First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria

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

600 km repeater-like quantum communications with dual-band stabilisation

Twin-field (TF) quantum key distribution (QKD) could fundamentally alter the rate-distance relationship of QKD, offering the scaling of a single-node quantum repeater. Although recent experiments have demonstrated the potential of TF-QKD, formidable challenges remain for its real world use. In particular, new methods are needed to extend both the distance beyond 500 km and key rates above current milli-bit per second values. Previous demonstrations have required intense stabilisation signals at the same wavelength as the quantum channel, thereby unavoidably generating noise due to Rayleigh scattering that limits the distance and bit rate. Here, we introduce a novel dual band stabilisation scheme based on wavelength division multiplexing that allows us to circumvent past limitations. An intense stabilisation signal that is spectrally isolated from the quantum channel is used to reduce the phase drift by three orders of magnitude, while a second, much weaker reference at the quantum wavelength locks the channel phase to a predetermined value. With this strategy, we realise a low noise implementation suitable for all the variants of TF-QKD protocols proposed so far and capable of generating real strings of bits for the first time. The setup provides repeater-like key rates over record communication distances of 555 km and 605 km in the finite-size and asymptotic regimes, respectively, and increases the secure key rate at long distance by two orders of magnitude to values of practical significance.Comment: 14 pages, 5 figures. Methods and supplementary materials are include

Mapping of Dietary Interventions Beneficial in the Prevention of Secondary Health Conditions in Spinal Cord Injured Population: A Systematic Review.

OBJECTIVES Individuals with spinal cord injury are at risk of secondary health conditions (SHC) that develop as a consequence of autonomic dysfunction, prolonged oxidative stress and inflammation, and physical inactivity coupled with inadequate energy and nutritional intake. SHC can be debilitating and even life-threatening, and its prevention remains one of the major challenges in the continuum of medical care of aging SCI population. An unhealthy diet is a major driver of inflammation, oxidative stress, and unfavourable metabolic status and may be a practical preventive target to tackle increased SHC risk post-injury. AIMS To provide a catalogue of dietary interventions beneficial in prevention of SHC among individuals with SCI by conducting a systematic review of the literature on dietary interventions and dietary supplementation in promoting health and well-being after the injury. In addition, we aimed to provide a summary of observational studies exploring the association between habitual diet (macro- and micronutrients intake and dietary patterns) and health patterns following the injury. METHOD This review was registered at PROSPERO (University of York) with registration number CRD42022373773. Four medical databases (EMBASE.com, MEDLINE [Ovid], Cochrane CENTRAL, and Web of Science Core Collection) and Google Scholar were searched from inception until 11th July 2022. Studies were included if they were clinical trials or observational studies conducted in adult individuals with SCI and provided information of interest. Based on strength of the study design and risk of bias assessment (using the NIH tool), we classified studies from Level 1 (most reliable studies) to Level 4 (least reliable studies). RESULTS Of 12,313 unique citations, 47 articles (based on 43 original studies) comprising 32 interventional (22 RCTs, 3 NRCT, and 7 pre-post studies) and 11 observational studies (2 cohort studies, 2 case-control, 1 post-intervention follow-up study, and 6 cross-sectional studies) were included in the present systematic review. Twenty studies (46.5%) were classified as Level 1 or 2, indicating high/moderate methodological quality. Based on those studies, dietary strategies including high protein diet, intermittent fasting, balanced diet in combination with physical conditioning and electrical stimulation, and dietary supplementation including alpha-lipoic acid, creatine, vitamin D, and cranberry-derived supplements and probiotics were mapped as the most promising in prevention of SHC among individuals with SCI. CONCLUSIONS To develop timely and effective preventive strategies targeting major SHC (e.g., cardiometabolic diseases, urinary tract infections) in SCI, further research is warranted to confirm the effectiveness of dietary strategies/interventions identified through the current systematic review of the literature

Evaluation of urinary porphyrin excretion in neonates born to mothers exposed to airborne hexachlorobenzene.

The existence of a link between hexachlorobenzene (HCB) and porphyria cutanea tarda has been known for a long time. However, the epidemiologic data on effects on health caused by prenatal exposure have not provided convincing evidence that HCB alters porphyrin metabolism. Our objectives were to analyze urinary porphyrin excretion and HCB in maternal serum and fetal cord blood in neonates born in a village (Flix) near a chlorinated solvent factory, to detect possible adverse effects in urinary porphyrin excretion caused by prenatal exposure, and to assess their relationship with HCB blood levels. We conducted a cross-sectional study in the Porphyria Unit at a tertiary care facility in Barcelona, Spain, and the Pediatric Unit of the Móra d'Ebre Hospital, the reference hospital of the study area. We included in the study all neonates (n = 68) born in Móra d'Ebre Hospital 1997-1999 and their mothers. We obtained 68 urine specimens of singleton neonates on the third day after birth to test for urinary porphyrin excretion. We obtained 52 fetal cord blood and 56 maternal serum samples for HCB analysis. Total urinary porphyrins were quantified using spectrofluorometry. Porphyrin profile was determined by HPLC. Serum HCB was analyzed by gas chromatography coupled with electron capture detection. In total population, median HCB levels were 1.08 ng/mL in cord blood and 3.31 ng/mL in maternal serum. Total urinary porphyrin concentration was 37.87 micromol/mol creatinine. Coproporphyrin I and coproporphyrin III were the major porphyrins excreted. We found no positive relationship between urinary porphyrin excretion and HCB levels. However, we observed an association between maternal smoking and coproporphyrin excretion. Although high environmental levels of HCB are reported in the town of Flix, we found no alteration in urinary porphyrin excretion

600-km repeater-like quantum communications with dual-band stabilization

Twin-field (TF) quantum key distribution (QKD) fundamentally alters the rate-distance relationship of QKD, offering the scaling of a single-node quantum repeater. Although recent experiments have demonstrated the new opportunities for secure long-distance communications allowed by TF-QKD, formidable challenges remain to unlock its true potential. Previous demonstrations have required intense stabilization signals at the same wavelength as the quantum signals, thereby unavoidably generating Rayleigh scattering noise that limits the distance and bit rate. Here, we introduce a dual-band stabilization scheme that overcomes past limitations and can be adapted to other phase-sensitive single-photon applications. Using two different optical wavelengths multiplexed together for channel stabilization and protocol encoding, we develop a setup that provides repeater-like key rates over communication distances of 555 km and 605 km in the finite-size and asymptotic regimes respectively and increases the secure key rate at long distance by two orders of magnitude to values of practical relevance

Liver Transplantation because of Acute Liver Failure due to Heme Arginate Overdose in a Patient with Acute Intermittent Porphyria

In acute attacks of acute intermittent porphyria, the mainstay of treatment is glucose and heme arginate administration. We present the case of a 58-year-old patient with acute liver failure requiring urgent liver transplantation after erroneous 6-fold overdose of heme arginate during an acute attack. As recommended in the product information, albumin and charcoal were administered and hemodiafiltration was started, which could not prevent acute liver failure, requiring super-urgent liver transplantation after 6 days. The explanted liver showed no preexisting liver cirrhosis, but signs of subacute liver injury and starting regeneration. The patient recovered within a short time. A literature review revealed four poorly documented cases of potential hepatic and/or renal toxicity of hematin or heme arginate. This is the first published case report of acute liver failure requiring super-urgent liver transplantation after accidental heme arginate overdose. The literature and recommendations in case of heme arginate overdose are summarized. Knowledge of a potentially fatal course is important for the management of future cases. If acute liver failure in case of heme arginate overdose is progressive, super-urgent liver transplantation has to be evaluated

Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients

Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. Design: This was designed as a retrospective, multicenter study. Setting: Thirteen University hospitals were studied. Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol “day-curve” (CDC) (target 150–300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS

An overview of the cutaneous porphyrias

This is an overview of the cutaneous porphyrias. It is a narrative review based on the published literature and my personal experience; it is not based on a formal systematic search of the literature. The cutaneous porphyrias are a diverse group of conditions due to inherited or acquired enzyme defects in the porphyrin–haem biosynthetic pathway. All the cutaneous porphyrias can have (either as a consequence of the porphyria or as part of the cause of the porphyria) involvement of other organs as well as the skin. The single commonest cutaneous porphyria in most parts of the world is acquired porphyria cutanea tarda, which is usually due to chronic liver disease and liver iron overload. The next most common cutaneous porphyria, erythropoietic protoporphyria, is an inherited disorder in which the accumulation of bile-excreted protoporphyrin can cause gallstones and, rarely, liver disease. Some of the porphyrias that cause blistering (usually bullae) and fragility (clinically and histologically identical to porphyria cutanea tarda) can also be associated with acute neurovisceral porphyria attacks, particularly variegate porphyria and hereditary coproporphyria. Management of porphyria cutanea tarda mainly consists of visible-light photoprotection measures while awaiting the effects of treating the underlying liver disease (if possible) and treatments to reduce serum iron and porphyrin levels. In erythropoietic protoporphyria, the underlying cause can be resolved only with a bone marrow transplant (which is rarely justifiable in this condition), so management consists particularly of visible-light photoprotection and, in some countries, narrowband ultraviolet B phototherapy. Afamelanotide is a promising and newly available treatment for erythropoietic protoporphyria and has been approved in Europe since 2014