretical network analyses.

Evaluating quality of life tools in North American patients with erythropoietic protoporphyria and X-linked protoporphyria.

Background: Erythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare photodermatoses presenting with severe phototoxicity. Although anecdotally, providers who treat EPP patients acknowledge their life-altering effects, tools that fully capture their impact on quality of life (QoL) are lacking.

Methods: Adult patients with EPP/XLP were given four validated QoL tools: the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), the Hospital Anxiety and Depression Scale (HADS), the Illness Perception Questionnaire Revised (IPQR), and an EPP-Specific tool.

Evaluating the Patient-Reported Outcomes Measurement Information System scales in acute intermittent porphyria.

Purpose: Acute intermittent porphyria (AIP) is a rare inborn error of heme biosynthesis characterized by life-threatening acute attacks. Few studies have assessed quality of life (QoL) in AIP and those that have had small sample sizes and used tools that may not have captured important domains.

Methods: Baseline data from the Porphyrias Consortium's Longitudinal Study were obtained for 259 patients, including detailed disease and medical history data, and the following Patient-Reported Outcomes Measurement Information System (PROMIS) scales: anxiety, depression, pain interference, fatigue, sleep disturbance, physical function, and satisfaction with social roles.

Injustice Appraisal, but not Pain Catastrophizing, Mediates the Relationship Between Perceived Ethnic Discrimination and Depression and Disability in Low Back Pain.

Despite growing evidence of significant racial disparities in the experience and treatment of chronic pain, the mechanisms by which these disparities manifest have remained relatively understudied. The current study examined the relationship between past experiences of racial discrimination and pain-related outcomes (self-rated disability and depressive symptomatology) and tested the potential mediating roles of pain catastrophizing and perceived injustice related to pain. Analyses consisted of cross-sectional path modeling in a multiracial sample of 137 individuals with chronic low back pain (Hispanics: n = 43; blacks: n = 43; whites: n = 51).

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

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.

International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias.

With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs with biochemically and clinically verified information.

Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria.

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.

Mobile work, multilocal dwelling and spaces of wellbeing.

Mobile work is increasingly common. For our purposes, mobile work entails long-distance commuting arrangements with periods living away from the primary domestic residence that may be considered 'home'. Mobile work reconfigures the relational fabric of 'home', introducing multilocal mooring points into worker's lives, and thus reshaping the spatial and temporal patterns and meanings of dwelling.

An 18-Year-Old With Acute-on-Chronic Abdominal Pain.

An 18-year-old woman with a complex past medical history presented with 2 days of vomiting and lower abdominal pain. She had been admitted for the majority of the previous 5 months for recurrent pancreatitis and had undergone a cholecystectomy. Additional symptoms included nausea, anorexia, constipation, and a 40-lb weight loss over 4 months.

Perceived injustice in chronic pain: an examination through the lens of predictive processing.

Chronic pain conditions have been shown to be exacerbated by psychological factors, and a better understanding of these factors can inform clinical practice and improve the efficacy of interventions. The current paper investigates perceived injustice, a novel psychosocial construct, within a framework influenced by the tenets of predictive processing. The proposed conceptual model derived from tenets of predictive processing yields a single hierarchical self-reconfiguring system driven by prediction, which accounts for a wide range of human experiences such as perception, behavior, learning and emotion.

Clinical, Biochemical, and Genetic Characterization of North American Patients With Erythropoietic Protoporphyria and X-linked Protoporphyria.

Importance: Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.

Objective: To describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP.

Acute hepatic porphyrias: Recommendations for evaluation and long-term management.

The acute hepatic porphyrias are a group of four inherited disorders, each resulting from a deficiency in the activity of a specific enzyme in the heme biosynthetic pathway. These disorders present clinically with acute neurovisceral symptoms which may be sporadic or recurrent and, when severe, can be life-threatening. The diagnosis is often missed or delayed as the clinical features resemble other more common medical conditions.

Pitfalls in Erythrocyte Protoporphyrin Measurement for Diagnosis and Monitoring of Protoporphyrias.

Background: Laboratory diagnosis of erythropoietic protoporphyria (EPP) requires a marked increase in total erythrocyte protoporphyrin (300-5000 μg/dL erythrocytes, reference interval <80 μg/dL) and a predominance (85%-100%) of metal-free protoporphyrin [normal, mostly zinc protoporphyrin (reference intervals for the zinc protoporphyrin proportion have not been established)]; plasma porphyrins are not always increased. X-linked protoporphyria (XLP) causes a similar increase in total erythrocyte protoporphyrin with a lower fraction of metal-free protoporphyrin (50%-85% of the total).

Content: In studying more than 180 patients with EPP and XLP, the Porphyrias Consortium found that erythrocyte protoporphyrin concentrations for some patients were much higher (4.

Acute Hepatic Porphyria.

The porphyrias comprise a set of diseases, each representing an individual defect in one of the eight enzymes mediating the pathway of heme synthesis. The diseases are genetically distinct but have in common the overproduction of heme precursors. In the case of the acute (neurologic) porphyrias, the cause of symptoms appears to be overproduction of a neurotoxic precursor.

Role of delta-aminolevulinic acid in the symptoms of acute porphyria.

Background: Attacks of neuropathic pain, usually abdominal, are characteristic of the acute porphyrias and accompanied by overproduction of heme-precursor molecules, specifically delta-aminolevulinic acid and porphobilinogen. The basis for the acute symptoms in these diseases has been speculative.

Methods: We review genetic acute porphyria, hereditary tyrosinemia, and an acquired condition, lead poisoning.