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Background: This study aimed to investigate the clinical and molecular genetic characteristics of ten children with ornithine carbamoyltransferase deficiency (OTCD) in southeastern China, as well as the correlation between the genotype and phenotype of OTCD. Methods: A retrospective analysis was performed on the clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 at Quanzhou Maternity and Children's Hospital of Fujian Province in China. Results: Five boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. In contrast, five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all presenting with hepatic impairment, and four with hepatic failure.Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T > A(p.M56K). Of seven patients who died, five had early-onset disease despite active treatment. Three patients survived, and two of them underwent liver transplantation. Conclusions: The clinical manifestations of OTCD lack specificity. However, elevated blood ammonia levels serve as a crucial diagnostic clue for OTCD. Genetic testing aids in more accurate diagnosis and prognosis assessment by clinicians. In addition, we identified two novel pathogenic variants and expand the mutational spectrum of the gene OTC, which may contribute to a better understanding of the clinical and genetic characteristics of OTCD patients. [ABSTRACT FROM AUTHOR]

Amino acid (AA)-related inherited metabolic disorders (IMDs) and urea cycle disorders (UCDs) require strict dietary management including foods low in protein such as fruits, vegetables and starchy roots. Despite this recommendation, there are limited data on the AA content of many of these foods. The aim of this study is to describe an analysis of the protein and AA content of a range of fruits, vegetables and starchy roots, specifically focusing on amino acids (AAs) relevant to AA-related IMDs such as phenylalanine (Phe), methionine (Met), leucine (Leu), lysine (Lys) and tyrosine (Tyr). AA analysis was performed using high-performance liquid chromatography (HPLC) on 165 food samples. Protein analysis was also carried out using the Dumas method. Foods were classified as either 'Fruits', 'Dried fruits', 'Cruciferous vegetables', 'Legumes', 'Other vegetables' or 'Starchy roots'. 'Dried fruits' and 'Legumes' had the highest median values of protein, while 'Fruits' and 'Cruciferous vegetables' contained the lowest median results. 'Legumes' contained the highest and 'Fruits' had the lowest median values for all five AAs. Variations were seen in AA content for individual foods. The results presented in this study provide useful data on the protein and AA content of fruits, vegetables and starchy roots which can be used in clinical practice. This further expansion of the current literature will help to improve diet quality and metabolic control among individuals with AA-related IMDs and UCDs. [ABSTRACT FROM AUTHOR]

Abstract Background The clinical presentation of ARG1‐D is characterised by elevated arginine levels leading to neurological and mobility impairments. Information about long‐term outcomes in adults is lacking, which prompted us to undertake a retrospective observational study. Methods We extracted ARG1‐D patient data spanning a 5‐year period from electronic health records. Ethical approval was not required for the study. Informed consent was obtained. Results We identified nine ARG1‐D patients from consanguineous backgrounds. Age of symptom onset ranged from infancy to age 7 years, age of diagnosis from infancy to 20 years. Patients had paraparesis or altered gait of varying degree and had experienced early ARG1‐D onset. Over 5 years, mobility declined in six (6/9, 67%) patients. Three patients (3/9, 33%) were fully dependent and hoisted. Two (2/9, 22%) reached adulthood before experiencing hyperammonaemia, another one (1/9, 11%) first experienced hyperammonaemia at age 15 years. One patient (1/9, 11%) started on ammonia scavenger therapy in adulthood, one (1/9, 11%) required a second scavenger to be added to their treatment regimen. Two patients (2/9, 22%) had gastrostomy tubes inserted for nutrition and supplements at age 9 years and 15 years. Six patients (6/9, 67%) had raised levels of ALT; of these, four (4/9, 44%) also had elevated AFP. Heterogeneity of ARG1‐D symptoms was evident, suggesting complex genetic and environmental interactions. Conclusion ARG1‐D presents significant lifelong challenges with deteriorating mobility and more frequent metabolic crises. Current management strategies are insufficient for preventing progression, highlighting the need for innovative treatments like enzyme replacement and gene therapy.

Abstract Background This study aimed to investigate the clinical and molecular genetic characteristics of ten children with ornithine carbamoyltransferase deficiency (OTCD) in southeastern China, as well as the correlation between the genotype and phenotype of OTCD. Methods A retrospective analysis was performed on the clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 at Quanzhou Maternity and Children’s Hospital of Fujian Province in China. Results Five boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. In contrast, five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all presenting with hepatic impairment, and four with hepatic failure.Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T > A(p.M56K). Of seven patients who died, five had early-onset disease despite active treatment. Three patients survived, and two of them underwent liver transplantation. Conclusions The clinical manifestations of OTCD lack specificity. However, elevated blood ammonia levels serve as a crucial diagnostic clue for OTCD. Genetic testing aids in more accurate diagnosis and prognosis assessment by clinicians. In addition, we identified two novel pathogenic variants and expand the mutational spectrum of the gene OTC, which may contribute to a better understanding of the clinical and genetic characteristics of OTCD patients.

Abstract Background Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality. Methods Herein we present 12 genetic variants identified in seven clinically well-characterized Chinese patients with CPS1 deficiency who were admitted to the Children’s Medical Center of Peking University First Hospital from September 2014 to August 2023. Results Seven patients (two male and five female patients including two sisters) experienced symptoms onset between 2 days and 13 years of age, and they were diagnosed with CPS1 deficiency between 2 months and 20 years. Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. Three patients showed early-onset CPS1 deficiency, with only one surviving after treatment with sodium phenylbutyrate, N-carbamoyl-L-glutamate, and liver transplantation at 4 months, showing a favorable outcome. The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles. Seven variants (c.149T > C, c.616 A > T, c.1145 C > T, c.1294G > A, c.3029 C > T, c.3503 A > T, and c.3793 C > T) resulted in single amino acid substitutions. Three frameshift variations (c.2493del, c.3067dup, and c.3241del) were identified, leading to enzyme truncation. One mutation (c.3506_3508del) caused an in-frame single amino acid deletion, while another (c.2895 + 2T > C) resulted in aberrant splicing. Conclusions Except for two known variants, all other variants were identified as novel. No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1.

Background: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality. Methods: Herein we present 12 genetic variants identified in seven clinically well-characterized Chinese patients with CPS1 deficiency who were admitted to the Children's Medical Center of Peking University First Hospital from September 2014 to August 2023. Results: Seven patients (two male and five female patients including two sisters) experienced symptoms onset between 2 days and 13 years of age, and they were diagnosed with CPS1 deficiency between 2 months and 20 years. Peak blood ammonia levels ranged from 160 to 1,000 µmol/L. Three patients showed early-onset CPS1 deficiency, with only one surviving after treatment with sodium phenylbutyrate, N-carbamoyl-L-glutamate, and liver transplantation at 4 months, showing a favorable outcome. The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets. Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles. Seven variants (c.149T > C, c.616 A > T, c.1145 C > T, c.1294G > A, c.3029 C > T, c.3503 A > T, and c.3793 C > T) resulted in single amino acid substitutions. Three frameshift variations (c.2493del, c.3067dup, and c.3241del) were identified, leading to enzyme truncation. One mutation (c.3506_3508del) caused an in-frame single amino acid deletion, while another (c.2895 + 2T > C) resulted in aberrant splicing. Conclusions: Except for two known variants, all other variants were identified as novel. No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1. [ABSTRACT FROM AUTHOR]

The genetic bases of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia due to hyperammonemia caused by mutations in urea cycle genes. The analysis was performed by pooled whole-exome sequencing (WES) of 90 patients and by searching for rare pathogenic variants in autosomal genes for enzymes or transporters of the urea cycle pathway. The survey returned two rare pathogenic coding mutations leading to citrullinemia type I: rs148918985, p.Arg265Cys, C>T; and rs121908641, p.Gly390Arg, G>A in the argininosuccinate synthase 1 (ASS1) gene. The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. These variants found in simple or compound heterozygosity can lead to the late-onset form of citrullinemia type I, associated with high ammonia levels, which can lead to cerebral dysfunction and thus to the development of dementia. The presence of urea cycle disorder-causing mutations can be used for the early initiation of antihyperammonemia therapy in order to prevent the neurotoxic effects. [ABSTRACT FROM AUTHOR]

Ornithine transcarbamylase deficiency (OTCD) is the most common disorder of the urea cycle and is caused by a mutation of the OTC gene, located on chromosome X. Its prevalence is estimated at 1 in 80,000 to 56,500 births, but this X-chromosomal inheritance results in males being more affected than females. In neonates affected with this disorder, hyperammonemia after birth can lead to neurological and liver damage that can be fatal. We present a child with a prenatal diagnosis based on an older sibling with the same pathology, which led us to adopt an intensive treatment since the delivery. He was admitted in a neonatal unit and treatment with protein restriction, 10% glucose saline serum and glycerol phenylbutyrate was initiated. To date, after 3.5 years of follow up, growth and neurological development have been adequate, biochemical control has been appropriate except for a simple and mild decompensation during the course of a gastroenteritis. This case emphasises the importance of early diagnosis and treatment to avoid potential complications.

Objective: Citrin, the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), is structurally and mechanistically the most complex SLC25 family member, because it consists of three domains and forms a homo-dimer. Each protomer has an N-terminal calcium-binding domain with EF-hands, followed by a substrate-transporting carrier domain and a C-terminal domain with an amphipathic helix. The absence or dysfunction of citrin leads to citrin deficiency, a highly prevalent pan-ethnic mitochondrial disease. Here, we aim to understand the role of different citrin domains and how they contribute to pathogenic mechanisms in citrin deficiency. Methods: We have employed structural modeling and functional reconstitution of purified proteins in proteoliposomes to assess the transport activity and calcium regulation of wild-type citrin and pathogenic variants associated with citrin deficiency. We have also developed a double knockout of citrin and aralar (AGC1), the two paralogs of the mitochondrial aspartate/glutamate carrier, in HAP1 cells to perform mitochondrial imaging and to investigate mitochondrial localisation. Results: Using 33 pathogenic variants of citrin we clarify determinants of subcellular localization and transport mechanism. We identify crucial elements of the carrier domain that are required for transport, including those involved in substrate binding, network formation and dynamics. We show that the N-terminal domain is not involved in calcium regulation of transport, as previously thought, but when mutated causes a mitochondrial import defect. Conclusions: Our work introduces a new role for the N-terminal domain of citrin and demonstrates that dysfunction of the different domains contributes to distinct pathogenic mechanisms in citrin deficiency.

A Black young adult female diagnosed with argininosuccinate lyase deficiency at 6 months of age encountered significant barriers to care for the first 16 years of her life due to socioeconomic factors and parental neglect. Once in the care of her paternal grandmother, she received appropriate treatment with a nitrogen scavenger, amino acid supplementation, and a low-protein diet. However, due to repeated hyperammonemic crises early in her life, she was minimally communicative and unable to perform activities of daily living. During her final hyperammonemic crisis, she presented to a hospital unfamiliar with urea cycle disorders and without a metabolic service. As a result, she did not receive optimal care and died.

Social determinants of health (SDOH) are conditions in which people are born, grow, live, work, and age. Variations in these conditions are largely responsible for health inequities, the differences in health status or distribution of health resources within a population. Despite recent increases in attention to SDOH in research and clinical practice, few, if any, resources exist to describe how these complex dynamics impact patients with inborn errors of metabolism. Recognizing the role real-life narratives have as a powerful educational tool, we compiled a series of 3 original cases, published as part of this special supplement, to illustrate challenges and learnings related to SDOH within the context of urea cycle disorders and phenylketonuria.

Introduction: To date, newborn screening (NBS) for proximal urea cycle disorders, including Ornithine transcarbamylase deficiency (OTCD), was not recommended due to the lack of appropriate tests and insufficient evidence of the benefits. This study aimed to investigate the potential of tandem mass spectrometry (MS/MS) for OTCD screening and its value in guiding further investigation to obtain a final diagnosis in high-risk patients. Methods: The study included patients with OTCD referred to the National Children's Hospital between April 2020 and November 2023. A retrospective evaluation of amino acid concentrations measured by MS/MS and their ratios in patients with early-onset and late-onset OTCD was conducted. Results: While all ten early-onset cases had glutamine concentrations above the upper limit, only five of them had citrulline concentrations below the lower limit of the reference interval. Only two late-onset cases had elevated glutamine levels, while all had citrulline within reference intervals. The Cit/Phe ratio was decreased, and the Gln/Cit and Met/Cit ratios were increased in all early-onset OTCD cases, while they were abnormal in only one late-onset case. Conclusions: The preliminary results suggest that hyperglutaminemia, in combination with low or normal citrulline concentrations and specific ratios (Gln/Cit, Met/Cit, and Cit/Phe), can serve as reliable markers for screening early-onset OTCD in high-risk patients. However, these markers proved less sensitive for detecting the late-onset form, even in symptomatic patients.

Hereditary amino acid metabolism disorders (aminoacidopathies) are clinically and genetically heterogeneous group of hereditary metabolic diseases caused by enzymes deficiency involved in amino acid metabolism, that finally leads to progressive damage of central nervous system, liver, kidneys, and other organs and systems. Hereditary urea cycle disorders occur because of enzyme deficiency leading to impaired urea synthesis and hyperammoniemia in patients. The age of disease onset and clinical manifestations severity range from milder, intermittent forms to severe, manifesting in the first hours of life. Expanded neonatal screening (implemented in Russian Federation at 01.01.2023) allows to diagnose diseases from these groups in the first days of life, to prescribe timely pathogenetic therapy. Altogether it helps to prevent the development of disease severe complications. Raising awareness about hereditary aminoacidopathies and urea cycle disorders among pediatricians, neonatologists, neurologists, gastroenterologists, ophthalmologists is a topical issue of modern pediatrics.

Argininemia or arginase-1 deficiency constitutes a rare, genetic, metabolic disorder caused by mutations in arginase 1—the last enzyme of the urea cycle—that hydrolyses L-arginine to ornithine and urea. The disease is associated with progressive development of spasticity and other symptoms, including seizures, developmental delay, cognitive impairment, and hepatic pathology. The present review attempts to summarize the current knowledge on the pathophysiology of the disease and highlight novel methods for its evaluation. Different factors, such as the accumulation of arginine, ammonia, and guanidino compounds, act as neurotoxins and may account for the neurological sequelae observed in the disease. New markers, such as arginine/ornithine ratio along with metabolomics, machine learning algorithms, and genetic methods, can be useful in the early diagnosis of argininemia, while mobile phone apps can assist argininemic patients in adhering to the strict diet required. Neurophysiology, multi-modal imaging, and new modelling methods, such as induced pluripotent stem cells, hold promise for providing new insights into the pathophysiology of the disease. There are still many uncertainties regarding the underlying mechanisms of argininemia, but the use of novel modelling methods and new technology can lead to the decipherment of its pathophysiology, improvement of diagnostic accuracy, and better disease management. [ABSTRACT FROM AUTHOR]

Urea cycle disorders (UCDs) are a group of rare inborn errors of metabolism caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. Current guidelines suggest that early diagnosis and treatment of mild UCDs may improve survival and prevent decompensation and neurocognitive impairment. Nevertheless, clinical studies are very difficult to carry out in this setting due to the rarity of the diseases, and high-level evidence is scant and insufficient to draw conclusions and provide clinical guidelines. With the early introduction of newborn screening, the Italian healthcare organization fostered an advancement in expertise in metabolic disease management and screening programs, by allocating resources, and favoring the expansion of newborn screening. A group of experts operating in Italian centers decided to share their experience and provide advice for the management of mild UCDs in clinical practice. A consensus was reached by the Estimate–Talk–Estimate (ETE) method. Five items were identified, and statements for each item were agreed. Briefly, the panel advised completing the diagnosis by expanded newborn screening (ENS) with biochemical and genetic confirmation and by following up with the patient during the first year of life, with a routine laboratory and metabolic profile as well as with clinical observation. Early initiation of therapy is advised and should be followed by therapy adjustment once the diagnostic profile is completed. The therapy should be based on a low-protein diet and nitrogen scavengers. The long-term follow-up is based on growth and nutritional assessment, clinical and neurocognitive evaluation, and laboratory and instrumental parameter monitoring. [ABSTRACT FROM AUTHOR]

Background: Deficiency of arginase-1, the final enzyme in the urea cycle, causes a distinct clinical syndrome and is characterized biochemically by a high level of plasma arginine. While conventional therapy for urea cycle disorders can lower these levels to some extent, it does not normalize them. Until now, research on plasma arginine levels in this disorder has primarily relied on data from specialized tertiary centers, which limits the ability to assess the natural history and treatment efficacy of arginase-1 deficiency due to the small number of patients in each center and technical variations in plasma arginine measurements among different laboratories. Method: In this study, we reported plasma arginine levels from 51 patients with arginase-1 deficiency in the database of Quest Diagnostics. The samples were collected from different US regions. Results: The mean plasma arginine level in these treated patients was 373 μmol/L and the median level was 368.4 μmol/L. Our data set from 30 arginase deficiency patients with plasma amino acid data from five or more collections revealed significant correlations between the levels of arginine and five other amino acids (citrulline, alanine, ornithine, glutamine, and asparagine). Conclusion: Despite treatment, the arginine levels remained persistently elevated and did not change significantly with age, suggesting the current treatment regimen is inadequate to control arginine levels and underscoring the need to seek more effective treatments for this disorder.

Abstract N‐acetyl glutamate synthase (NAGS) deficiency (OMIM #: 237310) is a rare urea cycle disorder that usually presents early in life with hyperammonemia. NAGS catalyzes the synthesis of N‐acetyl glutamate (NAG) which functions as an activator of the carbamoyl phosphate synthetase‐1 mediated conversion of ammonia to carbamoyl phosphate. The absence of NAG results in a proximal urea cycle disorder which can result in severe neurologic sequelae secondary to hyperammonemia and even death. Unlike the other urea cycle disorders, a specific pharmacological treatment for NAGS deficiency exists in the form of carglumic acid, an analog of NAG. Here we present a 29‐year‐old previously healthy female who presented with hyperammonemia and obtundation just after the birth of her first child. Exome sequencing revealed two novel variants in the NAGS gene, and plasma metabolomics revealed extremely low levels of NAG. Carglumic acid treatment led to prompt resolution of her biochemical abnormalities and symptoms. She tolerated two subsequent pregnancies, 2 years and 6 years after her initial presentation, while taking carglumic acid, and breastfed her third child, all without complications in the mother or children. This case report emphasizes the importance of considering urea cycle disorders in previously‐healthy adults presenting with neurological symptoms during periods of metabolic stress, including the postpartum period. It also highlights the efficacious and safe use of carglumic acid during pregnancy and while breastfeeding.

Abstract Arginase deficiency (ARG1‐D) is an autosomal recessive inborn error of metabolism that is often misdiagnosed. Classic presentation of ARG1‐D includes progressive symptoms of spasticity, delayed development, cognitive impairment, protein avoidance, and seizures. Patients who present atypically may evade diagnosis and require a thoughtful diagnostic workup. Here, we discuss three females of Latin American origin with differing clinical presentations, but who all have the same intronic pathogenic variant in ARG1. Importantly, we found that each case included elevated coagulopathy on laboratory testing and discussed one case in particular with manifestation of bleeding. When diagnosed early, treatment is favorable and can prevent progressive decline. While many states have added ARG1‐D to their expanded newborn screening panels, still many states and countries do not screen for ARG1‐D, and it can be missed in a healthy newborn. We aim to bring awareness to not only the classic presentation as a necessary consideration for otherwise unexplained spastic diplegia but also to the varied presentations of ARG1‐D.

Aim:Urea cycle disorders (UCD) still have poor neurological outcomes despite early diagnosis and treatment. We aimed to present the neurological outcomes of UCD patients and to determine the main simple and accessible factors affecting these outcomes.Materials and Methods:This was a descriptive cross-sectional study conducted in two pediatric metabolism centers on 29 patients from 25 unrelated families who were diagnosed and followed with UCD based on clinical presentation, neurological parameters, biochemical measurements, and molecular analysis.Results:Within the study population, the most common diagnosis was argininosuccinate synthase deficiency in 13 (44.82%) patients, followed by N-acetylglutamate synthase deficiency in five patients (17.24%), ornithine transcarbamylase deficiency in four patients (13.79%), arginase 1 deficiency in three patients (10.34%), carbamoyl phosphate synthase 1 deficiency in three patients (10.34%), and argininosuccinate lyase deficiency in one patient (3.44%). Peak ammonia levels were observed to be significantly higher in those patients with delayed milestones and patients who had Denver II 500 μmol/L (n=18). Those patients with abnormal neurological parameters had a significantly higher mean number of hyperammonemic episodes per year. Extracorporeal detoxification was given to eight patients, in combination with therapeutic hypothermia in two patients. Rapid regression was observed in brain edema in those who underwent therapeutic hypothermia.Conclusion:Our study emphasizes the effect of peak ammonia levels and the frequency of hyperammonemic episodes on neurological outcomes. There were still poor neurocognitive outcomes despite extracorporeal detoxification. This highlights the need to reassess current treatment strategies, including the threshold for starting extracorporeal detoxification if ammonia levels exceed 500 µmol/L. The use of therapeutic hypothermia by experienced teams may be promising due to its brain edema-reducing effects.

Abstract In urea cycle disorders (UCDs) ammonia scavenger drugs, usually sodium‐based, have been the mainstay of treatment. Increasingly, glycerol phenylbutyrate (GPB, Ravicti®) is being used but scant real‐world data exist regarding clinical outcomes. A retrospective study of UCD patients initiated on or switched to GPB was performed at a UK centre. Data on population characteristics, treatment aspects, laboratory measurements, and clinical outcomes were collected before and after patients started GPB with a sub‐group analysis undertaken for patients with ≥12 months of data before and after starting GPB. UCDs included arginosuccinate synthetase deficiency (n = 8), arginosuccinate lyase deficiency (n = 6), ornithine carbamoyltransferase deficiency (n = 3), and carbamoyl phosphate synthetase 1 deficiency (n = 3). In the sub‐group analysis (n = 11), GPB resulted in lower plasma ammonia (31 vs. 41 μmol/L, p = 0.037), glutamine (670 vs. 838 μmol/L, p = 0.002), annualised hyperammonaemic episodes (0.2 vs. 1.9, p = 0.020), hospitalisations (0.5 vs. 2.2, p = 0.010), and hyperammonaemic episodes resulting in hospitalisation (0.2 vs. 1.6, p = 0.035) reflecting changes seen in the whole group. Overall, patients exposed to sodium and propylene glycol levels above UK daily limits reduced by 78% and 83% respectively. Mean levels of branched chain amino acids, haemoglobin, and white cell count were unchanged. Two adverse drug reactions (pancytopenia, fatigue/appetite loss) resolved without GPB discontinuation. Patients/families preferred GPB for its lower volume, greater palatability and easier administration. GPB appeared to improve biochemical measures and clinical outcomes. The causes are multi‐factorial and are likely to include prolonged action of GPB and its good tolerability, even at higher doses, facilitating tighter control of ammonia.

Abstract Background Treatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle, but limited data are available regarding the use of citrulline. This study retrospectively reviewed clinical and biological data from patients with UCDs treated with citrulline and/or arginine at a reference center since 1990. The aim was to describe the prescription, impact, and safety of these therapies. Data collection included patient background, treatment details, changes in biochemical parameters (plasma ammonia and amino acids concentrations), decompensations, and patient outcomes. Results Overall, 79 patients (median age at diagnosis, 0.9 months) received citrulline and/or arginine in combination with a restricted protein diet, most with ornithine transcarbamylase (n = 57, 73%) or carbamoyl phosphate synthetase 1 (n = 15, 19%) deficiencies. Most patients also received ammonium scavengers. Median follow-up was 9.5 years and median exposure to first treatment with arginine + citrulline, citrulline monotherapy, or arginine monotherapy was 5.5, 2.5, or 0.3 years, respectively. During follow-up, arginine or citrulline was administered at least once (as monotherapy or in combination) in the same proportion of patients (86.1%); the overall median duration of exposure was 5.9 years for arginine + citrulline, 3.1 years for citrulline monotherapy, and 0.6 years for arginine monotherapy. The most common switch was from monotherapy to combination therapy (41 of 75 switches, 54.7%). During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P

Aim: Urea cycle disorders (UCD) still have poor neurological outcomes despite early diagnosis and treatment. We aimed to present the neurological outcomes of UCD patients and to determine the main simple and accessible factors affecting these outcomes. Materials and Methods: This was a descriptive cross-sectional study conducted in two pediatric metabolism centers on 29 patients from 25 unrelated families who were diagnosed and followed with UCD based on clinical presentation, neurological parameters, biochemical measurements, and molecular analysis. Results: Within the study population, the most common diagnosis was argininosuccinate synthase deficiency in 13 (44.82%) patients, followed by N-acetylglutamate synthase deficiency in five patients (17.24%), ornithine transcarbamylase deficiency in four patients (13.79%), arginase 1 deficiency in three patients (10.34%), carbamoyl phosphate synthase 1 deficiency in three patients (10.34%), and argininosuccinate lyase deficiency in one patient (3.44%). Peak ammonia levels were observed to be significantly higher in those patients with delayed milestones and patients who had Denver II <-2 standard deviation score results (p=0.032, p=0.026). Effect sizes were large in both groups. Delayed milestones were noted in 17 (94.4%) of the cases with peak ammonia >500 μmol/L (n=18). Those patients with abnormal neurological parameters had a significantly higher mean number of hyperammonemic episodes per year. Extracorporeal detoxification was given to eight patients, in combination with therapeutic hypothermia in two patients. Rapid regression was observed in brain edema in those who underwent therapeutic hypothermia. Conclusion: Our study emphasizes the effect of peak ammonia levels and the frequency of hyperammonemic episodes on neurological outcomes. There were still poor neurocognitive outcomes despite extracorporeal detoxification. This highlights the need to reassess current treatment strategies, including the threshold for starting extracorporeal detoxification if ammonia levels exceed 500 μmol/L. The use of therapeutic hypothermia by experienced teams may be promising due to its brain edema-reducing effects. [ABSTRACT FROM AUTHOR]

An infant with a prenatal diagnosis of citrullinemia, who started standard treatment at birth (L-arginine; sodium benzoate and a personalized diet characterized by a low protein intake and supplementation of essential nutrients and amino acids), presented at 4 months of age with extended, progressive, and severe skin lesions consistent with acrodermatitis dysmetabolica. Guidelines for the diagnosis and management of urea cycle disorders underline that a low-protein diet places patients at risk of essential fatty acids, trace elements, and vitamin deficiency. At hospital admission, our patient had normal levels of zinc and alkaline phosphatases. The plasmatic amino acid profile revealed a severe and generalized deficiency. In particular, the serum levels of arginine, valine, and isoleucine were very low and the dermatitis did not improve until the blood levels of these amino acids increased. In our patient, skin lesions happened despite an early diagnosis of citrullinemia and timely treatment due to compliance issues as a consequence of linguistic barriers. [ABSTRACT FROM AUTHOR]

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. A prompt diagnosis and relevant biochemical and genetic investigations allow the rapid introduction of the right treatment and prevent long-term complications and mortality. This narrative review outlines challenges in diagnosing and managing patients with late-onset OTCD. [ABSTRACT FROM AUTHOR]

Background: Treatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle, but limited data are available regarding the use of citrulline. This study retrospectively reviewed clinical and biological data from patients with UCDs treated with citrulline and/or arginine at a reference center since 1990. The aim was to describe the prescription, impact, and safety of these therapies. Data collection included patient background, treatment details, changes in biochemical parameters (plasma ammonia and amino acids concentrations), decompensations, and patient outcomes. Results: Overall, 79 patients (median age at diagnosis, 0.9 months) received citrulline and/or arginine in combination with a restricted protein diet, most with ornithine transcarbamylase (n = 57, 73%) or carbamoyl phosphate synthetase 1 (n = 15, 19%) deficiencies. Most patients also received ammonium scavengers. Median follow-up was 9.5 years and median exposure to first treatment with arginine + citrulline, citrulline monotherapy, or arginine monotherapy was 5.5, 2.5, or 0.3 years, respectively. During follow-up, arginine or citrulline was administered at least once (as monotherapy or in combination) in the same proportion of patients (86.1%); the overall median duration of exposure was 5.9 years for arginine + citrulline, 3.1 years for citrulline monotherapy, and 0.6 years for arginine monotherapy. The most common switch was from monotherapy to combination therapy (41 of 75 switches, 54.7%). During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P < 0.05). At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%). Two patients (2.5%) experienced three treatment-related gastrointestinal adverse reactions. Conclusions: This study underlines the importance of citrulline supplementation, either alone or together with arginine, in the management of patients with UCDs. When a monotherapy is considered, citrulline would be the preferred option in terms of increasing plasma arginine concentrations. [ABSTRACT FROM AUTHOR]

Acute encephalopathy is a critical medical condition that typically affects previously healthy children and young adults and often results in death or severe neurological sequelae. Inherited metabolic diseases that can cause acute encephalopathy include urea cycle disorders, amino acid metabolism disorders, organic acid metabolism disorders, fatty acid metabolism disorders, mutations in the thiamine-transporter gene, and mitochondrial diseases. Although each inherited metabolic disease is rare, its overall incidence is reported as 1 in 800–2500 patients. This narrative review presents the common inherited metabolic diseases that cause acute encephalopathy. Since diagnosing inherited metabolic diseases requires specific testing, early metabolic/metanolic screening tests are required when an inherited metabolic disease is suspected. We also describe the symptoms and history associated with suspected inherited metabolic diseases, the various tests that should be conducted in case of suspicion, and treatment according to the disease group. Recent advancements made in the understanding of some of the inherited metabolic diseases that cause acute encephalopathy are also highlighted. Acute encephalopathy due to inherited metabolic diseases can have numerous different causes, and recognition of the possibility of an inherited metabolic disease as early as possible, obtaining appropriate specimens, and proceeding with testing and treatment in parallel are crucial in the management of these diseases. [ABSTRACT FROM AUTHOR]

The mammalian urea cycle (UC) is responsible for siphoning catabolic waste nitrogen into urea for excretion. Disruptions of the functions of any of the enzymes or transporters lead to elevated ammonia and neurological injury. Carbamoyl phosphate synthetase 1 (CPS1) is the first and rate-limiting UC enzyme responsible for the direct incorporation of ammonia into UC intermediates. Symptoms in CPS1 deficiency are typically the most severe of all UC disorders, and current clinical management is insufficient to prevent the associated morbidities and high mortality. With recent advances in basic and translational studies of CPS1, appreciation for this enzyme's essential role in the UC has been broadened to include systemic metabolic regulation during homeostasis and disease. Here, we review recent advances in CPS1 biology and contextualize them around the role of CPS1 in health and disease.

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.

Abstract Background Citrullinemia type I (CTLN1) is a rare urea cycle disorder (UCD) with few adult cases described so far. Diagnosis of late-onset CTLN1 is difficult, and delayed treatment may increase the risk of severe hyperammonemia. Pregnancy is an important risk factor for women with CTLN1. However, the clinical manifestations of CTLN1 in a pregnant woman may be mistaken for pregnancy side effects and ultimately delay a timely diagnosis. Case presentation A 34-year-old woman developed vomiting and disturbance of consciousness after 12 weeks of gestation. A blood test showed hyperammonemia (454 μg/dL) with normal liver function tests. She fell into a deep coma, and her serum ammonia level increased to 800 μg/dL. Continuous renal replacement therapy (CRRT) was administered as a diagnostic treatment for UCD and serum ammonia. This patient’s case was complicated by co-infection; her dependents decided to withdraw life support and the patient died. She was diagnosed with CTLN1 by analyses of plasma amino acids, urinary orotic acid, and second-generation gene sequencing. Discussion and conclusion When a patient displays symptoms of emesis and disturbance of consciousness in early pregnancy, blood ammonia should be monitored, and UCD should be considered, particularly for patients with hyperammonemia in the absence of severe liver function abnormalities.

Abstract Background Carbamoyl phosphate synthetase deficiency (CPS1D) is a urea-cycle disorder (UCD). We report successful perioperative management of pediatric living donor liver transplantation (LDLT) in a CPS1D patient. Case presentation A 10-year-old female patient with CPS1D underwent LDLT. Proper administration of dextrose 50% and 60 kcal/kg/day with l-arginine and l-carnitine resulted in the avoidance of intraoperative hyperammonemia induced by hypercatabolism. Serum ammonia level transiently increased to 61 mmol/L in the anhepatic phase and decreased to 44 mmol/L after reperfusion. Conclusions We suggest anesthesia management with administration of dextrose to avoid hyperammonemia during LDLT in patients with CPS1D.

Individuals with inherited hyperammonemias often present developmental and intellectual deficiencies which are likely to be exaggerated by hyperammonemia episodes in long-term outcomes. In order to find a new, systemic marker common to the course of congenital hyperammonemias, we decided to measure the plasma level of S100 calcium-binding protein B (S100B), which is associated with cerebral impairment. Further, we analyzed three mechanistically diverged but linked with oxidative–nitrosative stress biochemical parameters: 3-nitrotyrosine (3-NT), a measure of plasma proteins' nitration; advanced oxidation protein products (AOPP), a measure of protein oxidation; and glutathione peroxidase (GPx) activity, a measure of anti-oxidative enzymatic capacity. The plasma biomarkers listed above were determined for the first time in congenital hyperammonemia. Also, the level of pro- and anti-inflammatory mediators (i.e., IL-12, IL-6, IL-8, TNF-α, IL-1β, and IL-10) and chemokines (IP-10, MCP-1, MIG, and RANTES) were quantified. S100B was positively correlated with plasma ammonia level, while noticeable levels of circulating 3-NT in some of the patients' plasma did not correlate with ammonia concentration. Overall, the linear correlation between ammonia and S100B but not standard oxidative stress-related markers offers a unique perspective for the future identification and monitoring of neurological deficits risk-linked with hyperammonemia episodes in patients with inherited hyperammonemias. The S100B measure may support the development of therapeutic targets and clinical monitoring in these disorders. [ABSTRACT FROM AUTHOR]

Argininemia or arginase-1 deficiency constitutes a rare, genetic, metabolic disorder caused by mutations in arginase 1—the last enzyme of the urea cycle—that hydrolyses L-arginine to ornithine and urea. The disease is associated with progressive development of spasticity and other symptoms, including seizures, developmental delay, cognitive impairment, and hepatic pathology. The present review attempts to summarize the current knowledge on the pathophysiology of the disease and highlight novel methods for its evaluation. Different factors, such as the accumulation of arginine, ammonia, and guanidino compounds, act as neurotoxins and may account for the neurological sequelae observed in the disease. New markers, such as arginine/ornithine ratio along with metabolomics, machine learning algorithms, and genetic methods, can be useful in the early diagnosis of argininemia, while mobile phone apps can assist argininemic patients in adhering to the strict diet required. Neurophysiology, multi-modal imaging, and new modelling methods, such as induced pluripotent stem cells, hold promise for providing new insights into the pathophysiology of the disease. There are still many uncertainties regarding the underlying mechanisms of argininemia, but the use of novel modelling methods and new technology can lead to the decipherment of its pathophysiology, improvement of diagnostic accuracy, and better disease management.

Urea cycle disorders (UCDs) are a group of rare inborn errors of metabolism caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. Current guidelines suggest that early diagnosis and treatment of mild UCDs may improve survival and prevent decompensation and neurocognitive impairment. Nevertheless, clinical studies are very difficult to carry out in this setting due to the rarity of the diseases, and high-level evidence is scant and insufficient to draw conclusions and provide clinical guidelines. With the early introduction of newborn screening, the Italian healthcare organization fostered an advancement in expertise in metabolic disease management and screening programs, by allocating resources, and favoring the expansion of newborn screening. A group of experts operating in Italian centers decided to share their experience and provide advice for the management of mild UCDs in clinical practice. A consensus was reached by the Estimate–Talk–Estimate (ETE) method. Five items were identified, and statements for each item were agreed. Briefly, the panel advised completing the diagnosis by expanded newborn screening (ENS) with biochemical and genetic confirmation and by following up with the patient during the first year of life, with a routine laboratory and metabolic profile as well as with clinical observation. Early initiation of therapy is advised and should be followed by therapy adjustment once the diagnostic profile is completed. The therapy should be based on a low-protein diet and nitrogen scavengers. The long-term follow-up is based on growth and nutritional assessment, clinical and neurocognitive evaluation, and laboratory and instrumental parameter monitoring.

BACKGROUND:To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS:Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS:Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS:The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS:Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to convert nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and liver transplantation. The aim of this study was to describe the characteristics and indication of liver transplantation in UCD in a tertiary hospital. We performed a retrospective study of children with UCD seen in the period 2000–2021. Data was collected on clinical onset, hyperammonemia severity, evolution and liver transplantation. There were 33 patients in the study period, whose diagnosis were: ornithine transcarbamylase (OTC, n = 20, 10 females), argininosuccinate synthetase (ASS, n = 6), carbamylphosphate synthetase 1 (CPS1, n = 4), argininosuccinate lyase (ASL, n = 2) and N-acetylglutamate synthetase (NAGS, n = 1) deficiency. Thirty one were detected because of clinical symptoms (45% with neonatal onset). The other 2 were diagnosed being presymptomatic, by neonatal/family screening. Neonatal forms (n = 14) were more severe, all of them presented during the first week of life as severe hyperammonemia (mean peak 1,152 µmol/L). Seven patients died (6 at debut) and all survivors received transplantation. There was no mortality among the late forms. Of the 27 patients who did not die in the neonatal period, 16 (59%) received liver transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation. The transplant's metabolic success was accompanied by neurologic sequelae in 69%, but there was no progression of brain damage. Decision of continuous medical treatment in 11 patients appeared to be related with preserved neurodevelopment and fewer metabolic crises.

Background: Citrullinemia type I (CTLN1) is a rare urea cycle disorder (UCD) with few adult cases described so far. Diagnosis of late-onset CTLN1 is difficult, and delayed treatment may increase the risk of severe hyperammonemia. Pregnancy is an important risk factor for women with CTLN1. However, the clinical manifestations of CTLN1 in a pregnant woman may be mistaken for pregnancy side effects and ultimately delay a timely diagnosis. Case presentation: A 34-year-old woman developed vomiting and disturbance of consciousness after 12 weeks of gestation. A blood test showed hyperammonemia (454 μg/dL) with normal liver function tests. She fell into a deep coma, and her serum ammonia level increased to 800 μg/dL. Continuous renal replacement therapy (CRRT) was administered as a diagnostic treatment for UCD and serum ammonia. This patient's case was complicated by co-infection; her dependents decided to withdraw life support and the patient died. She was diagnosed with CTLN1 by analyses of plasma amino acids, urinary orotic acid, and second-generation gene sequencing. Discussion and conclusion: When a patient displays symptoms of emesis and disturbance of consciousness in early pregnancy, blood ammonia should be monitored, and UCD should be considered, particularly for patients with hyperammonemia in the absence of severe liver function abnormalities. [ABSTRACT FROM AUTHOR]

Abstract Long‐term management of urea cycle disorders (UCDs) often involves unlicensed oral sodium benzoate (NaBz) which has a high volume and unpleasant taste. A more palatable treatment is licenced and available (glycerol phenylbutyrate [GPB], Ravicti) but guidance on how to transition patients from NaBz is lacking. A retrospective analysis of clinical and biochemical data was performed for eight children who transitioned from treatment with a single ammonia scavenger, NaBz, to GPB at a single metabolic centre; UCDs included arginosuccinic aciduria (ASA) (n = 5), citrullinaemia type 1 (n = 2) and carbamoyl phosphate synthetase I deficiency (CPS1) (n = 1). Patients transitioned either by gradual transition over 1–2 weeks (n = 3) or direct replacement of NaBz with GPB (n = 5). Median initial dose of GPB was 8.5 mL/m2/day based on published product information; doses were revisited subsequently in clinic and titrated individually (range 4.5–11 mL/m2/day). Pre‐transition and post‐transition mean ammonia levels were 37 μmol/L (SD 28 μmol/L) and 29 μmol/L (SD 22 μmol/L), respectively (p = 0.09), and mean glutamine levels were 664 μmol/L (SD 225 μmol/L) and 598 μmol/L (SD 185 μmol/L), respectively (p = 0.24). There were no reductions in levels of branched chain amino acids. No related adverse drug reactions were reported. Patients preferred GPB because of its lower volume and greater palatability. Direct replacement of NaBz with GPB maintained metabolic control and was simple for the health service and patients to manage. A more cautious approach with additional monitoring would be warranted in brittle patients and patients whose ammonia levels are difficult to control.

Stroke-like episodes (SLEs) are significant clinical manifestations of metabolic disorders affecting the central nervous system. Morphological equivalents presented in neuroimaging procedures are described as stroke-like lesions (SLLs). It is crucial to distinguish SLEs from cerebral infarction or intracerebral hemorrhage, mainly due to the variety in management. Another significant issue to underline is the meaning of the main pathogenetic hypotheses in the development of SLEs. The diagnostic process is based on the patient's medical history, physical and neurological examination, neuroimaging techniques and laboratory and genetic testing. Implementation of treatment is generally symptomatic and includes L-arginine supplementation and adequate antiepileptic management. The main aim of the current review was to summarize the basic and actual knowledge about the occurrence of SLEs in various inherited neurometabolic disorders, discuss the possible pathomechanism of their development, underline the role of neuroimaging in the detection of SLLs and identification of the electroencephalographic patterns as well as histological abnormalities in inherited disorders of metabolism. [ABSTRACT FROM AUTHOR]

Background: Carbamoyl phosphate synthetase deficiency (CPS1D) is a urea-cycle disorder (UCD). We report successful perioperative management of pediatric living donor liver transplantation (LDLT) in a CPS1D patient. Case presentation: A 10-year-old female patient with CPS1D underwent LDLT. Proper administration of dextrose 50% and 60 kcal/kg/day with l-arginine and l-carnitine resulted in the avoidance of intraoperative hyperammonemia induced by hypercatabolism. Serum ammonia level transiently increased to 61 mmol/L in the anhepatic phase and decreased to 44 mmol/L after reperfusion. Conclusions: We suggest anesthesia management with administration of dextrose to avoid hyperammonemia during LDLT in patients with CPS1D. [ABSTRACT FROM AUTHOR]

Acute hyperammonemia (HAA) is a medical emergency, that cause neurological damage, complications or even death. HAA occurs most frequently in patients with inborn errors of metabolism (IEM), especially in events of metabolic decompensation, and require intensive care. The IEM that mainly cause HAA include; urea cycle defects, organic acidemias, fatty acid oxidation disorders and carnitine cycle defects. In HAA, the primary aim is to preserve life and the integrity of the central nervous system, decreasing blood ammonia levels to normal, with urgent medical treatment, individualized life support and nutrition. Knowledge of the available drugs, the ammonium removal methods, as well as the energy and protein requirements, supplements, cofactors and vitamins; is very important for individualize the medical and nutritional treatment according to their biochemical, clinical profiles and underlying disease. The objective of this work is to present current concepts regarding the treatment of HAA in patients with inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

Objective: Citrin, the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), is structurally and mechanistically the most complex SLC25 family member, because it consists of three domains and forms a homo-dimer. Each protomer has an N-terminal calcium-binding domain with EF-hands, followed by a substrate-transporting carrier domain and a C-terminal domain with an amphipathic helix. The absence or dysfunction of citrin leads to citrin deficiency, a highly prevalent pan-ethnic mitochondrial disease. Here, we aim to understand the role of different citrin domains and how they contribute to pathogenic mechanisms in citrin deficiency., Methods: We have employed structural modeling and functional reconstitution of purified proteins in proteoliposomes to assess the transport activity and calcium regulation of wild-type citrin and pathogenic variants associated with citrin deficiency. We have also developed a double knockout of citrin and aralar (AGC1), the two paralogs of the mitochondrial aspartate/glutamate carrier, in HAP1 cells to perform mitochondrial imaging and to investigate mitochondrial localisation., Results: Using 33 pathogenic variants of citrin we clarify determinants of subcellular localization and transport mechanism. We identify crucial elements of the carrier domain that are required for transport, including those involved in substrate binding, network formation and dynamics. We show that the N-terminal domain is not involved in calcium regulation of transport, as previously thought, but when mutated causes a mitochondrial import defect., Conclusions: Our work introduces a new role for the N-terminal domain of citrin and demonstrates that dysfunction of the different domains contributes to distinct pathogenic mechanisms in citrin deficiency., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Ornithine transcarbamylase deficiency (OTCD) is the most common disorder of the urea cycle and is caused by a mutation of the OTC gene, located on chromosome X. Its prevalence is estimated at 1 in 80,000 to 56,500 births, but this X-chromosomal inheritance results in males being more affected than females. In neonates affected with this disorder, hyperammonemia after birth can lead to neurological and liver damage that can be fatal. We present a child with a prenatal diagnosis based on an older sibling with the same pathology, which led us to adopt an intensive treatment since the delivery. He was admitted in a neonatal unit and treatment with protein restriction, 10% glucose saline serum and glycerol phenylbutyrate was initiated. To date, after 3.5 years of follow up, growth and neurological development have been adequate, biochemical control has been appropriate except for a simple and mild decompensation during the course of a gastroenteritis. This case emphasises the importance of early diagnosis and treatment to avoid potential complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor CP-G declared a past collaboration with the authors ÁM-R and EM-H., (Copyright © 2024 Martín-Rivada, Murray Hurtado and Martín-Hernández.)

Background: The clinical presentation of ARG1-D is characterised by elevated arginine levels leading to neurological and mobility impairments. Information about long-term outcomes in adults is lacking, which prompted us to undertake a retrospective observational study., Methods: We extracted ARG1-D patient data spanning a 5-year period from electronic health records. Ethical approval was not required for the study. Informed consent was obtained., Results: We identified nine ARG1-D patients from consanguineous backgrounds. Age of symptom onset ranged from infancy to age 7 years, age of diagnosis from infancy to 20 years. Patients had paraparesis or altered gait of varying degree and had experienced early ARG1-D onset. Over 5 years, mobility declined in six (6/9, 67%) patients. Three patients (3/9, 33%) were fully dependent and hoisted. Two (2/9, 22%) reached adulthood before experiencing hyperammonaemia, another one (1/9, 11%) first experienced hyperammonaemia at age 15 years. One patient (1/9, 11%) started on ammonia scavenger therapy in adulthood, one (1/9, 11%) required a second scavenger to be added to their treatment regimen. Two patients (2/9, 22%) had gastrostomy tubes inserted for nutrition and supplements at age 9 years and 15 years. Six patients (6/9, 67%) had raised levels of ALT; of these, four (4/9, 44%) also had elevated AFP. Heterogeneity of ARG1-D symptoms was evident, suggesting complex genetic and environmental interactions., Conclusion: ARG1-D presents significant lifelong challenges with deteriorating mobility and more frequent metabolic crises. Current management strategies are insufficient for preventing progression, highlighting the need for innovative treatments like enzyme replacement and gene therapy., Competing Interests: Reena Sharma was a principal investigator for a clinical study funded by Aeglea Bio Therapeutics investigating the efficacy and safety of pegzilarginase in arginase 1 deficiency. John Bassett, Karolina Stepien, Andrew Oldham, Ana Jovanovic, Alison Woodall, and Diane Green declare no conflicts of interest., (© 2024 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Abstract Argininosuccinate lyase deficiency (ASLD, MIM #207900) is an inherited urea cycle disorder. There are mainly two clinical forms, an acute neonatal form which manifests as life‐threatening hyperammonemia, and a late‐onset form characterised by polymorphic neuro‐cognitive or psychiatric presentation with transient hyperammonemia episodes. Here, we report a late‐onset case of ASLD in a 72‐year‐old man carrying a homozygous pathogenic variant in the exon 16 of the ASL gene, presenting for the first time with fatal hyperammonemic coma. This case report shows the need to systematically carry out an ammonia assay when faced with an unexplained coma.

Abstract Background Urea cycle disorders (UCD) are inborn errors of metabolism, typically presenting neonatally. Excess ammonia builds rapidly within the body risking hyperammonemic episodes and potentially death. Long-term management of the condition includes restrictive protein consumption, pharmacological interventions and, in extreme cases, liver transplantation. Pharmacological treatments such as sodium benzoate and sodium phenylbutyrate have proven effective but not without a multitude of negative attributes including poor taste, higher dosage and associated gastrointestinal discomfort that impacts health-related quality of life. Glycerol phenylbutyrate (GPB) has recently become a widely available pharmacological treatment with early reports of improved qualities, including taste and administration method. The following study aims to explore the burden of pharmacological treatment and the effects of the transition to GPB on health-related quality of life in people with a UCD. Results Nine carers of children living with a UCD (mean age = 12.44, SD = 10.26) were interviewed regarding their experiences of pharmacological treatment in relation to their, and their child’s, health-related quality of life after transitioning to GPB. Three main themes were identified: psychological health, physical health and social participation. Carers struggled with anxiety surrounding their child’s condition and the battle of administering medication. Medication administration was perceived to have improved since the transition to GPB, alleviating distress for both carer and child. Issues involving school were described, ranging from difficulties integrating their child into mainstream schooling and the impact of treatment on participation in school and extracurricular activities. Carers encountered issues sourcing syringes to administer GPB, which induced stress. It could be suggested that some burden had been relieved by the transition to GPB. However, it appeared that difficulties associated with the illness would persist despite treatment, owing to the continuing nature of the condition. Conclusions Adhering to a strict pharmacological regime caused immense stress for both carers and children, severely impacting on typical social activities such as eating at a restaurant or going on holiday. GPB was perceived to have alleviated some burden in terms of administration given improved characteristics concerning taste and dosage, important characteristics for both carers and children living with UCD. Practitioners should consider these findings when making clinical decisions for children with UCD and the effect of pharmacological treatment on carer’s health-related quality of life. Outreach work to facilitate greater understanding of the condition should be conducted with key locations, such as children’s schools. This would also help to alleviate carer burden.

An infant with a prenatal diagnosis of citrullinemia, who started standard treatment at birth (L-arginine; sodium benzoate and a personalized diet characterized by a low protein intake and supplementation of essential nutrients and amino acids), presented at 4 months of age with extended, progressive, and severe skin lesions consistent with acrodermatitis dysmetabolica. Guidelines for the diagnosis and management of urea cycle disorders underline that a low-protein diet places patients at risk of essential fatty acids, trace elements, and vitamin deficiency. At hospital admission, our patient had normal levels of zinc and alkaline phosphatases. The plasmatic amino acid profile revealed a severe and generalized deficiency. In particular, the serum levels of arginine, valine, and isoleucine were very low and the dermatitis did not improve until the blood levels of these amino acids increased. In our patient, skin lesions happened despite an early diagnosis of citrullinemia and timely treatment due to compliance issues as a consequence of linguistic barriers.

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. A prompt diagnosis and relevant biochemical and genetic investigations allow the rapid introduction of the right treatment and prevent long-term complications and mortality. This narrative review outlines challenges in diagnosing and managing patients with late-onset OTCD.

Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating the prognosis of its triggering disease. In small children it is a rare condition usually associated to inborn errors of the metabolism. As age rises, and especially in adults, it may be precipitated by heterogeneous causes such as liver disease, drugs, urinary infections, shock, or dehydration. In older patients, it is often overlooked, or its danger minimized. This protocol was drafted to provide an outline of the clinical measures required to normalise ammonia levels in patients of all ages, aiming to assist clinicians with no previous experience in its treatment. It is an updated protocol developed by a panel of experts after a review of recent publications. We point out the importance of frequent monitoring to assess the response to treatment, the nutritional measures that ensure not only protein restriction but adequate caloric intake and the need to avoid delays in the use of specific pharmacological therapies and, especially, extrarenal clearance measures. In this regard, we propose initiating haemodialysis when ammonia levels are >200–350 µmol/L in children up to 18 months of age and >150–200 µmol/L after that age. [ABSTRACT FROM AUTHOR]