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Hematology, Transfusion and Cell Therapy Apr 2024
PubMed: 38719715
DOI: 10.1016/j.htct.2024.02.027 -
Cureus Mar 2022Erythropoietic protoporphyria is a rare skin condition that commonly presents in childhood. We report a case of a 35-year-old Hispanic male with a history of sun...
Erythropoietic protoporphyria is a rare skin condition that commonly presents in childhood. We report a case of a 35-year-old Hispanic male with a history of sun sensitivity, presenting with complaints of immediate burning and itching of the skin on his face and upper extremities upon sun exposure. On examination, there was minimal face erythema and calluses over the knuckles. Laboratory workup demonstrated substantially increased protoporphyrin (over 10 times the upper limit of normal) along with elevated liver enzyme levels. Liver biopsy confirmed stage 4 cirrhosis. Our patient's cutaneous manifestations were the primary complaint that led to the diagnosis of his terminal hepatic illness. We recommend screening for erythropoietic protoporphyria in patients who present with a life-long history of non-blistering, burning and itching of the skin, which begins immediately upon sun exposure.
PubMed: 35449677
DOI: 10.7759/cureus.23253 -
Photodiagnosis and Photodynamic Therapy Mar 2023Patients with erythropoietic protoporphyria (EPP) are hypersensitive to long wave ultraviolet (UVA) radiation and visible light and they experience severe skin pain by... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with erythropoietic protoporphyria (EPP) are hypersensitive to long wave ultraviolet (UVA) radiation and visible light and they experience severe skin pain by light exposure. The patients have very limited treatment options. Sunless skin tanning with dihydroxyacetone (DHA) is now being investigated as a possible treatment modality of skin photosensitivity in EPP.
METHODS
We simulated the theoretical light protection factor provided by DHA application. In addition, we present 19 cases with EPP who were treated at our department with DHA weekly during spring and summer from 2018 to 2021 inclusive.
RESULTS
The protection factor against UVA and visible light was estimated to approximately two. Out of the 19 patients with EPP who were treated with DHA in 2018, 11 patients experienced a sustained good effect and continued to use the treatment on a weekly basis in the spring and summer of 2019, 2020, and 2021.
CONCLUSION AND PERSPECTIVES
Both the theoretical estimates and the uncontrolled study suggest that sunless tanning with DHA reduces photosensitivity in patients with EPP. Our hypothesis is that skin treated with DHA can tolerate twice the daylight dose compared to untreated skin before onset of skin symptoms. To validate this conclusion, we plan a randomized clinical trial to determine the effect of DHA application to reduce photosensitivity in patients with EPP under controlled clinical conditions. The study protocol for this trial is presented in the paper.
Topics: Humans; Protoporphyria, Erythropoietic; Dihydroxyacetone; Photochemotherapy; Photosensitizing Agents; Light; Photosensitivity Disorders
PubMed: 36690194
DOI: 10.1016/j.pdpdt.2023.103302 -
Molecular Genetics and Metabolism Nov 2019Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses, generally presenting in childhood with severe and painful phototoxicity.... (Observational Study)
Observational Study
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses, generally presenting in childhood with severe and painful phototoxicity. EPP has been reported to negatively affect quality of life (QoL), but there is limited information on the psychosocial issues faced by patients and families. To address this, an online focus group study was conducted to explore the perspective of parents of children with EPP, and young adults and children with EPP. Five focus groups were conducted in a semi-structured format, with moderator-led discussions exploring the impact on QoL. Three focus groups included parents of children with EPP, one with children aged 10-11 years, and another with young adults aged 24-25 years, for a total of 24 participants. Thematic data analysis showed that parents experience guilt for being unable to protect their children and frustration with the current state of knowledge of EPP. Parents also admitted that the disease can lead to stress within family members which is difficult to manage. Young adults expressed embarrassment over having to explain the disease to others. They reported that the teenage years were the most difficult to navigate; however, they learned to adapt to their disease as they grew older. Children expressed that they had limited understanding of their disease and wished they were told what symptoms to expect by physicians earlier in life. Our findings emphasize the significant impact on QoL for these families and a lack of age appropriate information for children with EPP. These findings can help improve counseling and support resources for patients and caregivers.
Topics: Adult; Child; Counseling; Dermatitis, Phototoxic; Family; Female; Focus Groups; Humans; Longitudinal Studies; Male; Middle Aged; Parents; Protoporphyria, Erythropoietic; Qualitative Research; Quality of Life; Social Behavior; Young Adult
PubMed: 30711301
DOI: 10.1016/j.ymgme.2019.01.023 -
ACS Omega Oct 2023Antisense oligonucleotides (ASOs) are short, single-stranded nucleic acid molecules that alter gene expression. However, their transport into appropriate cellular...
Antisense oligonucleotides (ASOs) are short, single-stranded nucleic acid molecules that alter gene expression. However, their transport into appropriate cellular compartments is a limiting factor in their potency. Here, we synthesized splice-switching oligonucleotides (SSOs) previously developed to treat the rare disease erythropoietic protoporphyria. Using chemical ligation-quantitative polymerase chain reaction (CL-qPCR), we quantified the SSOs in cells and subcellular compartments following free uptake. To drive nuclear localization, we covalently conjugated nuclear localization signal (NLS) peptides to a lead 2'--methoxyethyl phosphorothioate SSO using thiol-maleimide chemistry. The conjugates and parent SSO displayed similar RNA target-binding affinities. CL-qPCR quantification of the conjugates in cells and subcellular compartments following free uptake revealed one conjugate with better nuclear accumulation relative to the parent SSO. However, compared to the parent SSO, which altered the splicing of the target pre-mRNA, the conjugates were inactive at splice correction under free uptake conditions . Splice-switching activity could be conferred on the conjugates by delivering them into cells via cationic lipid-mediated transfection or by treating the cells into which the conjugates had been freely taken up with chloroquine, an endosome-disrupting agent. Our results identify the major barrier to the activity of the peptide-oligonucleotide conjugates as endosomal entrapment.
PubMed: 37929104
DOI: 10.1021/acsomega.3c05144 -
Molecular Medicine (Cambridge, Mass.) Jan 2019X-linked protoporphyria (XLP) (MIM 300752) is an erythropoietic porphyria due to gain-of-function mutations in the last exon (Ducamp et al., Hum Mol Genet 22:1280-88,...
BACKGROUND
X-linked protoporphyria (XLP) (MIM 300752) is an erythropoietic porphyria due to gain-of-function mutations in the last exon (Ducamp et al., Hum Mol Genet 22:1280-88, 2013) of the erythroid-specific aminolevulinate synthase gene (ALAS2). Five ALAS2 exon 11 variants identified by the NHBLI Exome sequencing project (p.R559H, p.E565D, p.R572C, p.S573F and p.Y586F) were expressed, purified and characterized in order to assess their possible contribution to XLP. To further characterize the XLP gain-of-function region, five novel ALAS2 truncation mutations (p.P561X, p.V562X, p.H563X, p.E569X and p.F575X) were also expressed and studied.
METHODS
Site-directed mutagenesis was used to generate ALAS2 mutant clones and all were prokaryotically expressed, purified to near homogeneity and characterized by protein and enzyme kinetic assays. Standard deviations were calculated for 3 or more assay replicates.
RESULTS
The five ALAS2 single nucleotide variants had from 1.3- to 1.9-fold increases in succinyl-CoA V and 2- to 3-fold increases in thermostability suggesting that most could be gain-of-function modifiers of porphyria instead of causes. One SNP (p.R559H) had markedly low purification yield indicating enzyme instability as the likely cause for XLSA in an elderly patient with x-linked sideroblastic anemia. The five novel ALAS2 truncation mutations had increased V values for both succinyl-CoA and glycine substrates (1.4 to 5.6-fold over wild-type), while the Ks for both substrates were only modestly changed. Of interest, the thermostabilities of the truncated ALAS2 mutants were significantly lower than wild-type, with an inverse relationship to V fold-increase.
CONCLUSIONS
Patients with porphyrias should always be assessed for the presence of the ALAS2 gain-of-function modifier variants identified here. A key region of the ALAS2 carboxyterminal region is identified by the truncation mutations studied here and the correlation of increased thermolability with activity suggests that increased molecular flexibility/active site openness is the mechanism of enhanced function of mutations in this region providing further insights into the role of the carboxyl-terminal region of ALAS2 in the regulation of erythroid heme synthesis.
Topics: 5-Aminolevulinate Synthetase; Enzyme Stability; Exons; Gain of Function Mutation; Kinetics; Polymorphism, Single Nucleotide
PubMed: 30678654
DOI: 10.1186/s10020-019-0070-9 -
International Journal of Environmental... Mar 2023Erythropoietic protoporphyria (EPP) is an ultra-rare inborn error of metabolism characterised by painful phototoxic burn injuries after short exposure times to visible...
Erythropoietic protoporphyria (EPP) is an ultra-rare inborn error of metabolism characterised by painful phototoxic burn injuries after short exposure times to visible light. Patients with EPP are highly adapted to their condition which makes the quantification of their health-related quality of life (QoL) challenging. In the presented patient-initiated feasibility study, we describe a new approach to assess treatment benefits in EPP by measuring QoL with the generic EQ-5D instrument in five patients under long-term (≥two years) treatment with afamelanotide, the first approved therapy for EPP. For the study, we selected patients with EPP who in addition were affected by an involuntary treatment interruption (caused by a temporary reimbursement suspension) because we hypothesized that individuals who had previously unlearned their adaptation are better able to assess their life without treatment than treatment-naïve patients. QoL under treatment was comparable to the age-matched population norm, and retrospective results for a treatment interruption and phototoxic reaction time point were comparable to the QoL of patients with chronic neuropathic pain and acute burn injuries, respectively. The results were accepted by the National Institute for Health and Care Excellence in England for their evaluation of the cost-effectiveness of afamelanotide, i.e., the calculation of quality-adjusted life years.
Topics: Humans; Protoporphyria, Erythropoietic; Quality of Life; Retrospective Studies; Quality-Adjusted Life Years; Rare Diseases; Feasibility Studies
PubMed: 37047912
DOI: 10.3390/ijerph20075296 -
Pharmacology Research & Perspectives Jun 2023Dersimelagon (formerly MT-7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for...
Absorption, metabolism, and excretion of [ C]dersimelagon, an investigational oral selective melanocortin 1 receptor agonist, in preclinical species and healthy volunteers.
Dersimelagon (formerly MT-7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for the treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis (dcSSc). Findings of studies evaluating the absorption, distribution, metabolism, and excretion (ADME) of dersimelagon following a single dose of [ C]dersimelagon in healthy adult volunteers (N = 6) who participated in phase 1, single-center, open-label, mass balance study (NCT03503266), and in preclinical animal models are presented. Rapid absorption and elimination were observed following oral administration of [ C]dersimelagon in clinical and nonclinical studies, with a mean T of 30 min in rats and 1.5 h in monkeys, and a median T of 2 h in humans. In rats, there was a widespread distribution of [ C]dersimelagon-related material, but little or no radioactivity was detected in the brain or fetal tissues. In humans, elimination of radioactivity in urine was negligible (excretion of radioactivity into the urine: 0.31% of dose), and the primary route of excretion was feces, with more than 90% of the radioactivity recovered through 5 days postdose. Based on these findings, dersimelagon is not retained in the human body. Findings from humans and animals suggest dersimelagon is extensively metabolized to the glucuronide in the liver, which is eliminated in bile, and hydrolyzed to unchanged dersimelagon in the gut. The results to date for this orally administered agent elucidate the ADME of dersimelagon in human and animal species and support its continued development for the treatment of photosensitive porphyrias and dcSSc.
Topics: Adult; Animals; Humans; Rats; Bile; Feces; Healthy Volunteers; Liver; Receptor, Melanocortin, Type 1
PubMed: 37078227
DOI: 10.1002/prp2.1084 -
Journal of Photochemistry and... Mar 2021In the knowledge that human ultra-weak photon emission (UPE) is mainly due to the metabolic oxidative stress processes that the skin cells undergo in the presence of... (Review)
Review
In the knowledge that human ultra-weak photon emission (UPE) is mainly due to the metabolic oxidative stress processes that the skin cells undergo in the presence of reactive oxygen species (ROS), external stressors (like UV radiation), but also internal stressors (like diseases or brain activity) might strongly influence the UPE. This manuscript revises the scientific advances focused on the influence of internal factors on the human UPE. According to literature, the UPE seems to be influenced by some diseases (including diabetes, hemiparesis, protoporphyria, or a typical cold), and even by the cerebral intention/relaxation (brain activity/meditation). These allow to consider UPE as a natural and promising non-invasive spectroscopic tool for helping during the diagnosis of a variety of illnesses or stress- / mood-state disorders. Nonetheless, further research is required for answering some still unresolved controversial points.
Topics: Brain; Diabetes Mellitus; Humans; In Vitro Techniques; Luminescent Measurements; Meditation; Paresis; Photons; Reactive Oxygen Species; Skin; Ultraviolet Rays
PubMed: 33540236
DOI: 10.1016/j.jphotobiol.2021.112141 -
Scientific Reports Apr 2022Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage....
Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage.
Topics: Ferrochelatase; Humans; Liver; Phlebotomy; Porphyria, Erythropoietic
PubMed: 35414164
DOI: 10.1038/s41598-022-10089-z