urea cycle defect

Argininosuccinate lyase deficiency (ASLD) is a recessive metabolic disorder caused by variants in ASL. In an essential step in urea synthesis, ASL breaks down argininosuccinate (ASA), a pathognomonic ASLD biomarker. The severe disease forms lead to hyperammonemia, neurological injury, and even early death. The current treatments are unsatisfactory, involving a strict low-protein diet, arginine supplementation, nitrogen scavenging, and in some cases, liver transplantation. An unmet need exists for improved, efficient therapies...

A 63-year-old man with type 2 diabetes mellitus, alcohol consumption in moderation, and three episodes of hepatic encephalopathy presented with symmetrical lower limb distal weakness, sensory ataxia, thickened palpable nerves, mood disturbances for seven years, and a family history of schizophreniform disorders. Nerve conduction studies showed demyelinating sensorimotor polyradiculoneuropathy. CSF analysis showed mild albumino-cytological dissociation. MRI brain and lumbosacral plexus showed thickened fifth cranial nerves and lumbosacral roots...

Background and aims: Defective enzymes, cofactors, or transporters of metabolic pathways cause inherited metabolic disorders (IMDs), a group of genetic disorders. Several IMDs have serious consequences for the affected neonates. Newborn screening for IMDs is conducted by measuring specific metabolites between 3 and 7 days of life. Herein, we analyzed the incidence, spectrum, and genetic characteristics of IMDs in newborns in the Zhuzhou area. Methods: Tandem mass spectrometry was conducted on 90,829 newborns who were admitted to the Women and Children Healthcare Hospital of Zhuzhou and requested for screening for IMDs...

The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation...

Bagasse-derived carbon electrodes were developed by doping with nitrogen functional groups and compositing with high-capacity MnO2 nanoparticles (MnO2 /NBGC). The bagasse-derived biochar was N-doped by refluxing in urea, followed by the deposition of MnO2 nanoparticles onto its porous surface via the hydrothermal reduction of KMnO4 . Different initial KMnO4 loading concentrations ( i.e. 5, 10, 40, and 100 mM) were applied to optimize the composite morphology and the corresponding electrochemical performance...

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S )-4-(3-18 F-fluoropropyl)-l-glutamate ([18 F]FSPG)...

The group of rare metabolic defects termed urea cycle disorders (UCDs) occur within the ammonia elimination pathway and lead to significant neurocognitive sequelae for patients surviving decompensation episodes. Besides orthotopic liver transplantation, curative options are lacking for UCDs, with dietary management being the gold clinical standard. Novel therapeutic approaches are essential for UCDs; however, such effort presupposes preclinical testing in cellular models that effectively capture disease manifestation...

Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver-directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver-targeting, including gene editing...

In this paper, an ammonia-urea system was developed to induce the shedding of carboxymethylcellulose carbon aerogels to form defects, and the specific surface area of the aerogels was significantly increased after carbonization, and the three-dimensional disordered pore structure of cellulose was preserved. The material showed the selective adsorption of gadolinium ions using the carboxylate active sites provided by carboxymethylation and the microporous or mesoporous structures formed after carbon burning...

Citrullinemia type 1 (CTLN1) is a rare autosomal recessive urea cycle disorder caused by deficiency of the cytosolic enzyme argininosuccinate synthetase 1 (ASS1) due to pathogenic variants in the ASS1 gene located on chromosome 9q34.11. Even though hyperammenomia is considered the major pathomechanistic factor for neurological impairment and cognitive dysfunction, a relevant subset of individuals presents with a neurodegenerative course in the absence of hyperammonemic decompensations. Here we show, that ASS1 deficiency induced by antisense-mediated knockdown of the zebrafish ASS1 homologue is associated with defective neuronal differentiation ultimately causing neuronal cell loss and consecutively decreased brain size in zebrafish larvae in vivo...

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD. We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022...

UNLABELLED: Pseudomonas aeruginosa is an opportunistic nosocomial pathogen responsible for catheter-associated urinary tract infections (CAUTI). In a murine model of P. aeruginosa CAUTI, we previously demonstrated that urea within urine suppresses quorum sensing and induces the Entner-Douderoff (E-D) pathway. The E-D pathway consists of the genes zwf, pgl, edd , and eda . Zwf and Pgl convert glucose-6-phosphate into 6-phosphogluconate. Edd hydrolyzes 6-phosphogluconate to 2-keto-3-deoxy-6-phosphogluconate (KDPG)...

BACKGROUND: Maresin1 (MaR1) is a potent lipid mediator that exhibits significant anti-inflammatory activity in the context of several inflammatory diseases. A previous study reported that MaR1 could suppress MSU crystal-induced peritonitis in mice. To date, the molecular mechanism by which MaR1 inhibits MSU crystal-induced inflammation remains poorly understood. METHODS: Mousebone marrow-derived macrophages (BMDMs) were pretreated with MaR1 and then stimulated with FAs (palmitic, C16:0 and stearic, C18:0) plus MSU crystals (FAs + MSUc)...

Phillip L. Pearl Seminars in Pediatric Neurology Volume 23, Issue 2, May 2016, Pages 158-166 Vitamin-dependent epilepsies and multiple metabolic epilepsies are amenable to treatment that markedly improves the disease course. Knowledge of these amenably treatable severe pediatric epilepsies allows for early identification, testing, and treatment. These disorders present with various phenotypes, including early onset epileptic encephalopathy (refractory neonatal seizures, early myoclonic encephalopathy, and early infantile epileptic encephalop athy), infantile spasms, or mixed generalized seizure types in infancy, childhood, or even adolescence and adulthood...

OBJECTIVES: Acylcarnitine and amino acid analyses of dried blood spot (DBS) samples using tandem mass spectrometry in newborn screening (NBS) programmes can generate false positive (FP) results. Therefore, implementation of second-tier tests (2TTs) using DBS samples has become increasingly important to avoid FPs. The most widely used 2TT metabolites include methylmalonic acid, 3-hydroxypropionic acid, methylcitric acid, and homocysteine. METHODS: We simultaneously measured 46 underivatised metabolites, including organic acids, acylglycine and acylcarnitine isomers, homocysteine, and orotic acid, in DBS samples using tandem mass spectrometry...

In this work, we study the influence of reduced graphene oxide (rGO) on the morphology and chemistry of highly porous N,S-doped carbon cryogels. Simultaneously, we propose an easily upscalable route to prepare such carbons by adding graphene oxide (GO) in as-received suspended form to the aqueous solution of the ι-carrageenan and urea precursors. First, 1.25-5 wt% GO was incorporated into the dual-doped polymer matrix. The CO2 , CO, and H2 O emitted during the thermal treatments resulted in the multifaceted modification of the textural and chemical properties of the porous carbon...

Ornithine transcarbamylase deficiency (OTCD) is the most common inherited disorder of the urea cycle and, in general, is transmitted as an X-linked recessive trait. Defects in the OTC gene cause an impairment in ureagenesis, resulting in hyperammonemia, which is a direct cause of brain damage and death. Patients with late-onset OTCD can develop symptoms from infancy to later childhood, adolescence or adulthood. Clinical manifestations of adults with OTCD vary in acuity. Clinical symptoms can be aggravated by metabolic stressors or the presence of a catabolic state, or due to increased demands upon the urea...

OBJECTIVES: Chylothorax without chylous ascites after liver transplant is rare. We present 2 cases of isolated chylothorax after liver transplant and a literature review. MATERIALS AND METHODS: We compiled a literature review of chylothorax cases after abdominal surgery and analyzed the cases related to liver transplant. The demographic information, follow-up results, and treatment details of our 2 cases of chylothorax after living-donor pediatric liver transplant were discussed...

BACKGROUND: Carbamoyl phosphate synthetase I defect (CPS1D) is a rare disease with clinical case reports mainly in early neonates or adults, with few reports of first onset in late neonatal to childhood. We studied the clinical and genotypic characteristics of children with childhood onset CPS1D caused by two loci mutations (one of these is a rarely reported non-frame shift mutation) in the CPS1. CASE PRESENTATION: We present a rare case of adolescent-onset CPS1D that had been misdiagnosed due to atypical clinical features, and further investigations revealed severe hyperammonemia (287µmol/L; reference range 11...

BACKGROUND: Arginine (Arg) is a semiessential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. In vivo, Arg bioavailability is regulated by a combination of dietary intake, protein catabolism, and limited biosynthesis through portions of the urea cycle. Interestingly, despite the importance of bioavailable Arg to support cellular proliferation, many forms of cancer are functionally auxotrophic for this amino acid due to the epigenetic silencing of argininosuccinate synthetase 1 (ASS1), an enzyme responsible for the conversion of citrulline and aspartate into the Arg precursor argininosuccinate...